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The 2007 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2 - therapy. Sibutramine is safe and effective for weight loss in obese patients whose hypertension is well controlled with angiotensin-converting enzyme inhibitors The effect of treatment based on a diuretic (indapamide) +/- ACE inhibitor (perindopril) on fractures in the Hypertension in the Very Elderly Trial (HYVET). Serum Lipoproteins During Treatment with the Antihypertensive Agent Indapamide Metoprolol Versus Thiazide Diuretics in Hypertension Morbidity Results From the MAPHY Study Plasma renin activity predicts blood pressure responses to beta-blocker and thiazide diuretic as monotherapy and add-on therapy for hypertension. Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients: a double-blind controlled trial. 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Combination therapy for hypertension in the elderly: a sub-analysis of the Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) Trial Outcome Results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in Patients With Hypertension and NIDDM Comparison of candesartan with lisinopril on ambulatory blood pressure and morning surge in patients with systemic hypertension. Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial. Comparison of captopril and hydrochlorothiazide alone and in combination in mild to moderate essential hypertension. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Serum lipoprotein levels during chlorthalidone therapy. A Veterans Administration-National Heart, Lung, and Blood Institute cooperative study on antihypertensive therapy: mild hypertension. Randomized Prospective Study of a Nonthiazide Diuretic, Indapamide, in Preventing Calcium Stone Recurrences The 2001 Canadian recommendations for the management of hypertension: Part two--Therapy. Treatment of elderly hypertensive patients with epithelial sodium channel inhibitors combined with a thiazide diuretic reduces coronary mortality and sudden cardiac death. 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Comparison of effects of exercise and diuretic on left ventricular geometry, mass, and insulin resistance in older hypertensive adults. The relationship of weight change to changes in blood pressure, serum uric acid, cholesterol and glucose in the treatment of hypertension. Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study. The case for low dose diuretics in hypertension: comparison of low and conventional doses of cyclopenthiazide. Cost-effectiveness of antihypertensive treatment: metoprolol versus thiazide diuretics. 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Effects of Thiazide Diuretic Therapy on Bone Mass, Fractures, and Falls Impact of angiotensin receptor blockade in combination with hydrochlorothiazide 25 mg in 2121 patients with stage 1–2 hypertension Relative value of beta blockers and thiazides for initiating antihypertensive therapy. Beta blockers or thiazides in hypertension. Relationship of Antihypertensive Treatment Regimens and Change in Blood Pressure to Risk for Heart Failure in Hypertensive Patients Randomly Assigned to Doxazosin or Chlorthalidone: Further Analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE). Double-blind comparison of indapamide with a placebo in hypertensive patients treated by practicing physicians. Different concepts in first-line treatment of essential hypertension. Comparison of a low-dose reserpine-thiazide combination with nitrendipine monotherapy. German Reserpine in Hypertension Study Group. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial Effect of thiazide on rates of bone mineral loss: a longitudinal study. Blood pressure-lowering efficacy of the fixed-dose combination of azilsartan medoxomil and chlorthalidone: a factorial study. A double-blind study of tienilic acid with two year follow-up of patients with mild to moderate essential hypertension. Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly. Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men. Efficacy of eprosartan in combination with HCTZ in patients with essential hypertension [The optimal dose of bendroflumethiazide in hypertension. A randomized double-blind dose-response study]. Comparison of the antihypertensive efficacy and adverse reactions to two doses of bendrofluazide and hydrochlorothiazide and the effect of potassium supplementation on the hypotensive action of bendrofluazide: substudies of the Medical Research Council's trials of treatment of mild hypertension: Med Isolated systolic hypertension: data from the European Working Party on High Blood Pressure in the Elderly. Serum glucose levels during long-term observation of treated and untreated men with mild hypertension. The Oslo study. Comparative effects of potassium chloride and bicarbonate on thiazide-induced reduction in urinary calcium excretion. Diuretic-based treatment and cardiovascular events in patients with mild renal dysfunction enrolled in the systolic hypertension in the elderly program. Twenty-four hour antihypertensive efficacy of indapamide, 1.5-mg sustained release: results of two randomized double-blind controlled studies. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled tri Effectiveness of Chlorthalidone Plus Amiloride for the Prevention of Hypertension: The PREVER‐Prevention Randomized Clinical Trial Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. The efficacy and safety of furosemide and a combination of spironolactone and hydrochlorothiazide in congestive heart failure. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. Low-dose bisoprolol/hydrochlorothiazide: an option in first-line, antihypertensive treatment. Diuretic use and bone mineral density in older USA men: the osteoporotic fractures in men (MrOS) study. Effectiveness of Add-On Low-Dose Diuretics in Combination Therapy for Hypertension: Losartan/Hydrochlorothiazide vs. Candesartan/Amlodipine Evidence Supporting a Systolic Blood Pressure Goal of Less Than 150 mm Hg in Patients Aged 60 Years or Older: The Minority View Low-renin hypertension. Restoration of normotension and renin responsiveness. The efficacy and tolerability of amlodipine and hydrochlorothiazide in Nigerians with essential hypertension. Mechanism(s) of selective systolic blood pressure reduction after a low-dose combination of perindopril/indapamide in hypertensive subjects: comparison with atenolol. 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Use of diuretics is associated with reduced risk of Alzheimer's disease: the Cache County Study Systolic Hypertension in the Elderly Program (SHEP): antihypertensive efficacy of chlorthalidone. Hydrochlorothiazide is superior to isradipine for reduction of left ventricular mass: results of a multicenter trial. The Isradipine Study Group. Twenty-four hour ambulatory blood pressure in the International Nifedipine GITS Study Intervention as a Goal in Hypertension Treatment (INSIGHT) Predictors of Hyperkalemia Risk following Hypertension Control with Aldosterone Blockade Antihypertensive efficacy and side effects of three beta‐blockers and a diuretic in elderly hypertensives: a report from the STOP‐Hypertension study Beta-blocker/thiazide combination for treatment of hypertensive children: a randomized double-blind, placebo-controlled trial. Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. National Intervention Cooperative Study in Elderly Hypertensives Study Group. A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy ('polypill') on cardiovascular risk factors. Thiazide diuretic agents and the incidence of hip fracture. Blood pressure lowering and potassium conservation by triamterene‐hydrochlorothiazide and amiloride‐hydrochlorothiazide in hypertension
Blood pressure ( BP ) and metabolic variables were determined initially and after 1 , 2 , 4 , 6 and 10 years ' treatment in two groups of hypertensive men ( n = 53 each ) r and omized to bendroflumethiazide 2.5 - 5 mg/day or propranolol 160 - 320 mg daily . There was no significant differences in BP or metabolic variables between the two groups at entry . BP was reduced to the same degree by both treatments . Five men in the propranolol group and one man in the thiazide group developed clinical ly overt diabetes during follow-up . Fasting blood sugar increased slightly but significantly though equally in both groups . Oral glucose tolerance was initially impaired to the same degree in both groups but improved significantly during treatment with both drugs . Fasting insulin increased slightly but to the same degree . While serum potassium decreased significantly in the thiazide group , the total body potassium was unchanged in this group . In the propranolol group , serum potassium rose , while total body potassium decreased significantly . Serum urate increased in both groups , though slightly more during thiazide treatment . One case of gout was found in each group . There was no difference in serum lipids between the two groups . The finding in this long-term trial indicate that in middle-aged men with mild to moderate hypertension a low-dose thiazide diuretic like bendroflumethiazide is as effective and safe an antihypertensive agent as the beta-blocker propranolol is and that it does not induce diabetes . The total clinical picture favors the retention of thiazide diuretics as a first choice drug in hypertension Thiazide diuretics are widely used in the drug treatment of hypertension but their dose-response curves for the antihypertensive and adverse metabolic effects differ . To characterize the lower end of the dose-response curve a double-blind , parallel group trial was performed as multicentre study in Sc and inavia . One hundred and eleven patients with newly diagnosed or previously treated mild to moderate hypertension ( untreated diastolic blood pressure of 95 - 115 mmHg after 4 weeks placebo ) were r and omly allocated to various doses of hydrochlorothiazide ( 3 , 6 , 12.5 or 25 mg ) or placebo for 6 weeks . Blood pressure and biochemical variables ( plasma renin activity , serum potassium , magnesium , urate , fasting glucose , total cholesterol , HDL-cholesterol , triglycerides and apolipoproteins A1 and B were measured . 12.5 mg hydrochlorothiazide had a borderline effect on blood pressure whilst 25 mg had a definite antihypertensive effect . Biochemical changes were seen in plasma renin activity , serum potassium and urate after the 12.5 and 25 mg dose . Three and 6 mg had no effect on blood pressure or metabolic parameters BACKGROUND To attain goal blood pressure ( BP ) , many hypertensive patients require combination antihypertensive therapy . Thiazide diuretic/beta-blocker regimens lower BP , and clinical studies indicate that they reduce the risk for cardiovascular consequences of hypertension . Fixed-dose combination tablets can simplify multidrug treatment regimens . METHODS This multicenter , r and omized , double-blind , placebo-controlled , unbalanced factorial study ( N = 1571 ) was design ed to determine whether hydrochlorothiazide ( HCT ) and extended release ( ER ) metoprolol both contribute to an antihypertensive effect .  Hypertensive adults with sitting diastolic BP ( SiDBP ) 95 to 114 mm Hg and systolic BP ( SiSBP ) < 180 mm Hg received one of three hydrochlorothiazide doses ( 6.25 mg , 12.5 mg , or 25 mg ) , one of four ER-metoprolol doses ( 25 mg , 50 mg , 100 mg , 200 mg ) , or one of nine of the combinations or placebo for 8 weeks . RESULTS Blood pressure decreased with all combinations ( P < .001 v placebo ) ; reductions were dose related , ranging from 8.7 to 15.7 mm Hg ( SiDBP ) and 9.7 to 18.9 mm Hg ( SiSBP ) ( model-derived values ) . Reductions with placebo were 5.3 ( SiDBP ) and 4.2 mm Hg ( SiSBP ) . Both active agents contributed to the combination effect ( P = .0015 for SiDBP ; P = .0006 for SiSBP ) . Several low-dose combinations were approximately as effective as high doses of the individual agents ( differences within 1 to 2.5 mm Hg ) . The adverse event discontinuation rate was 2.9 % . Serum potassium decreased and uric acid increased with increasing doses of HCT . CONCLUSIONS Extended-release metoprolol/hydrochlorothiazide is an effective antihypertensive combination that offers additive antihypertensive contributions from both components To achieve the target blood pressure recommended by the latest guidelines , multiple antihypertensive drugs are needed in most patients . In this study , the efficacy of treatment using an angiotensin II receptor antagonist ( ARB ) combined with a calcium channel blocker ( CCB ) or a diuretic was compared from multiple perspectives in patients with hypertension . Twenty-nine patients with essential hypertension , who had failed to achieve their target blood pressure ( < 130/85 mm Hg for patients < 65 years old and < 140/90 mm Hg for those ⩾65 years ) when treated with the ARB olmesartan at 20 mg day−1 , were additionally given 8–16 mg day−1 of the CCB azelnidipine or 1–2 mg day−1 of trichlormethiazide ( a thiazide diuretic ) in a r and omized crossover manner for 4 months each . At the end of each combination therapy period , blood and urine sample s were collected and arterial stiffness was evaluated by measuring the cardio-ankle pulse wave velocity . Compared with monotherapy , the blood pressure was reduced similarly by adding azelnidipine ( −12/−10 mm Hg ) or trichlormethiazide ( −14/−9 mm Hg ) . The heart rate was decreased with the CCB by 4 b.p.m . ( P<0.05 ) , whereas it was unchanged with the thiazide . Serum K , lipids and blood glucose were not significantly changed with either combination , whereas serum uric acid was increased with the thiazide ( P<0.01 ) but was unchanged with azelnidipine  . Plasma levels of renin , angiotensin II and aldosterone were also increased with the thiazide period , whereas high-sensitivity C-reactive protein and oxidized low-density lipoprotein were decreased with azelnidipine . In addition , the cardio-ankle vascular index , a parameter of arterial stiffness , was decreased with the azelnidipine period but was unchanged with the thiazide period ( P<0.01 ) . It is suggested that the combination of olmesartan and azelnidipine has advantages over the combination of olmesartan and a thiazide with respect to avoiding hyperuricemia , sympathetic activation , renin – angiotensin-aldosterone system stimulation , inflammation , oxidative stress , and increased arterial stiffness in patients with moderate hypertension . These properties may provide cardiovascular protection in addition to the hypotensive effect In a r and omized primary prevention trial including 3,234 men with mild to moderate uncomplicated hypertension , the effect of the beta-blocker metoprolol or a thiazide diuretic as an initial antihypertensive therapy was compared regarding the risk of sudden cardiovascular death during a follow-up ranging from 2.3 to 10.8 years ( median of 4.2 years ) . Only men aged 40 to 64 years were included in the study . The r and omization of patients into the metoprolol ( n = 1,609 ) or diuretic group ( n = 1,625 ) was performed after stratification for age , smoking habits , serum cholesterol , and systolic blood pressure . At baseline the two treatment groups were well matched . Metoprolol was given in a mean dose of 174 mg daily and the mean dose of thiazide diuretic was either 46 mg hydrochlorothiazide daily or 4.4 mg bendroflumethiazide daily . Identical blood pressure control was achieved using the fixed therapeutic schedule . Total and cardiovascular mortality were significantly lower for metoprolol than for diuretics , owing to fewer deaths from coronary heart disease and stroke . Of the cardiovascular deaths , 78 % were classified as sudden cardiovascular deaths ( occurred within 24 h after the onset of symptoms ) . There were significantly fewer sudden cardiovascular deaths in the metoprolol group compared to the diuretic group ( 32 v 45 , P = .017 ) . The present results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of sudden cardiovascular deaths than initial diuretic treatment in uncomplicated hypertension To evaluate whether the combination of nifedipine with chlorthalidone exerts an additive antihypertensive effect when compared to single-drug treatment , 66 uncomplicated essential hypertensives , whose diastolic blood pressure was > 100 and < 115 mm Hg at the end of a 1-month washout placebo period , received , according to a r and omized , double-blind , crossover design , nifedipine ( 20 mg b.i.d . ) , chlorthalidone ( 25 mg o.d . ) , the two drugs combined at the same doses , and the corresponding placebo . When compared to the r and omized placebo the three active treatments significantly ( p < 0.001 ) reduced blood pressure without changing heart rate and body weight . However , blood prssure values were similarly reduced under nifedipine and the combination and were significantly lower ( p < 0.05 ) than those under chlorthalidone . Moreover , the percentage of responders and normalized patients under nifedipine and the two drugs combined were similar and significantly ( normalized , p < 0.001 ; responders , p < 0.02 ) greater than those under chlorthalidone . Under chlorthalidone and its combination with nifedipine , plasma potassium tended to decrease and blood glucose and serum uric acid were significantly ( p < 0.05 ) increased . These data show that the combination of nifedipine with chlorthalidone does not exert any additive antihypertensive effect when compared to nifedipine alone and that this combination increases both blood glucose and serum uric acid . Taken together these findings indicate that the combination of a dihydropyridine calcium antagonist with a thiazide diuretic is devoid of any clinical significance in the treatment of uncomplicated essential hypertensives Context Thiazide diuretics reduce urinary calcium excretion and increase bone mineral density , but do they prevent bone fractures ? Contribution In this population -based cohort study of 7891 older adults , patients taking thiazides for more than 1 year had a lower risk for hip fracture than those not taking thiazides  ( hazard ratio , 0.46 [ 95 % CI , 0.21 to 0.96 ] ) . Within 4 months of stopping thiazides , the risk for hip fracture returned to its pretreatment value . Implication s Thiazide diuretics may reduce hip fractures . Whether they have effects similar or additive to those of other bone protective agents merits study . The Editors Hip fractures are associated with substantial morbidity and mortality . The costs of surgery and rehabilitation are a burden on public health re sources , especially because the incidence of hip fracture increases as the population ages ( 1 , 2 ) . Most hip fractures are related to osteoporosis , and treating accelerated bone loss may therefore be an important strategy to prevent hip fractures ( 3 ) . Thiazide diuretics are widely used as antihypertensive agents . They are inexpensive and effective and have few important adverse effects ( 4 ) . Thiazides are thought to protect against age-related bone loss by reducing urinary calcium excretion ( 5 ) . This bone-sparing effect could lead to reduced fracture incidence in patients treated for hypertension . Several epidemiologic studies have examined the effect of thiazides on bone mineral density and fracture incidence . Although bone mineral density was found to be increased in thiazide users , the difference was often small ( 6 - 12 ) . Thiazides were found to have a protective effect on hip fracture in most studies ( 9 , 12 - 17 ) , but occasionally an increased risk was found ( 18 ) . Most of the studies , however , had limitations . Some studies included detailed drug-dispensing data but limited information on potential confounders and effect modifiers ( 15 , 18 , 19 ) . Other studies had small patient sample s or used only baseline interview data on thiazide use ( 9 , 12 , 16 , 20 ) without accounting for timing of thiazide use ( 14 , 20 , 21 ) . Detailed information on thiazide dose and duration of use was often absent or unreliable because no data on day-to-day use were available . Because of these limitations , it is still unclear how long thiazides have to be taken to affect fracture incidence and how long this effect persists after thiazide use is discontinued . We conducted a prospect i ve , population -based cohort study using detailed drug-dispensing information , as well as extensive information on potential risk factors , to examine the association between current and past use of thiazides and the incidence of hip fractures in men and women 55 years of age and older . We also studied the effect of discontinuing thiazide use on fracture risk . Methods Study Sample This study was conducted as part of the Rotterdam Study , a prospect i ve , population -based cohort study on the occurrence and determinants of disease and disability in elderly persons ( 22 ) . In 1990 , all inhabitants of Ommoord , a suburb of Rotterdam in the Netherl and s , who were 55 years of age or older and had lived in the district for at least 1 year were invited to participate in the study . Of the 10 275 eligible persons , 7983 ( 78 % ) participated . Participants gave informed consent and permission to retrieve information from medical records . At baseline , between 1990 and 1993 , trained interviewers administered an extensive question naire covering socioeconomic background and medical history , among other topics , during a home interview . During subsequent visits to the study center , additional interviewing , laboratory assessment s , and clinical examinations were performed . Information on vital status is obtained at regular time intervals from the municipal authorities in Rotterdam . The Medical Ethics Committee of the Erasmus MC , Rotterdam , the Netherl and s , approved the study . For the present study , all participants were followed from 1 June 1991 until they had an incident hip fracture , died , or reached the end of the study at 31 December 1999 , whichever came first . Exposure Definition In the research area , there are 7 fully computerized pharmacies that are linked to 1 network . During the study , all participants filled their prescriptions in 1 of these 7 pharmacies . Data on all dispensed drugs since 1 January 1991 are available in computerized format on a day-to-day basis . The data include the date of prescribing , the total amount of drug units per prescription , the prescribed daily number of units , product name , and the Anatomical Therapeutic Chemical ( ATC ) code ( 23 ) . The exposure of interest included plain thiazides and thiazides combined with potassium and potassium-sparing agents . Although formally not a thiazide , chlorthalidone was included because it has a similar effect on calcium excretion . In a previous study , these 2 diuretics did not differ ( 12 ) . Therefore , we did not distinguish between them . When a hip fracture occurred , the date was defined as the index date and the cumulative duration of use of thiazides on that date was calculated for each participant . Current use was defined as use of thiazides at the index date and was expressed as the number of consecutive days of use . Past use was defined as use of thiazides after baseline and before but not on the index date itself . Past use was expressed as the number of days since discontinuing use . To study the effect of duration of thiazide use , exposure at the index date was divided into 7 mutually exclusive categories , defined a priori : never use , current use for 1 to 42 days , current use for 43 to 365 days , current use for more than 365 days , discontinuation of use since 1 to 60 days , discontinuation of use since 61 to 120 days , and discontinuation of use since more than 120 days . We selected the first duration of 42 days because in the first 6 weeks of thiazide use , the decrease in circulating volume can cause dizziness and relative cerebral ischemia . We anticipated that this might be associated with a transiently increased risk for falls that should be distinguished from a potentially protective effect after prolonged use . After 42 days , the circulating volume in most patients is within normal limits ( 24 ) . The duration of more than 365 days was chosen because trials on incidence of nonvertebral fractures with use of antiosteoporotic agents , such as bisphosphonates , all had at least 1 year of follow-up as well . Finally , the duration of 60 days after discontinuing use was chosen because it was used in an earlier study ( 15 ) . We expressed the prescribed daily dosage during current use at the index date as a proportion of the defined daily dosage ( 25 ) . The defined daily dosage of thiazide diuretics is the st and ard recommended adult daily dosage for treating patients with hypertension in the Netherl and s. To avoid potential misclassification of exposure at baseline , we ensured that all participants had potential pharmacy data for at least 5 months before baseline . Outcome Definition The study participants ' general practitioners report all fatal and nonfatal events , such as fractures , through a computerized system . These data cover about 80 % of the study sample . For participants who were not covered in this system , research physicians performed annual checks on the complete medical records of all general practitioners in the Rotterdam Study . Two research physicians independently coded all fractures that occurred during the study period using the International Classification of Diseases , 10th revision ( ICD-10 ) ( 26 ) . A medical expert in the field who was unaware of patients ' history and medication use ( including thiazides )  review ed all coded events for a final classification . Fractures with ICD-10 codes S72.0 , S72.1 , and S72.2 were included , but pathologic hip fractures ( M84.4 ) and fractures in prosthetic hips ( M96.6 ) were excluded . Cofactors The following baseline patient characteristics , all determined by interview , were individually assessed as potential confounders : age , sex , score on the Mini-Mental State Examination ( < 26 points ) ( 27 ) , use of a walking aid , any fracture in the past 5 years , history of hysterectomy , thyroid disease , frequency of falling ( once per month ) , current smoking , intake of alcohol ( > 2 g/d ) , and dizziness . Participants were interviewed about a previous diagnosis of Parkinson disease or use of antiparkinsonian drugs and were screened for symptoms of Parkinson disease by study physicians at the research center . Diabetes mellitus was defined as the use of glucose-lowering medication  or a r and om or postload serum glucose level of 11.1 mmol/L ( 200 mg/dL ) or greater . Hypertension ( systolic blood pressure > 160 mm Hg , diastolic blood pressure > 95 mm Hg , or use of any antihypertensive drug ) , visual impairment in 1 or both eyes , and body mass index ( kg/m2 ) were measured at the research center . Presence of peripheral arterial disease was measured ( as described elsewhere [ 28 ] ) by using a single measurement of systolic blood pressure taken at both the left and the right posterior tibial artery . The ratio of the systolic blood pressure at the ankle to the systolic blood pressure at the arm was calculated for each leg . Peripheral arterial disease was considered present when the blood pressure at the arm was lower than 0.9 mm Hg on at least 1 side . Lower-limb disability was assessed by using a modified version of the Stanford Health Assessment Question naire ( 29 ) and by calculating the mean score of answers to questions about rising , walking , bending , and getting in and out of a car ( 30 ) . A score of 0 indicates no disability , a score between 0 and 1 indicates mild disability , and a score of more than 1 indicates severe disability . Intake of calcium was adjusted for the total caloric intake according to the method of Willett and associates ( 31 ) . Bone mineral density of the femoral neck was measured by using dual-energy x-ray absorptiometry ( DPX-L densitometer , Lunar Objective : To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses . Design : Double blind r and omised crossover study of two 12 week treatment periods with either low dose ( 1.25 mg ) or conventional dose ( 5.0 mg ) bendrofluazide given after a six week placebo run in period . Setting : Outpatient clinics serving the greater Belfast area . Subjects : 16 white non-diabetic patients ( 9 male ) under 65 with essential hypertension recruited from general practice s within the greater Belfast area . Main outcome measures : Systolic and diastolic blood pressure and peripheral and hepatic insulin action . Results : One man failed to complete the study . There were no differences between doses in their effects on systolic and diastolic blood pressure .  Bendrofluazide 1.25 mg had substantially less effect20on serum potassium concentration than the 5.0 mg dose . There were no intertreatment differences in fasting glucose , insulin , cholesterol , and triglyceride concentrations .  Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline ( mean 10.9 ( SD 1.2 ) v 10.0 ( 0.8 ) μmol/kg/min ) , whereas bendrofluazide 1.25 mg did not . Postabsorptive endogenous glucose20production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg ( 10.9 ( 1.2 ) v 9.9 ( 0.8 ) μmol/kg/min ) but was suppressed to a similar extent after insulin ( bendrofluazide 5.0 mg202.8 ( 1.5 ) μmol/kg/min v bendrofluazide 1.25 mg 2.2 ( 1.5 ) μmol/kg/min ) . Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were20similar to baseline . Conclusions : Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect . In contrast with conventional doses , how dose bendrofluazide has no effect on hepatic insulin action . There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity We tested the hypothesis that xanthine oxidase inhibition among African Americans receiving the thiazide-type diuretic chlorthalidone  may improve blood pressure control with fewer hyperuricemia-related side effects . We performed a r and omized , double-blind , placebo-controlled study of African Americans with Stage 1 hypertension without clinical ly significant renal disease . One hundred fifty African American men or women between the ages of 18 and 65 years who met the exclusion/ inclusion criteria with untreated or treated hypertension were started on chlorthalidone ( 25 mg/d ) and potassium chloride . After a 5-week run-in on chlorthalidone , baseline testing was performed and they were r and omized to allopurinol ( 300 mg/dL ) or placebo with doses adjusted based on uric acid levels and followed for 8 weeks . One hundred ten subjects completed the study . Baseline systolic blood pressures after the 5-week chlorthalidone run-in were 119.9 ± 13.6 in the allopurinol group and 117 ± 11.2 in the placebo group indicating excellent blood pressure control with the single agent . After at least 4 week postr and omization , the difference in mean change in systolic blood pressure  in allopurinol less placebo from visits 5 to 3 was 4.3 mm Hg ( 95 % confidence interval , -0.2 to 8.7 ; P = .059 ) . The difference in mean change in uric acid levels over the same period was 2.1 mg/dL ( 95 % confidence interval , 1.7 - 2.6 ; P < .001 ) . The use of chlorthalidone with or without allopurinol result ed in excellent blood pressure control . The addition of allopurinol tended to improve clinic blood pressure , but the difference from the group receiving chlorthalidone alone was not statistically significant The present primary prevention study aim ed at investigating whether metoprolol given as initial antihypertensive treatment would lower cardiovascular complications of high blood pressure to a greater extent than thiazide diuretics .  Patients were r and omized to metoprolol ( n = 1,609 , 8,110 patient-years ) or a thiazide diuretic ( n = 1,625 , 8,070 patient-years ) . At r and omization , 535 patients in the metoprolol group and 524 patients in the diuretic group were classified as smokers . Blood pressure control during follow-up was equally effective regardless of smoking habits at r and omization . Cardiovascular and coronary heart disease mortality was three to four times higher in smokers than in nonsmokers , underlining the importance of smoking as a risk factor . Total and cardiovascular mortality were significantly lower for the metoprolol group than for the thiazide diuretic group in the whole study population ( p = 0.028 and p = 0.012 ) , as well as in smokers ( p = 0.013 and p = 0.016 ) . Coronary heart disease mortality was significantly lower for patients on metoprolol  than for patients on diuretics  in the whole study population ( p = 0.048 ) as well as in smokers ( p = 0.02l ) . The results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of total , cardiovascular , and coronary heart disease mortality as compared with initial diuretic treatment , both in the whole study population and in smokers . The favorable effect of metoprolol must be mediated via mechanisms other than the blood pressure-lowering effect of metoprolol because equal blood pressure control was achieved with both types of medication , irrespective of smoking habits at r and omization A moderate reduction in salt intake lowers blood pressure in individuals with hypertension and improves blood pressure control in those taking a converting enzyme inhibitor . However , it is unclear how effective reduction of salt intake is compared with addition of other drugs , in particular , thiazide diuretics . We directly compared the separate effects on blood pressure of reducing sodium intake or adding a thiazide diuretic in the pressure of a converting enzyme inhibitor in a double-blind , r and omized , crossover study . We studied 11 subjects with essential hypertension who had been taking 25 mg captopril twice daily for at least 1 month . In the double-blind study , after 1 month of captopril alone , supine blood pressure was 151 + /- 5/95 + /- 4 ( SEM ) mm Hg . With the addition of 25 mg hydrochlorothiazide once daily for 1 month , blood pressure fell to 137 + /- 5/87 + /- 3 mm Hg . When a moderate reduction in salt intake ( from 206 + /- 26 to 109 + /- 20 mmol urinary sodium/24 h ) was added to captopril for 1 month , blood pressure was reduced by a similar amount ( to 137 + /- 4/90 + /- 3 mm Hg ) . Plasma potassium fell during the diuretic treatment ( 3.9 + /- 0.1 to 3.7 + /- 0.1 mmol/L , P < .05 ) but increased nonsignificantly during salt reduction ( 3.9 + /- 0.1 to 4.1 + /- 0.2 mmol/L ) . These results clearly demonstrate that moderate salt reduction , which can be easily achieved , is as effective as a thiazide diuretic in lowering blood pressure in the presence of a converting enzyme inhibitor and has the particular advantage that plasma potassium does not decrease . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Previous studies often of short duration have raised concerns that antihypertensive therapy with diuretics and beta-blockers adversely alters levels of other cardiovascular disease risk factors . METHODS The Systolic Hypertension in the Elderly Program was a community-based , multicenter , r and omized , double-blind , placebo-controlled clinical trial of treatment of isolated systolic hypertension in men and women aged 60 years and older . This retrospective analysis evaluated development of diabetes mellitus in all 4736 participants in the Systolic Hypertension in the Elderly Program , including changes in serum chemistry test results in a subgroup for 3 years . Patients were r and omized to receive placebo or treatment with active drugs , with the dose increased in stepwise fashion if blood pressure control goals were not attained : step 1 , 12.5 mg of chlorthalidone or 25.0 mg of chlorthalidone ; and step 2 , the addition of 25 mg of atenolol or 50 mg of atenolol or reserpine or matching placebo . RESULTS After 3 years , the active treatment group had a 13/4 mm Hg greater reduction in systolic and diastolic blood pressure than the placebo group ( both groups , P<.001 ) . New cases of diabetes were reported by 8.6 % of the participants in the active treatment group and 7.5 % of the participants in the placebo group ( P=.25 ) . Small effects of active treatment compared with placebo were observed with fasting levels of glucose ( + 0.20 mmol/L [ + 3.6 mg/dL ] ; P<.01 ) , total cholesterol ( + 0.09 mmol/L [ + 3.5 mg/dL ] ; P<.01 ) , high-density lipoprotein cholesterol ( -0.02 mmol/L [ -0.77 mg/dL ] ; P<.01 ) and creatinine ( + 2.8 micromol/L [ + 0.03 mg/dL ] ; P<.001 ) . Larger effects were seen with fasting levels of triglycerides ( + 0.9 mmol/L [ + 17 mg/dL ] ; P<.001 ) , uric acid ( + 35 micromol/L [ + .06 mg/dL ] ; P<.001 ) , and potassium ( -0.3 mmol/L ; P<.001 ) . No evidence was found for a subgroup at higher risk of risk factor changes with active treatment . CONCLUSIONS Antihypertensive therapy with low-dose chlorthalidone ( supplemented if necessary ) for isolated systolic hypertension lowers blood pressure and its cardiovascular disease complications and has relatively mild effects on other cardiovascular disease risk factor levels This prospect i ve , r and omized trial evaluated the effect of monotherapy and different combination therapies on cardiovascular target organ damage and metabolic profile in 520 hypertensive patients . Patients were allocated to a single agent : carvedilol 25 mg , amlodipine 10 mg , enalapril 20 mg , or losartan 50 mg ( groups C , A , E , and L , respectively ) . After 2 months ( level 2 ) , nonresponders received a low-dose thiazide diuretic , and after 4 months ( level 3 ) , amlodipine ( groups E , C , and L ) and carvedilol ( group A ) . Twenty-four-hour blood pressure was significantly lowered in all treatment groups . Blood pressure control was more pronounced in patients receiving two or three drugs . At the end of the study , the carotid intima-media thickness decreased in group L ( P<.01 ) , left ventricular mass index in groups E and L ( P<.05 and P<.001 , respectively ) , with a concomitant reduction in cholesterol in group L ( P<.03 ) . Diastolic function improved significantly in group L ( P<.05 ) . This study describes the need to control blood pressure with two or more drugs in most hypertensive patients and illustrates good clinical outcomes , independent of blood pressure lowering , using combination therapy with losartan , low-dose thiazide , and amlodipine Hydrochlorothiazide in a daily dose of 150 mg and spironolactone in a daily dose of 400 mg ( 100 mg of the currently available preparation ) were found to have equivalent antihypertensive effects — reducing basal blood pressure , decreasing the pressor response to levarterenol bitartrate ( norepinephrine ) and angiotensin amide , and increasing the depressor response to a ganglion-blocking agent , trimethaphan camsylate — in a double-blind study of 11 hypertensive patients . The two diuretics , when given together , appear to act independently and additively in their antihypertensive effects . Serum potassium level , lowered by hydrochlorothiazide , was in the normal range during administration of spironolactone alone or in combination with hydrochlorothiazide . Spironolactone can thus be a useful substitute for a benzothiadiazine derivative in the treatment of hypertension . The administration of a combination of these diuretics , a thiazide and an aldosterone antagonist , can render hypertension more readily manageable Abstract Background . Arterial hypertension is commonly associated with hyperuricemia . Several studies have shown that allopurinol reduces arterial blood pressure in animal models and in adolescent patients with newly diagnosed hypertension . Moreover , allopurinol has shown beneficial effects on endothelial function and arterial wave reflection in contrast to uricosuric agents . Antihypertensive drugs produce different effects on serum uric acid levels . Objective . The aim of the study was to evaluate the influence of allopurinol on blood pressure and aortic compliance in patients with arterial hypertension depending on hypotensive therapy with angiotensin-converting enzyme inhibitor ( ACE-I ) or thiazide diuretic , hypotensive drugs with distinct effects on serum uric acid levels and conversely , a positive influence on pulse wave velocity ( PWV ) in the aorta . Material and Methods . Sixty-six patients aged 25–70 ( mean age 46.17 ± 10.89 ) with mild and moderate arterial hypertension diagnosed on the basis of office blood pressure , were studied . They were r and omized to antihypertensive therapy on either perindopril ( n = 35 ) or hydrochlorothiazide ( n = 31 ) . After 8 weeks of antihypertensive therapy , 150 mg of allopurinol daily was added for the next 8 weeks . Measurement of the serum uric acid level , PWV and 24-h ambulatory blood pressure monitoring ( ABPM ) were performed at baseline , after 8 weeks antihypertensive therapy and again after the final 8 weeks with the additional allopurinol . Results . No significant changes in systolic ( SBP ) and diastolic blood pressure ( DBP ) or ABPM were observed after allopurinol treatment in either of the subgroups receiving ACE-I or thiazide-based antihypertensive therapy . The mean PWV decreased from 10.7 ± 1.4 m/s to 10.0 ± 1.2 m/s ( p = 0.00008 ) in the ACE-I-based therapy subgroup and from 11.5 ±1.7 m/s to 10.4 ± 1.5 m/s ( p = 0.00002 ) in the thiazide-based therapy subgroup after treatment with allopurinol . However , significant correlations were found between PWV changes and the basic PWV ( r = −0.52 ; p < 0.001 ) or SBP changes ( r = 0.29 ; p < 0.019 ) after allopurinol treatment . Conclusions . Allopurinol does not produce additional antihypertensive effects in patients with treated arterial hypertension . Allopurinol increases aortic compliance independently of ACE-I or thiazide-based , antihypertensive therapy . However , this effect is significantly dependent on the initial PWV in the aorta and on SBP changes during allopurinol therapy Because obesity-associated hypertension has unique hemodynamic and hormonal profiles , certain classes of antihypertensive agents may be more effective than others as monotherapy . Thus , we compared the efficacy and safety of the angiotensin-converting enzyme inhibitor lisinopril and the diuretic hydrochlorothiazide in a 12-week , multicenter , double-blind trial in 232 obese patients with hypertension . Patients with an office diastolic pressure between 90 and 109 mm Hg were r and omized to treatment with daily doses of lisinopril ( 10 , 20 , or 40 mg ) ,  hydrochlorothiazide  ( 12.5 , 25 , or 50 mg ) , or  placebo . Mean body mass indexes were similar for all patients . At week 12 , lisinopril and hydrochlorothiazide effectively lowered office diastolic ( -8.3 and -7.7 versus -3.3 mm Hg , respectively ; P<.005 ) and systolic ( -9.2 and -10.0 versus -4.6 mm Hg , respectively ; P<.05 ) pressures compared with placebo .  Ambulatory blood pressure monitoring confirmed that lisinopril and hydrochlorothiazide effectively lowered 24-hour blood pressure compared with placebo ( P<.001 ) . Significant dose-response differences were observed between treatments . Sixty percent of patients treated with lisinopril had an office diastolic pressure < 90 mm Hg compared with 43 % of patients treated with hydrochlorothiazide ( P<.05 ) . Responses to therapies differed with both race and age . Neither treatment significantly affected insulin or lipid profiles ; however , plasma glucose increased significantly after 12 weeks of hydrochlorothiazide therapy compared with lisinopril ( + 0.31 versus -0.21 mmol/L ; P<.001 ) . Hydrochlorothiazide also decreased serum potassium levels by 0.4 mmol/L from baseline . In conclusion , lisinopril was as effective as hydrochlorothiazide in treating obese patients with hypertension . Treatment with angiotensin-converting enzyme inhibitors may show greater efficacy as monotherapy at lower doses compared with thiazide diuretics , may have a more rapid rate of response , and may offer advantages in patients at high risk of metabolic disorders Azilsartan medoxomil , an effective , long-acting angiotensin II receptor blocker , is a new treatment for hypertension that is also being developed in fixed-dose combinations with chlorthalidone , a potent , long-acting thiazide-like diuretic . We compared once-daily fixed-dose combinations of azilsartan medoxomil/chlorthalidone force titrated to a high dose of either 40/25 mg or 80/25 mg with a fixed-dose combination of the angiotensin II receptor blocker olmesartan medoxomil plus the thiazide diuretic hydrochlorothiazide force titrated to 40/25 mg . The design was a r and omized , 3-arm , double-blind , 12-week study of 1071 participants with baseline clinic systolic blood pressure 160 to 190 mm Hg and diastolic blood pressure ⩽119 mm Hg . Patients had a mean age of 57 years ; 59 % were men , 73 % were white , and 22 % were black . At  baseline , mean clinic blood pressure was 165/96 mm Hg and 24-hour mean blood pressure was 150/88 mm Hg . Changes in clinic ( primary end point ) and ambulatory systolic blood pressures at week 12 were significantly greater in both azilsartan medoxomil/chlorthalidone arms than in the olmesartan/hydrochlorothiazide arm ( P<0.001 ) . Changes in clinic systolic blood pressure ( mean±SE ) were −42.5±0.8 , −44.0±0.8 , and −37.1±0.8 mm Hg , respectively . Changes in 24-hour ambulatory systolic blood pressure were −33.9±0.8 , −36.3±0.8 , and −27.5±0.8 mm Hg , respectively . Adverse events leading to permanent drug discontinuation occurred in 7.9 % , 14.5 % , and 7.1 % of the groups given azilsartan medoxomil/chlorthalidone 40/25 mg , azilsartan medoxomil/chlorthalidone 80/25 mg , and olmesartan/hydrochlorothiazide 40/25 mg , respectively . This large , forced-titration study has demonstrated superior antihypertensive efficacy of azilsartan medoxomil/chlorthalidone fixed-dose combinations compared with the maximum approved dose of olmesartan/hydrochlorothiazide BACKGROUND Losartan , an angiotensin II receptor antagonist , has been shown to decrease serum uric acid and to increase urinary excretion of uric acid . METHODS To determine if this effect can increase the risk of acute urate nephropathy , 63 hypertensive patients with thiazide-induced asymptomatic hyperuricemia ( serum uric acid 7.0 to 12.0 mg/dl ) were r and omized double-blind to losartan 50 mg every day ( q.d . ) , losartan 50 mg plus hydrochlorothiazide ( HCTZ ) 50 mg q.d . , HCTZ 50 mg q.d . , or placebo for three weeks . To potentiate the risk of crystal formation , patients received a 2 g/kg protein diet one day prior to each clinic visit on days 0 ( baseline ) , 1 , 7 , and 21 . RESULTS Adverse events typically associated with acute urate nephropathy , for example , flank pain , hematuria , or increased blood urea nitrogen/creatinine , were not reported . Uric acid excretion and urine pH increased four and six hours after losartan on day 1 compared with day 0 . Dihydrogen urate , the primary risk factor for crystal formation , decreased at four and six hours on day 1 compared with day 0 associated with the concurrent rise in urine pH. Day 7 and 21 changes , compared with day 0 , in uric acid excretion rate , urine pH , and dihydrogen urate with losartan were comparable to day 1 results but were not statistically significant . Serum uric acid was significantly reduced after 21 days of therapy with losartan . CONCLUSION Losartan decreased serum uric acid and increased uric acid excretion without increasing urinary dihydrogen urate , the primary risk factor for acute urate nephropathy , during 21 days of dosing in hypertensive patients with thiazide-induced hyperuricemia Men aged 40 - 64 years with mild to moderate hypertension [ diastolic blood pressure ( DBP ) 100 - 130 mmHg ] were r and omized to treatment with a  diuretic ( n = 3272 ) or a  beta-blocker ( n = 3297 ) , with additional drugs if necessary , to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease ( CHD ) events and death .  Patients with previous CHD , stroke or other serious diseases , or with contraindications to diuretics or beta-blockers were excluded . If normotension ( DBP less than 95 mmHg ) was not achieved by monotherapy , other antihypertensive drugs were added , but the two basic drugs were not crossed over . Patients were assessed at 6-monthly intervals . The mean follow-up for end-points was 45.1 months . Blood pressure ( BP ) side effects and end-points were recorded in a st and ardized manner . Entry characteristics and the BP reduction achieved were very similar in both treatment groups . All analyses were made on an intention-to-treat basis . The incidence of CHD did not differ between the two treatment groups . The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group . Total mortality and the total number of end-points were similar in both groups . The percentage of patients withdrawn due to side effects was similar , whereas the number of reported symptoms , according to a question naire , was higher for patients on beta-blockers . The incidence of diabetes did not differ between the two groups . Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers , and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD . Beta-blockers and thiazide diuretics were approximately equally well tolerated . The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group . Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications , including CHD , to a different extent The concept of initiating treatment of mild-to-moderate hypertension with a low-dose combination of reserpine and the thiazide clopamide in comparison to monotherapy with an ACE inhibitor was investigated . A total of 127 adult out patients with diastolic blood pressure between 100 and 114 mmHg were r and omized into this double-blind , parallel group study . After a 2-week wash-out period and a subsequent 2-week placebo run-in period , they were allocated to once-daily treatment with 0.1 mg reserpine plus 5 mg clopamide ( R/C ) , or 5 mg enalapril . If diastolic blood pressure was not normalized after 3 weeks of therapy ( i.e. DBP < 90 mmHg ) , the dosage was doubled from week 4 to 6 . The primary efficacy variables were the change from baseline in mean sitting diastolic and systolic blood pressure ( DBP/SBP ) after 3 weeks of therapy . Secondary variables included the change in DBP and SBP after 6 weeks of therapy , the BP normalization rates at 3 and 6 weeks and , concerning tolerability , the rates of adverse events after 6 weeks of therapy . An intent-to-treat analysis was performed . The reserpine/ clopamide and enalapril groups did not differ with regard to demographic and baseline characteristics ( mean age 57 or 58 years , respectively ; 63 % or 56 % males , respectively ; mean SBP/DBP after the 2-week placebo period = 156 mmHg/104 mmHg in both groups ) . After 3 weeks of treatment with one capsule daily , mean SBP/DBP reduction from baseline ( 24 h after last medication intake ) in the R/C combination group was -19.6/ -17.0 mmHg , in the enalapril group -6.1/ -9.5 mmHg ( between-group comparison : 2p < 0.01 for both parameters ) . The normalization rates for DBP ( < 90 mmHg ) were 64.1 % ( R/C ) and 28.6 % ( enalapril ) ( 2p < 0.01 ) . Adverse events that were considered possibly or definitely drug-related by the investigator were noted in 11 patients ( 17.2 % ) in the R/C group and in 9 patients ( 14.3 % ) in the enalapril group ( NS ) . Two patients in the enalapril group discontinued the study prematurely due to adverse events ( cough ; skin eruption ) . In the treatment of mild-to-moderate hypertension , a low-dose combination of reserpine and clopamide once a day is considerably more effective than , and as tolerable as , 5 - 10 mg of enalapril once a day . These findings suggest that treatment with a combination of different antihypertensives with different modes of action in low doses is a rational alternative to conventional monotherapy in the first-line treatment of hypertension . Besides , the " old " reserpine-diuretic regimen also in these days appears to be a rational alternative to " modern " monotherapies OUTCOMES Extensive data from r and omised controlled trials have shown the benefit of treating hypertension . The target blood pressure ( BP ) for antihypertensive management is systolic < 140 mmHg and diastolic < 90 mmHg with minimal or no drug side-effects ; however , stricter BP control is required for patients with end-organ damage , co-existing risk factors and co-morbidity , e.g. diabetes mellitus . The reduction of BP in the elderly and in those with severe hypertension should be achieved gradually over 1 month . Co-existent risk factors should also be controlled . BENEFITS Benefits of management include reduced risks of stroke , cardiac failure , chronic kidney disease and coronary heart disease . RECOMMENDATIONS The correct BP measurement procedure is described , and evaluation of cardiovascular risk factors and recommendations for antihypertensive therapy are stipulated . The total cardiovascular disease risk profile should be determined for all patients to inform management strategies . Lifestyle modification and patient education are cornerstones in the management of every patient . Major indications , pre caution s and contra-indications to each recommended antihypertensive drug are listed . Combination therapy should be considered ab initio if the BP is ≥ 20/10 mmHg . First-line drug therapy for uncomplicated hypertension includes low-dose thiazide-like diuretics , calcium channel blockers ( CCBs ) or angiotensin-converting enzyme inhibitors ( ACE-Is ) ( or ARBs - angiotensin II receptor blockers ) . If the target BP is not obtained , a second antihypertensive should be added from the aforementioned list . If the target BP is still not met , the third remaining antihypertensive agent should be used . In black patients  either thiazide-like diuretics or CCBs can be used initially , because response rates are better than with ACE-Is or β-blockers . In treating resistant hypertension , a central ly acting drug , vasodilator , α-blocker , spironolactone or β-locker should be added . This guideline includes management of specific situations , i.e. hypertensive emergency and urgency , severe hypertension with target organ damage , hypertension in diabetes mellitus , resistant hypertension , fixed drug combinations , new trials in hypertension , and interactions of antihypertensive agents with other drugs . VALIDITY The guideline was developed by the Southern African Hypertension Society UNLABELLED This study compares the loop diuretic piretanide 6 mg in a slow-release formulation ( PIR ) with hydrochlorothiazide 25 mg ( HCT ) and the fixed combination altizide 15 mg-spironolactone 25 mg ( ALT-SP ) in hypertension . 1105 mild to moderate hypertensive patients entered a three-week placebo wash-out period ; 899 were r and omized in a 6-month , double-blind , parallel group treatment phase ; 800 completed the study . Primary end-points ; serum potassium concentration and quality of life at one month ; secondary end-points : ionic , renal and metabolic variables ; blood pressure ( BP ) measurements . HCT and ALT-SP were compared only to PIR using Dunnett 's or chi 2 tests . RESULTS No difference was found for the overall quality of life . No change of serum potassium concentration at one month was found in PIR while small decreases were detected with ALT-SP ( -0.1 mM ) and HCT ( -0.26 mM ) . Serum creatinine concentration increased significantly in ALT-SP when compared to PIR . All the drugs were effective in reducing BP : HCT had a higher rate of responders than PIR with similar mean BP falls and ALT-SP induced greater falls in blood pressure . CONCLUSION PIR proves to be a potent antihypertensive drug without significant effect on serum electrolytes , plasma glucose and lipids . HCT was slightly more potent but induced a fall in serum potassium concentration with a significant risk of hypokalaemia . The addition of SP to ALT led to a more potent diuretic with a higher level of serum potassium and plasma creatinine disturbances The present study of primary prevention in white men aged 40 to 64 years attempts to investigate whether a beta-blocker given as initial antihypertensive treatment would lower total mortality to a greater extent than thiazide diuretics .  Patients were r and omized to metoprolol ( n = 1609 , 8110 patient-years ) or a thiazide diuretic ( n = 1625 , 8070 patient-years ) . The median follow-up time was 4.2 years . The mean dose of metoprolol was 174 mg/d , and of thiazide diuretics , 46 mg/d of hydrochlorothiazide or 4.4 mg/d of bendroflumethiazide . Identical control of blood pressure was achieved using a fixed therapeutic schedule . Total mortality was significantly lower for metoprolol than for thiazide diuretics because of fewer deaths from coronary heart disease and stroke . Total mortality was also significantly lower in smokers r and omized to metoprolol .  The benefit demonstrated in patients treated with metoprolol seems to have important implication s for clinical practice Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given  spironolactone , 400 mg/d , or chlorthalidone , 100mg/d , in a double-blind , r and om-sequence , crossover trial . The sequence of treatments was placebo for 2 months , one active drug for 2 months , placebo again for 1 month and the other active drug for 2 months . With both active treatments the average systolic , diastolic and mean arterial pressures decreased significantly . The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment . Body weight , 24 - -hour urinary excretion of sodium , the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug . Both drugs reduced the body weight and increased the stimulated plasma renin level activity .  Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level . Three patients experienced orthostatic dizziness during spironolactone therapy , but no adverse symptoms were observed with chlorthalidone therapy . Thus , spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension Summary The antihypertensive efficacy both of angiotensin converting enzyme ( ACE ) inhibitors and thiazide diuretics has been cl aim ed to be influenced by plasma renin activity , which declines with age and is low in blacks . In a double-blind , placebo-controlled , double-dummy , r and omized , parallel-group preliminary study , the antihypertensive efficacy and tolerability of the ACE inhibitor enalapril ( 20 mg day−1 ) and hydrochlorothiazide ( 50 mg day−1 ) were evaluated and compared for 4 weeks in 20 African patients with essential hypertension . The two groups had similar baseline clinical features and serum Na+ and K+ levels .  Hydrochlorothiazide caused a significant and sustained fall in erect blood pressure with a reflex tachycardia .  Enalapril exerted only a modest antihypertensive action , but significantly reduced erect heart rate . Direct comparison of hydrochlorothiazide — and enalapril — induced hypotension suggested a greater fall in subjects on the thiazide . The 95 % confidence limits for the thiazide-enalapril difference in antihypertensive action at the end of the study was 39.5 to −7.5 mm Hg systolic and 22.0 to −6.6 mm Hg diastolic . The maximal blood pressure fall after hydrochlorothiazide was positively correlated with age ( r=0.50;p<0.05 ) , whilst that of enalapril was inversely related age to (r=−0.57,p<0.05).The results are compatible with the notion that ACE inhibitor monotherapy may be less effective than thiazide diuretic treatment in African and black patients with essential hypertension . The findings also support the concept that age and racial factors may influence the response to antihypertensive treatment Objectives Current guidelines recommend the use of multiple medications for hypertension . The present study was aim ed at determining which combination was optimal to prevent cardiovascular events . Methods We conducted a prospect i ve , r and omized , open-label , blinded-endpoint trial . Hypertensive out patients aged between 40 and 85 years who did not achieve target blood pressure ( BP<140/90 mmHg ) with calcium channel blocker ( CCB ) benidipine 4 mg/day were r and omly assigned to receive angiotensin receptor blocker ( ARB ) , & bgr;-blocker , or thiazide diuretic in addition to benidipine . Results Among a total of 3501 patients ( 1167 , benidipine-ARB ; 1166 , benidipine-&bgr;-blocker ; and 1168 , benidipine-thiazide ) , 3293 patients ( 1110 , 1089 , and 1094 , respectively ) who received each combination treatment were included in the analysis . Median follow-up was 3.61 years . At the end of the treatment , 64.1 , 66.9 , and 66.0 % of patients in the benidipine-ARB , benidipine-&bgr;-blocker , and benidipine-thiazide groups achieved target BP , respectively . The cardiovascular composite endpoint occurred in 41 ( 3.7 % ) , 48 ( 4.4 % ) , and 32 ( 2.9 % ) patients , respectively : the hazard ratio was 1.26 in the benidipine-ARB ( P = 0.3505 ) and 1.54 in the benidipine-&bgr;-blocker ( P = 0.0567 ) groups compared with the benidipine-thiazide group . The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes ( P = 0.0109 ) and benidipine and ARB significantly reduced new-onset diabetes ( P = 0.0240 ) compared with benidipine and & bgr;-blocker . All trial treatments were safe and well tolerated . Conclusion CCB combined with ARB , & bgr;-blocker , or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP The efficacy of low dosages of diuretics was evaluated in two studies . In one , 62 ( 48 % ) of 130 patients became normotensive with 2.5 mg/day of metolazone . In the other , 28 ( 49 % ) of 57 patients became normotensive with 25 mg of chlorthalidone , compared with 12 ( 22 % ) of 55 patients given placebo . There was a marked variation in blood pressure response and the occurrence of hypokalemia ( less than 3.5 mEq/L of potassium ) from center to center and within patient groups in both studies . The mean decrease in serum potassium was between 0.5 and 0.6 mEq/L in the metolazone group and 0.44 mEq/L in the chlorthalidone-treated patients . This degree of hypokalemia is only slightly less than that noted when larger dosages of thiazide diuretics are used ( 0.6 to 0.7 mEq/L ) . It is concluded that 2.5 mg/day of metolazone or 25 mg/day of chlorthalidone are effective antihypertensive agents but that blood pressure lowering may be inconsistent at these dosage levels . It is reasonable , therefore , to begin diuretic therapy with low dosages , but larger dosages ( 5 mg of metolazone or 50 mg of chlorthalidone ) should be tried before adding another drug or concluding that diuretic therapy is ineffective if an acceptable blood pressure response is not obtained . The degree of hypokalemia that occurs at lower-dose therapy is variable but may be of less clinical significance than that noted with higher dosages of diuretics in some patients . ( ABSTRACT TRUNCATED AT 250 WORDS Current guidelines from the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure recommend first-line treatment with a thiazide diuretic but do not provide specific guidance for obese patients . The renin system is activated in obesity-associated arterial hypertension . Therefore , we tested the hypothesis that the oral direct renin inhibitor aliskiren could provide additive blood pressure lowering in obese patients with hypertension ( body mass index ≥30 kg/m2 ; mean sitting diastolic blood pressure : 95 to 109 mm Hg ) who had not responded to 4 weeks of treatment with hydrochlorothiazide ( HCTZ ) 25 mg . After a 2- to 4-week washout , 560 patients received single-blind HCTZ ( 25 mg ) for 4 weeks ; 489 nonresponders were r and omly assigned to double-blind aliskiren ( 150 mg ) , irbesartan ( 150 mg ) , amlodipine ( 5 mg ) , or placebo for 4 weeks added to HCTZ ( 25 mg ) , followed by 8 weeks on double the initial doses of aliskiren , irbesartan , or amlodipine . After 8 weeks of double-blind treatment ( 4 weeks on the higher dose ) , aliskiren/HCTZ  lowered blood pressure by 15.8/11.9 mm Hg , significantly more ( P<0.0001 ) than placebo/HCTZ ( 8.6/7.9 mm Hg ) . Aliskiren/HCTZ  provided blood pressure reductions similar to those with irbesartan/HCTZ and amlodipine/HCTZ ( 15.4/11.3 and 13.6/10.3 mm Hg , respectively ) , with similar tolerability to placebo/HCTZ . Adverse event rates were highest with amlodipine/HCTZ because of a higher incidence of peripheral edema ( 11.1 % versus 0.8 % to 1.6 % in other groups ) . In conclusion , combination treatment with aliskiren is a highly effective and well-tolerated therapeutic option for obese patients with hypertension who fail to achieve blood pressure control with first-line thiazide diuretic treatment The objective of this study was to determine which of the common groups of antihypertensive drugs is most effective at lowering systolic blood pressure ( SBP ) in elderly patients with previously untreated hypertension and the percentage of patients controlled with single or sequential monotherapy . Subjects were recruited from patients attending other outpatient clinics and entered into the study if their SBP was more than 150 mm Hg after three visits . Patients were given a low and high dose of each of the main classes of drugs or placebo for 1 month each . The study was a balanced , r and omized crossover design with five periods : placebo ; angiotensin converting enzyme inhibitors ; beta-blocking drugs ; calcium-blocking drugs ; and thiazide diuretics .  Blood pressure ( BP ) was measured 24 to 26 h after the previous dose . A question naire for side effects was administered at each visit . Seventy-four patients entered the study . beta-Blockers could not be used in 15 patients because of asthma or bronchospasm and these had two placebo periods . There were 9 of 66 patients on P , 9 of 46 on beta-blockers , 4 of 65 on calcium-blocking drugs , 4 of 65 on diuretic , and 1 of 62 patients on ACE inhibitors who did not progress to the higher dose because of side effects . Decreases in SBP compared to r and omized placebo were calcium-blocking drugs 15 mm Hg = diuretic 13 mm Hg > ACE inhibitors 8 mm Hg = beta-blockers 5 mm Hg . Blood pressure decrease correlated with placebo BP ( P < .0005 , r = 0.53 to 0.70 ) . When corrected for placebo , target SBP ( < 140 mm Hg ) was reached in between 6 % to 15 % of patients on monotherapy . Sequential monotherapy achieved target in 29 % . Angiotensin converting enzyme inhibitors , calcium-blocking drugs , and diuretics had no more side effects than placebo . Patients on beta-blockers had more side effects and the well-being score was reduced . Diuretics and calcium-blocking drugs are more effective in elderly patients at lowering SBP pressure . beta-Blockers were relatively ineffective , were frequently contraindicated , and had more side effects . Monotherapy achieved control in only a small number of patients . In elderly people with essential hypertension , therapy should be instituted with diuretics or calcium-blocking drugs , but combination therapy will usually be required to achieve goal OBJECTIVE To provide up date d , evidence -based recommendations for the prevention and management of hypertension in adults . OPTIONS AND OUTCOMES For lifestyle and pharmacological interventions , evidence was review ed from r and omized controlled trials and systematic review s of trials . Changes in cardiovascular morbidity and mortality were the primary outcomes of interest . However , for lifestyle interventions , blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field . For treatment of patients with kidney disease , the progression of kidney dysfunction was also accepted as a clinical ly relevant primary outcome . EVIDENCE A Cochrane collaboration librarian conducted an independent MEDLINE search from 2005 to August 2006 to up date the 2006 Canadian Hypertension Education Program recommendations . In addition , reference lists were scanned and experts were contacted to identify additional published studies . All relevant articles were review ed and appraised independently by both content and method ological experts using prespecified levels of evidence . RECOMMENDATIONS Dietary lifestyle modifications for prevention of hypertension , in addition to a well-balanced diet , include a dietary sodium intake of less than 100 mmol/day . In hypertensive patients , the dietary sodium intake should be limited to 65 mmol/day to 100 mmol/day . Other lifestyle modifications for both normotensive and hypertensive patients include : performing 30 min to 60 min of aerobic exercise four to seven days per week ; maintaining a healthy body weight ( body mass index of 18.5 kg/m2 to 24.9 kg/m2 ) and waist circumference ( less than 102 cm in men and less than 88 cm in women ) ; limiting alcohol consumption to no more than 14 units per week in men or nine units per week in women ; following a diet reduced in saturated fat and cholesterol , and one that emphasizes fruits , vegetables and low-fat dairy products , dietary and soluble fibre , whole grains and protein from plant sources ; and considering stress management in selected individuals with hypertension . For the pharmacological management of hypertension , treatment thresholds and targets should take into account each individual 's global atherosclerotic risk , target organ damage and any comorbid conditions : blood pressure should be lowered to lower than 140/90 mmHg in all patients and lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease . Most patients require more than one agent to achieve these blood pressure targets . In adults without compelling indications for other agents , initial therapy should include thiazide diuretics ; other agents appropriate for first-line therapy for diastolic and /or systolic hypertension include angiotensin-converting enzyme ( ACE ) inhibitors ( except in black patients ) , long-acting calcium channel blockers ( CCBs ) , angiotensin receptor blockers ( ARBs ) or beta-blockers ( in those younger than 60 years of age ) . First-line therapy for isolated systolic hypertension includes long-acting dihydropyridine CCBs or ARBs . Certain comorbid conditions provide compelling indications for first-line use of other agents : in patients with angina , recent myocardial infa rct ion , or heart failure , beta-blockers and ACE inhibitors are recommended as first-line therapy ; in patients with cerebrovascular disease , an ACE inhibitor plus diuretic combination is preferred ; in patients with nondiabetic chronic kidney disease , ACE inhibitors are recommended ; and in patients with diabetes mellitus , ACE inhibitors or ARBs ( or , in patients without albuminuria , thiazides or dihydropyridine CCBs ) are appropriate first-line therapies . All hypertensive patients with dyslipidemia should be treated using the thresholds , targets and agents outlined in the Canadian Cardiovascular Society position statement ( recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease ) . Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy . Once blood pressure is controlled , acetylsalicylic acid therapy should be considered . VALIDATION All recommendations were grade d according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence -Based Recommendations Task Force . All recommendations reported here achieved at least 95 % consensus . These guidelines will continue to be up date d annually Sibutramine treatment in obesity results in significantly greater weight reduction compared with placebo , although weight loss with sibutramine may be accompanied by small but statistically significant mean increases in blood pressure ( BP ) . This 52-week , placebo-controlled , double-blind , r and omised study investigated the effects of sibutramine 20 mg once daily or placebo on body weight in 220 obese ( body mass index ( BMI ) 27–40 kg/m2 ) , hypertensive patients . At r and omisation , hypertension was well controlled ( ⩽95 mm Hg diastolic blood pressure ( DBP ) ) with an angiotensin-converting enzyme ( ACE ) inhibitor , with or without concomitant thiazide diuretic therapy . Therapy for hypertension continued for the 52 weeks of the study . Sibutramine 20 mg produced significantly greater weight loss compared with placebo : 4.5 kg with sibutramine compared with 0.4 kg with placebo ( last observation carried forward ( LOCF ) ; P ⩽ 0.05 ) . A total of 62 patients ( 42.8 % ) treated with sibutramine lost ⩾5 % of their body weight compared with six patients ( 8.3 % ) treated with placebo ; 19 patients ( 13.1 % ) treated with sibutramine lost ⩾10 % of their body weight compared with two patients ( 2.8 % ) treated with placebo ( LOCF ; P⩽ 0.05 for both comparisons ) . Hypertension remained well controlled for the 52 weeks of the study with both sibutramine and placebo treatment . After 52 weeks , the differences between placebo treatment and sibutramine  treatment for both mean supine systolic blood pressure ( SBP ) and DBP were approximately 3 mm Hg : mean DBP was 82.8 mm Hg with placebo treatment compared with 85.5 mm Hg with sibutramine treatment ( LOCF ; P = 0.004 ) and mean SBP was 130.4 mm Hg with placebo compared with 133.1 mm Hg with sibutramine ( LOCF ; P = 0.0497 ; both comparisons , sibutramine vs placebo ) . The mean increases in SBP and DBP did not appear to change the overall risk category for coronary heart disease end points . Changes in pulse rate at week 52 were a decrease of 0.3 beats per minute ( bpm ) for placebo treatment compared with an increase of 5.7 bpm for sibutramine treatment ( P < 0.001 ) . M and ated withdrawals from the study due to protocol -defined changes in BP were not statistically different between the two treatment groups . Greater favourable changes in lipid profile , serum glucose , and uric acid could be accounted for by greater weight losses occurring in the sibutramine treatment group . Sibutramine was well tolerated . This study indicates that in obese patients whose hypertension is well controlled at the outset with an ACE inhibitor  , with or without concomitant thiazide diuretic therapy  , sibutramine safely and effectively achieves weight loss without compromising good BP control BACKGROUND fractures may have serious implication s in an elderly individual , and fracture prevention may include a careful choice of medications . DESIGN the Hypertension in the Very Elderly Trial ( HYVET ) was a double-blind placebo-controlled trial of a thiazide-like diuretic ( indapamide 1.5 mg SR ) with the optional addition of the angiotensin-converting enzyme ( ACE ) inhibitor ( perindopril 2 - 4 mg ) . Fracture was a secondary end point of the trial . SETTING HYVET recruited participants from Eastern and Western Europe , China , Australasia , and Tunisia . SUBJECTS all participants were > or = 80 years of age and hypertensive . METHODS participants were r and omised to receive a thiazide-like diuretic ( indapamide 1.5 mg SR ) + /- ACE inhibitor ( perindopril 2 - 4 mg ) or matching placebos .  Incident fractures were vali date d and analysed based on time to first fracture . RESULTS there were 3,845 participants in HYVET and a total 102 reported fractures  ( 42 in the active and 60 in the placebo group ) . When taking only vali date d first fractures , 90 were included in the analyses ( 38 in the active and 52 in the placebo group ) . Cox proportional hazard regression , adjusted for key baseline risk factors , result ed in a point estimate of 0.58 ( 95 % CI 0.33 - 1.00 , P = 0.0498 ) . CONCLUSIONS despite the lowering of blood pressure , treatment with a thiazide-like diuretic and an ACE inhibitor does not increase and may decrease fracture rate Considering the documented , potentially undesirable influence of various thiazide-type or loop diuretics on serum lipoproteins , we prospect ively investigated in 69 men(mean age ± SEM , 32 ± 1 years ) the metabolic effects of the new diuretic-antihypertensive compound indapamide . Compared to placebo , indapamide ( 2.5 mg/day ) given for 6 to 8 weeks lowered ( p < 0.02 to < 0.001 ) blood pressure(supine values from 148/98 ± 3/2 to 137/93 ± 3/2 ) in 29 men with mild to moderate essential hypertension , but not in 40 healthy men . In both groups , significant ( p < 0.05 to < 0.001 ) decreases in body weight ( −0.8 kg ) and plasma potassium ( −0.6 mmol/L ) , and increases in plasma uric acid (= 20 % ) , renin activity (= 200 % ) , and aldosterone documented good compliance . There were no significant changes hi total cholesterol(in all subjects , from 208 ± 6 to 213 ± 6 mg/dl ) , low- or very low-density lipoprotein(VLDL ) cholesterol ( 127 ± 6 to 129 ± 6 and 21 ± 1 to 21 ± 2 respectively ) , high-density lipoprotein cholesterol ( 50 ± 1 to 51 ± 1 mg/dl ) , total triglycerides(Tg ) ( 108 ± 5 to 112 ± 6 mg/dl ) , VLDL-Tg , apoproteins Al and A2 , plasma glucose , epinephrine , norepinephrine , sodium , calcium , magnesium , and creatinine ; apoprotein B ( 84 ± 2 to 88 ± 3 mg/dl ) and plasma insulin after glucose loading dose tended to be increased minimally . The absence of distinct lipoprotein alterations after short-term indapamide treatment may be of clinical and epidemiological interest.(Hypertension 7 [ Suppl II ] : II-164–II-169 , 1985 The present study in hypertensive men ( 40 - 64 years old ) with untreated diastolic blood pressure above 100 mm Hg was aim ed at investigating whether metoprolol ( n = 1,609 ) given as initial treatment would lower the risk for coronary events ( sudden death and myocardial infa rct ion ) more effectively than thiazide diuretics ( n=1,625 ) . A substantial part of this study was the metoprolol arm of the Heart Attack Primary Prevention in Hypertension ( HAPPHY ) study . The HAPPHY study was a pooling of the effect of different /J-blockers , mainly metoprolol and atenolol , in which no favorable effect in relative risk was observed for atenolol as compared with diuretics . In the present study , 255 patients suffered definite coronary events during follow-up ; 25 % of these events were fatal , 39 % were acute myocardial infa rct ions , and 36 % were silent myocardial infa rct ions . The risk for coronary events was significantly lower in patients on metoprolol  than in patients on diuretics  ( 111 versus 144 cases , p=0.001 , corresponding to 143 versus 18.8 cases/1,000 patient years and a relative risk of 0.76 at the end of the trial ; 95 % confidence interval 0.58 - 0.98 ) . This difference in risk has potentially important implication s for clinical practice because of the large number of hypertensive patients who are at increased risk for coronary events . Because a placebo group , for ethical reasons , could not be included , relative risk can only be expressed in relation to diuretics . There was no difference between the two treatment groups in baseline characteristics , blood pressure during follow-up , or stroke rates . Thus , the difference in risk for coronary events is probably mediated via mechanisms other than blood pressure control . However , present data might suggest that different /3-blockers may have different efficacy in preventing coronary events . The reasons for this possibility are as yet unknown . ( Hypertension 1991:17 : BACKGROUND Age and race categories or renin profiling have been recommended to predict blood pressure responses to monotherapy with a beta-blocker or thiazide diuretic . Whether these or other characteristics predict blood pressure responses when the drugs are administered as add-on therapy is uncertain . METHODS We evaluated predictors of blood pressure response in 363 men and women < or = 65 years of age with primary hypertension ( 152 blacks , 211 whites ) , 86 of whom ( 24 % ) were untreated and 277 of whom ( 76 % ) were withdrawn from previous antihypertensive drugs before r and omization to either atenolol followed by addition of hydrochlorothiazide ( N = 180 ) or hydrochlorothiazide followed by addition of atenolol ( N = 183 ) . Responses were determined by home blood pressure averages before and after each drug administration . Race , age , plasma renin activity , and other characteristics including pretreatment blood pressure levels were incorporated into linear regression models to quantify their contributions to prediction of blood pressure responses . RESULTS Plasma renin activity and pretreatment blood pressure level consistently contributed to prediction of systolic and diastolic responses to each drug administered as mono- and as add-on therapy . Higher plasma renin activity was consistently associated with greater blood pressure responses to atenolol and lesser responses to hydrochlorothiazide . The predictive effects of plasma renin activity were statistically independent of race , age , and other characteristics . CONCLUSIONS Plasma renin activity and pretreatment blood pressure level predict blood pressure responses to atenolol and hydrochlorothiazide administered as mono- and as add-on therapy in men and women < or = 65 years of age A blood lipid-lipoprotein elevating effect of the diuretics hydrochlorothiazide and chlorthalidone in mildly hypertensive men has been established by a cross-over , r and omized controlled trial , confirming previous clinical observations . Compared to baseline , plasma total cholesterol increased 6 % and 8 % and triglycerides 17 % and 15 % under treatment with hydrochlorothiazide and chlorthalidone , respectively . A cholesterol-lowering diet largely prevents this increase . Because these effects may be long-lasting and may cancel part of the potential benefit of blood pressure control in mildly hypertensive patients , with thiazide diuretics attention should be given to prescription of a cholesterol-lowering diet and to periodic monitoring of blood lipid levels . Different antihypertensive agents might be considered in patients with elevated blood lipid levels . Other antihypertensive agents currently in use need to be studied for potential effects on lipid metabolism Unlike some thiazide diuretics , indapamide -- a non-thiazide chlorosulphonamide derivative -- has been shown to have a magnesium-sparing effect in normotensive subjects . This effect has not been studied in hypertensive subjects . In a r and omised double-blind trial indapamide 2,5 mg and placebo were given daily to a group of elderly patients with mild hypertension , with and without supplemental magnesium chloride .  Blood pressure and serum and red blood cell cations were measured . The significant antihypertensive effect of indapamide was confirmed . There was no effect of indapamide on serum and red cell magnesium concentrations compared with placebo , both with and without magnesium supplementation . Indapamide induced hypokalaemia with a shift of sodium into the red cells . In this group of elderly hypertensive subjects  indapamide induced potassium but not magnesium loss Atenolol was compared with five other beta-blockers and a thiazide diuretic in a r and omised cross-over trial of once-daily treatment of essential hypertension .  Atenolol was significantly better at reducing resting and exercise blood pressures at 24 hours than any of the other drugs and had a low incidence of side effects . Both timolol and acebutolol had a significant hypotensive effect at 24 hours and a low incidence of side effects , suggesting that further increases in dosage might be effective and well tolerated . Labetalol proved ineffective when given once daily , and the high incidence of side effects , equalled only by pindolol , would probably prohibit further increases in dosage .  Bendrofluazide  was equal or superior to all the beta-blockers except atenolol at reducing resting blood pressure , and its cheapness still makes it an agent of first choice in mild or moderate essential hypertension The objective of the study is to compare fatal and nonfatal cardiovascular endpoints in hypertensive patients r and omised to the calcium-channel blocker , nifedipine GITS or a thiazide diuretic , co-amilozide . A total of 6592 patients from nine countries ( UK , France , Israel , Spain , Italy , The Netherl and s , Sweden , Denmark and Norway ) will be recruited , aged 55 - 80 and with a blood pressure ( BP ) > or = 150/95 or > or = 160 mm Hg ( systolic ) . All patients will have at least one other major cardiovascular risk factor . Patients will be minimised by country and risk factors and r and omised to double-blind treatment with either nifedipine GITS or diuretic . After a single dose titration , additional treatment will be atenolol or enalapril ( where beta-blockade is contra-indicated ) . After achieving a target BP of 140/90 mm Hg patients will be followed for a total of 3 years . Primary endpoints are myocardial infa rct ion , stroke , subarachnoid haemorrhage , heart failure and sudden cardiac death . The study has a power of 80 % at 5 % significance to detect a difference between 8 % event rate over 3 years in diuretic-treated patients and 6 % in those receiving nifedipine BACKGROUND We sought to determine the incidence of newly diagnosed diabetes in treated elderly hypertensive patients and the prognostic impact of diabetes on long-term survival . METHODS The Second Australian National Blood Pressure ( ANBP2 ) study r and omized 6,083 hypertensive patients aged 65 - 84 years to angiotensin-converting enzyme inhibitor ( ACEI ) or thiazide diuretic-based therapy and followed them for a median of 4.1 years . Long-term survival was determined in 5,678 patients over an additional median of 6.9 years after ANBP2 ( post-trial ) . RESULTS After ANBP2 , the cohort was classified into preexisting ( 7.2 % ) , newly diagnosed ( 5.6 % ) , and no diabetes ( 87.2 % ) groups . A 44 % higher incidence of newly diagnosed diabetes was observed in patients r and omized to thiazide diuretic compared with ACEI-based treatment . The other predictors of newly diagnosed diabetes were having a higher body mass index , having a higher r and om blood glucose , and living in a regional location compared to major cities ( a geographical classification based on accessibility ) at study entry . After completion of ANBP2 , compared with those with no diabetes , the preexisting diabetes group experienced higher cardiovascular ( hazards ratio ( HR ) = 1.65 ; 95 % confidence interval ( CI ) = 1.03 - 2.65 ) and all-cause mortality ( HR = 1.40 ; 95 % CI = 1.02 - 1.92 ) when adjusted for age , sex , and treatment . A similar pattern was observed after including the post-trial period for cardiovascular ( HR = 1.52 ; 95 % CI = 1.20 - 1.93 ) and all-cause mortality ( HR = 1.50 ; 95 % CI = 1.29 - 1.73 ) . However , when the newly diagnosed group was compared with the no diabetes group , no significant difference was observed in cardiovascular ( HR = 0.33 ; 95 % CI = 0.11 - 1.05 ) or all-cause mortality ( HR = 0.76 ; 95 % CI = 0.47 - 1.23 ) either during the ANBP2 trial or including post-trial follow-up ( cardiovascular : HR = 0.82 ; 95 % CI = 0.58 - 1.17 ; all-cause mortality : HR = 1.04 ; 95 % CI = 0.85 - 1.27 ) . CONCLUSIONS Long-term presence of diabetes reduces survival . Compared with thiazide diuretics , ACEI-based antihypertensives may delay the development of diabetes in those at risk and thus potentially improve cardiovascular outcome in the elderly No adverse effect upon cognitive function has been detected during the first 9 months of treatment by a thiazide diuretic ( Moduretic ; Merck Sharp & Dohme , Hoddesdon , UK ) or a beta-blocking agent ( atenolol ) of moderately elevated blood pressure in a cohort of 2630 men and women aged between 65 and 74 years . Furthermore , no association was discovered between levels of systolic or diastolic blood pressure at outset and responses to st and ard tests of cognitive function . This study was carried out in general practice s as part of the current Medical Research Council Treatment Trial of Mild Hypertension in the Elderly We investigated serum glucose and insulin levels result ing from thiazide or thiazide-like diuretic administration and determined whether they were associated with serum or intracellular potassium or magnesium values . We also explored the role of obesity both alone and with thiazides on serum insulin and glucose . Hypertensive men were withdrawn from  diuretics  and repleted with oral potassium and magnesium and then r and omized to 2 months of treatment with ( 1 ) hydrochlorothiazide , ( 2 ) hydrochlorothiazide with oral potassium , ( 3 ) hydrochlorothiazide with oral potassium and magnesium ( 4 ) hydrochlorothiazide and triamterene , ( 5 ) chlorthalidone , or ( 6 ) placebo . Serum was available from 202 participants for insulin and glucose determinations . Mean fasting serum glucose and insulin did not change significantly after 2 months of r and omized therapy with the exception of participants r and omized to chlorthalidone , who had significant increases in both serum insulin and glucose ( P < .05 and P < .01 , respectively ) . As body mass index increased , there was a corresponding increase in serum insulin and to a lesser degree in serum glucose . Also , as body mass index increased , participants taking hydrochlorothiazide had a corresponding increase of serum insulin ( P < .05 ) . After treatment , intracellular potassium and magnesium were both associated with higher serum insulin ( P < .001 for each ) , and serum potassium was associated with higher and serum magnesium with lower serum glucose ( P < .01 for each ) . In most hypertensive men , treatment with 50 mg chlorthalidone increases glucose and insulin levels , whereas administration of 50 mg hydrochlorothiazide , with or without potassium and /or magnesium conserving strategies , does not . ( ABSTRACT TRUNCATED AT 250 WORDS AIMS It has been suggested that the adverse metabolic effects of antihypertensive therapy offset some of the benefits of blood pressure reduction . It has also been suggested that angiotensin converting enzyme ( ACE ) inhibitors reduce insulin resistance and that , if used together with thiazide diuretics , the adverse effects of thiazides on insulin sensitivity may be eliminated . We examined the effects on insulin sensitivity of captopril either alone or in combination with bendrofluazide in 11 hypertensive Type 2 diabetic patients . METHODS Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind , r and omized , crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril ( C ) ( 100 mg ) alone or in combination with bendrofluazide ( CB ) ( 2.5 mg ) . RESULTS Blood pressure was lower following CB compared to C ( 128/82 vs. 144/ 88 mmHg ; P<0.005 ) and both were lower than baseline ( 162/101 mmHg ; P < 0.001 ) . CB result ed in a significant increase in fasting plasma glucose compared to C ( 9.7+/-0.8 vs. 8.5+/-0.6 mmol/ ; P < 0.05 ) . Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C ( 22.3+/-2.4 vs. 27.4+/-4.2 mol x kg(-1 ) x min(-1 ) ; P < 0.05 ) . Suppression of endogenous glucose production was reduced after CB compared to baseline ( 4.0+/-0.6 vs. 2.4+/-0.5 mol x kg(-1 ) x min(-1 ) ; P < 0.05 ) . CONCLUSIONS Combination of bendrofluazide with captopril lowered blood pressure but result ed in deleterious effects on insulin action compared to captopril alone CONTEXT Few cardiovascular outcome data are available for blacks with hypertension treated with angiotensin-converting enzyme ( ACE ) inhibitors or calcium channel blockers ( CCBs ) . OBJECTIVE To determine whether an ACE inhibitor or CCB is superior to a thiazide-type diuretic in reducing cardiovascular disease ( CVD ) incidence in racial subgroups . DESIGN , SETTING , AND PARTICIPANTS Prespecified subgroup analysis of ALLHAT , a r and omized , double-blind , active-controlled , clinical outcome trial conducted between February 1994 and March 2002 in 33,357 hypertensive US and Canadian patients aged 55 years or older ( 35 % black ) with at least 1 other cardiovascular risk factor . INTERVENTIONS Antihypertensive regimens initiated with a CCB ( amlodipine ) or an ACE inhibitor ( lisinopril ) vs a thiazide-type diuretic ( chlorthalidone ) . Other medications were added to achieve goal blood pressures ( BPs ) less than 140/90 mm Hg . MAIN OUTCOME MEASURES The primary outcome was combined fatal coronary heart disease ( CHD ) or nonfatal myocardial infa rct ion ( MI ) , analyzed by intention-to-treat . Secondary outcomes included all-cause mortality , stroke , combined CVD ( CHD death , nonfatal MI , stroke , angina , coronary revascularization , heart failure [ HF ] , or peripheral vascular disease ) , and end-stage renal disease . RESULTS No significant difference was found between treatment groups for the primary CHD outcome in either racial subgroup . For amlodipine vs chlorthalidone only , HF was the only prespecified clinical outcome that differed significantly ( overall : relative risk [ RR ] , 1.37 ; 95 % confidence interval [ CI ] , 1.24 - 1.51 ; blacks : RR , 1.46 ; 95 % CI , 1.24 - 1.73 ; nonblacks : RR , 1.32 ; 95 % CI , 1.17 - 1.49 ; P<.001 for each comparison ) with no difference in treatment effects by race ( P = .38 for interaction ) . For lisinopril vs chlorthalidone , results differed by race for systolic BP ( greater decrease in blacks with chlorthalidone ) , stroke , and combined CVD outcomes ( P<.001 , P = .01 , and P = .04 , respectively , for interactions ) . In blacks and nonblacks , respectively , the RRs for stroke were 1.40 ( 95 % CI , 1.17 - 1.68 ) and 1.00 ( 95 % CI , 0.85 - 1.17 ) and for combined CVD were 1.19 ( 95 % CI , 1.09 - 1.30 ) and 1.06 ( 95 % CI , 1.00 - 1.13 ) . For HF , the RRs were 1.30 ( 95 % CI , 1.10 - 1.54 ) and 1.13 ( 95 % CI , 1.00 - 1.28 ) , with no significant interaction by race . Time-dependent BP adjustment did not significantly alter differences in outcome for lisinopril vs chlorthalidone in blacks . CONCLUSIONS In blacks and nonblack subgroups , rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary CHD or any other prespecified clinical outcome , and diuretic-based treatment result ed in the lowest risk of heart failure . While the improved outcomes with chlorthalidone were more pronounced for some outcomes in blacks than in nonblacks , thiazide-type diuretics remain the drugs of choice for initial therapy of hypertension in both black and nonblack hypertensive patients BACKGROUND Increasing concern over long-term drug treatment of mild hypertension has stimulated several studies of weight reduction . Phase I of the Trial of Antihypertensive Interventions and Management demonstrated a short-term effect of weight loss on blood pressure control in overweight persons with mild hypertension , who were either taking placebo or taking low-dose monotherapy .  Phase II investigates the long-term benefit of weight loss on the ability to maintain blood pressure control . METHODS From 10148 community-based screenees , 587 persons ( 5.8 % ) , aged 21 to 65 years , entered a multicenter , r and omized drug ( double-blind , placebo-controlled ) and diet trial . Participants had a diastolic blood pressure between 90 and 100 mm Hg and were at 110 % to 160 % of their ideal weight . They were r and omized to a usual diet ( n = 296 ) or to a weight loss diet ( n = 291 ) and within each diet group to placebo , chlorthalidone , 25 mg/d , or atenolol , 50 mg/d . Treatment failure was defined as using additional antihypertensive medications if diastolic blood pressure rose above 90 mm Hg according to protocol -specified criteria . RESULTS At baseline ,  mean diastolic blood pressure was 93 mm Hg ; systolic blood pressure  , 143 mm Hg ; weight , 88 kg ; percent ideal weight , 137 % ; age , 48 years ; 56 % were men ; and 33 % were black . Mean follow-up was 4.5 years . There was a net loss of 2 to 3 kg with weight loss diet compared with usual diet over most of the follow-up period . The 5-year incidence of treatment failure was 56.7 per 100 participants with usual diet and 49.8 per 100 with weight loss . Long-term weight loss decreased failure of blood pressure control for those receiving placebo or low-dose diuretic or beta-blocker by 23 % . The results were similar in direction in each drug group . CONCLUSIONS The Trial of Antihypertensive Interventions and Management demonstrated that weight reduction is an effective long-term therapy for maintaining blood pressure in the normal range when used as monotherapy or in combination with either thiazide diuretics or beta-blockers . Consequently , weight loss should be recommended for the management of obese individuals with mild hypertension Hypertension is the most common condition seen in primary care and leads to myocardial infa rct ion , stroke , renal failure , and death if not detected early and treated appropriately . Patients want to be assured that blood pressure ( BP ) treatment will reduce their disease burden , while clinicians want guidance on hypertension management using the best scientific evidence . This report takes a rigorous , evidence -based approach to recommend treatment thresholds , goals , and medications in the management of hypertension in adults . Evidence was drawn from r and omized controlled trials , which represent the gold st and ard for determining efficacy and effectiveness . Evidence quality and recommendations were grade d based on their effect on important outcomes . There is strong evidence to support treating hypertensive persons aged 60 years or older to a  BP goal  of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg ; however , there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal , or in those younger than 30 years for a diastolic goal , so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion . The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease ( CKD ) as for the general hypertensive population younger than 60 years . There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor , angiotensin receptor blocker , calcium channel blocker , or thiazide-type diuretic in the nonblack hypertensive population , including those with diabetes . In the black hypertensive population , including those with diabetes , a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy . There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes . Although this guideline provides evidence -based recommendations for the management of high BP and should meet the clinical needs of most patients , these recommendations are not a substitute for clinical judgment , and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient To determine whether the combination of nifedipine + chlorthalidone exerts an additive antihypertensive effect when compared with single-drug treatment , we studied 66 uncomplicated essential hypertensives , with diastolic blood pressure of greater than 100 and less than 115 mmHg . At the end of a 1-month washout placebo period , using a double-blind crossover design , the patients were r and omly allocated to nifedipine ( 20 mg twice a day ) , chlorthalidone ( 25 mg once a day ) , the two drugs combined at the same doses and the corresponding placebo . Compared with the r and omly allocated placebo , the three active treatments significantly reduced blood pressure without changing the heart rate or body weight . Both the absolute and percentage decreases in mean blood pressure induced by nifedipine and the combination compared with placebo were similar and significantly greater than those induced by chlorthalidone . Taken together , these data show that the combination of nifedipine + chlorthalidone does not exert any additive antihypertensive effect compared with nifedipine alone . This finding indicates that the combination of a dihydropyridine calcium antagonist + a thiazide diuretic is probably devoid of any particular clinical significance in the treatment of uncomplicated essential hypertensives BACKGROUND Although high blood pressure is associated with significant morbidity and mortality , the proportion reaching the goal blood pressures as outlined in the Seventh Report of the Joint National Committee on Prevention , Detection , Evaluation , Treatment of High Blood Pressure ( JNC 7 ) is low . We conducted a r and omized trial in primary care practice s of a multifactorial intervention targeted to improve providers ' adherence to hypertension guidelines . METHOD A total of 61 primary care practice s in North Carolina were r and omized to receive either a multifactorial intervention ( guideline dissemination via a continuing medical education session , academic detailing sessions , audit and feedback on preintervention rates of adherence , and automated blood pressure machines ) or an attention control of similar magnitude but targeted at a different guideline . Outcomes were determined through review of patient charts conducted by an independent masked quality assurance organization . RESULTS We found no difference between the 2 groups in any of the adherence measures including no difference in the percentage of patients at goal ( intervention 49.2 % , control 50.6 % ) , with undiagnosed hypertension  ( 18.1 % vs 13.6 % ) , average systolic ( 126 vs 125.1 mm Hg ) , or diastolic blood pressure ( 73.1 vs 73.4 mm Hg ) . Similarly , there was no difference in provider adherence to treatment recommendations ( use of thiazide-type diuretic as first-line therapy : 32 % vs 29.5 % ; use of 2-drug therapy in stage 2 hypertension : 11.3 % vs 10.4 % ) . CONCLUSION An intensive , multifactorial intervention did not improve adherence to national hypertension guidelines among community-based primary care . Efforts should be focused on other types of interventions to improve rates of control of hypertension BACKGROUND The optimal combination drug therapy for hypertension is not established , although current U.S. guidelines recommend inclusion of a diuretic . We hypothesized that treatment with the combination of an angiotensin-converting-enzyme ( ACE ) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic . METHODS In a r and omized , double-blind trial , we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide . The primary end point was the composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for angina , resuscitation after sudden cardiac arrest , and coronary revascularization . RESULTS The baseline characteristics of the two groups were similar . The trial was terminated early after a mean follow-up of 36 months , when the boundary of the prespecified stopping rule was exceeded . Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group . There were 552 primary - outcome events in the benazepril-amlodipine group ( 9.6 % ) and 679 in the benazepril-hydrochlorothiazide group ( 11.8 % ) , representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2 % and a relative risk reduction of 19.6 % ( hazard ratio , 0.80 , 95 % confidence interval [ CI ] , 0.72 to 0.90 ; P<0.001 ) . For the secondary end point of death from cardiovascular causes , nonfatal myocardial infa rct ion , and nonfatal stroke , the hazard ratio was 0.79 ( 95 % CI , 0.67 to 0.92 ; P=0.002 ) . Rates of adverse events were consistent with those observed from clinical experience with the study drugs . CONCLUSIONS The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events . ( Clinical Trials.gov number , NCT00170950 . BACKGROUND The combination of three blood-pressure-lowering drugs at low doses , with a statin , aspirin , and folic acid ( the polypill ) , could reduce cardiovascular events by more than 80 % in healthy individuals . We examined the effect of the Polycap on blood pressure , lipids , heart rate , and urinary thromboxane B2 , and assessed its tolerability . METHODS In a double-blind trial in 50 centres in India , 2053 individuals without cardiovascular disease , aged 45 - 80 years , and with one risk factor were r and omly assigned , by a central secure website , to the Polycap ( n=412 ) consisting of low doses of thiazide ( 12.5 mg ) , atenolol ( 50 mg ) , ramipril ( 5 mg ) , simvastatin ( 20 mg ) , and aspirin ( 100 mg ) per day , or to eight other groups , each with about 200 individuals , of aspirin alone , simvastatin alone , hydrochlorthiazide alone , three combinations of the two blood-pressure-lowering drugs , three blood-pressure-lowering drugs alone , or three blood-pressure-lowering drugs plus aspirin . The primary outcomes were LDL for the effect of lipids , blood pressure for antihypertensive drugs , heart rate for the effects of atenolol , urinary 11-dehydrothromboxane B2 for the antiplatelet effects of  aspirin , and rates of discontinuation of drugs for safety . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00443794 . FINDINGS Compared with groups not receiving blood-pressure-lowering drugs , the Polycap reduced systolic blood pressure by 7.4 mm Hg ( 95 % CI 6.1 - 8.1 ) and diastolic blood pressure by 5.6 mm Hg ( 4.7 - 6.4 ) , which was similar when three blood-pressure-lowering drugs were used , with or without aspirin . Reductions in blood pressure increased with the number of drugs used ( 2.2/1.3 mm Hg with one drug , 4.7/3.6 mm Hg with two drugs , and 6.3/4.5 mm Hg with three drugs ) . Polycap reduced LDL cholesterol by 0.70 mmol/L ( 95 % CI 0.62 - 0.78 ) , which was less than that with simvastatin alone ( 0.83 mmol/L , 0.72 - 0.93 ; p=0.04 ) ; both reductions were greater than for groups without simvastatin ( p<0.0001 ) . The reductions in heart rate with Polycap and other groups using atenolol were similar ( 7.0 beats per min ) , and both were significantly greater than that in groups without atenolol ( p<0.0001 ) . The reductions in 11-dehydrothromboxane B2 were similar with the Polycap ( 283.1 ng/mmol creatinine , 95 % CI 229.1 - 337.0 ) compared with the three blood-pressure-lowering drugs plus aspirin ( 350.0 ng/mmol creatinine , 294.6 - 404.0 ) , and aspirin alone ( 348.8 ng/mmol creatinine , 277.6 - 419.9 ) compared with groups without aspirin . Tolerability of the Polycap was similar to that of other treatments , with no evidence of increasing intolerability with increasing number of active components in one pill . INTERPRETATION This Polycap formulation could be conveniently used to reduce multiple risk factors and cardiovascular risk The Combination Therapy of Hypertension to Prevent Cardiovascular Events ( COPE ) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker ( ARB ) , a β-blocker , or a thiazide diuretic ( thiazide ) were similarly effective in preventing cardiovascular events and achieving the target blood pressure ( BP ; < 140/90 mm Hg ) . We further evaluated the efficacy and safety of these combination therapies in older ( ⩾65 years ) and younger ( < 65 years ) hypertensive patients . In this sub- analysis of the COPE trial 3293 patients ( 1533⩾65 years old and 1760 < 65 years old ) were r and omly assigned to receive benidipine-based therapy with an ARB , a β-blocker or a thiazide . In each group , the average BP did not differ among the three treatment groups . The incidence of the primary cardiovascular composite end point in the older group was higher than in the younger group ( 12.7 vs. 8.3 per 1000 person-years , P=0.023 ) . The primary composite cardiovascular end point , achievement ( % ) of target BP , and cardiovascular hard composite end points were similar among the three treatment groups . However , the hazard ratios and 95 % confidence intervals in older patients were 2.74 ( 1.08–6.96 ; β-blocker vs. thiazide , P=0.022 ) for fatal and non-fatal stroke , and 2.47 ( 1.03–5.91 ; β-blocker vs. ARB , P=0.043 ) for new-onset diabetes . Thus , benidipine combined with an ARB , a β-blocker , or a thiazide was similarly effective in preventing cardiovascular events and achieving the target BP in both older and younger hypertensive patients . Further studies will be necessary to evaluate the usefulness of benidipine combined with a β-blocker in terms of the incidence of stroke and new-onset diabetes in older patients OBJECTIVE ACE inhibitors and calcium antagonists may favorably affect serum lipids and glucose metabolism . The primary aim of the Fosinopril Versus Amlodipine Cardiovascular Events R and omized Trial ( FACET ) was to compare the effects of fosinopril and amlodipine on serum lipids and diabetes control in NIDDM patients with hypertension . Prospect ively defined cardiovascular events were assessed as secondary outcomes . RESEARCH DESIGN AND METHODS Inclusion criteria included a diagnosis of NIDDM and hypertension ( systolic blood pressure of > 140 mmHg or diastolic blood pressure of > 90 mmHg ) . Exclusion criteria included a history of coronary heart disease or stroke , serum creatinine > 1.5 mg/dl , albuminuria > 40 μg/min , and use of lipid-lowering drugs , aspirin , or antihypertensive agents other than beta-blockers or diuretics . A total of 380 hypertensive diabetics were r and omly assigned to open-label fosinopril ( 20 mg/day ) or amlodipine ( 10 mg/day ) and followed for up to 3.5 years . If blood pressure was not controlled , the other study drug was added . RESULTS Both treatments were effective in lowering blood pressure . At the end of followup , between the two groups there was no significant difference in total serum cholesterol , HDL cholesterol , HbA1c , fasting serum glucose , or plasma insulin . The patients receiving fosinopril had a significantly lower risk of the combined outcome of acute myocardial infa rct ion , stroke , or hospitalized angina than those receiving amlodipine ( 14/189 vs. 27/191 ; hazards ratio = 0.49 , 95 % CI = 0.26–0.95 ) . CONCLUSIONS Fosinopril and amlodipine had similar effects on biochemical measures , but the patients r and omized to fosinopril had a significantly lower risk of major vascular events , compared with the patients r and omized to amlodipine We performed a prospect i ve crossover study in 73 essential hypertensives to compare the effects of c and esartan and lisinopril on ambulatory blood pressure ( BP ) and early-morning BP . Twenty-four-hour ambulatory BP monitoring was performed at baseline and for each active treatment . Small doses of thiazide diuretic were added as needed . The effects of both drugs on 24-hour BP were almost identical and satisfactory . When we classified patients into the morning surge group ( the highest quartile of morning systolic BP surge > 36 mm Hg ) and the non-morning surge group ( the remaining 3 quartiles of morning BP surge ) , c and esartan was superior in decreasing morning BP and morning BP surge Objective : This study compares the antihypertensive efficacy and tolerability of valsartan , a novel angiotensin II antagonist , given with hydrochlorothiazide ( HCTZ ) vs placebo or vs valsartan or HCTZ alone . Design : 871 adult out- patients with essential hypertension participated in this double-blind study . Patients were r and omised in equal number to receive either combination therapy of valsartan ( 80 mg or 160 mg ) and HCTZ ( 12.5 mg or 25 mg ) , or valsartan ( 80 mg or 160 mg ) or HCTZ ( 12.5 mg or 25 mg ) alone , or placebo . Patients were treated once daily for 8 weeks and assessed at 2 , 4 and 8 weeks after r and omisation . Main outcome measures : The primary efficacy variable was change from baseline in mean sitting diastolic blood pressure ( MSDBP ) at end-point . The secondary variable was change in mean sitting systolic blood pressure ( MSSBP ) from baseline to end-point . Results : All active treatments produced a statistically significant difference in MSDBP ( P < 0.001 ) from baseline to end-point compared with placebo . similar results were obtained for mssbp . all combination regimens produced a statistically significantly greater reduction in msdpb and mssbp than the corresponding monotherapies . dizziness and headache were the most common treatment-related adverse experiences reported . hypokalaemia , associated with the use of thiazide diuretics , was more commonly reported in the higher dose hctz 25 mg groups . Conclusions : Valsartan 80 mg and 160 mg act additively with HCTZ 12.5 mg or 25 mg to lower MSDBP and MSSBP in patients with essential hypertension . The addition of HCTZ to valsartan 80 mg or 160 mg was well tolerated BACKGROUND Obesity is a highly prevalent medical condition and is commonly accompanied by hypertension . This study assessed the efficacy and safety of treatment with sibutramine hydrochloride for promoting and maintaining weight loss in obese patients with controlled hypertension , including a subset analysis of African American patients . PATIENTS AND METHODS Obese patients with a body mass index ( BMI , calculated as weight in kilograms divided by the square of height in meters ) between 27 and 40 and a history of hypertension controlled with a calcium channel blocker ( with or without concomitant thiazide diuretic treatment ) were r and omized to receive sibutramine ( n = 150 ) or placebo ( n = 74 ) with minimal behavioral intervention for 52 weeks . African Americans constituted 36 % of enrolled patients . Efficacy assessment s were body weight and related parameters ( BMI and waist and hip circumferences ) , metabolic parameters ( serum levels of triglycerides , high-density lipoprotein cholesterol [ HDL-C ] , low-density lipoprotein cholesterol [ LDL-C ] , total cholesterol , glucose , and uric acid ) , and quality -of-life measures . Safety assessment s included recording of blood pressure , pulse rate , adverse events , and reasons for discontinuation . RESULTS For patients receiving sibutramine , weight loss occurred during the first 6 months of the trial and was maintained to the end of the 12-month treatment period . Among patients receiving sibutramine , 40.1 % lost 5 % or more of body weight ( 5 % responders ) and 13.4 % lost 10 % or more of body weight ( 10 % responders ) compared with 8.7 % and 4.3 % of patients in the placebo group , respectively ( P<.05 ) . Changes in body weight were similar among African Americans and whites . Sibutramine-induced  weight loss was associated with significant improvements in serum levels of triglycerides , HDL-C , glucose , and uric acid . Waist circumference and quality -of-life measures also improved significantly in patients receiving sibutramine . Sibutramine-treated patients had small but statistically significant mean increases in diastolic blood pressure ( 2.0 mm Hg ) and pulse rate ( 4.9 beats/min ) compared with placebo-treated patients ( -1.3 mm Hg and 0.0 beats/min ; P<.05 ) ; these changes were similar among African Americans and whites . Most adverse events were mild to moderate in severity and transient . The most common adverse event result ing in discontinuation among patients receiving sibutramine was hypertension ( 5.3 % of patients receiving sibutramine vs 1.4 % of patients receiving placebo ) . CONCLUSIONS In obese patients with controlled hypertension , sibutramine was an effective and well-tolerated treatment for weight loss and maintenance .  Sibutramine-induced  weight loss result ed in improvements in serum levels of triglycerides , HDL-C , uric acid , and glucose , and in waist circumference and quality -of-life measures . Blood pressure and heart rate increased by a small amount . Efficacy and safety profiles for sibutramine among African American and white obese patients with controlled hypertension were similar 1 A placebo-controlled , r and omised double-blind comparison of captopril 25 mg three times a day , hydrochlorothiazide 15 mg three times a day , and the combination was conducted in 207 patients with essential hypertension with supine diastolic blood pressures of 92 - 110 mm Hg . Significant decreases in blood pressure were seen in all three groups ; the magnitude of decrease seen with captopril and hydrochlorothiazide was similar , while the combination produced an additive response greater ( p less than 0.001 ) than captopril or hydrochlorothiazide alone . 2 The major side effect reported was a rash in fewer than 6 % of patients taking  captopril  alone or in combination . Loss of taste or proteinuria was not observed . 3 The addition of captopril of hydrochlorothiazide blunted the hypokalaemia and hyperuricaemia observed with hydrochlorothiazide alone in addition to its antihypertensive synergy . These observations indicate that this relatively low dose of captopril is safe and efficacious in the treatment of mild to moderate hypertension alone and particularly when combined with a thiazide diuretic BACKGROUND Elevated blood glucose levels are reported with thiazide-type diuretic treatment of hypertension . The significance of this finding is uncertain . Our objectives were to compare the effect of first-step antihypertensive drug therapy with thiazide-type diuretic , calcium-channel blocker , or angiotensin-converting enzyme inhibitor on fasting glucose ( FG ) levels and to determine cardiovascular and renal disease risks associated with elevated FG levels and incident diabetes mellitus ( DM ) in 3 treatment groups . METHODS We performed post hoc subgroup analyses from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) among nondiabetic participants who were r and omized to receive treatment with chlorthalidone ( n = 8419 ) , amlodipine ( n = 4958 ) , or lisinopril ( n = 5034 ) and observed for a mean of 4.9 years . RESULTS Mean FG levels increased during follow-up in all treatment groups . At year 2 , those r and omized to the chlorthalidone group had the greatest increase ( + 8.5 mg/dL [ 0.47 mmol/L ] vs + 5.5 mg/dL [ 0.31 mmol/L ] for amlodipine and + 3.5 mg/dL [ 0.19 mmol/L ] for lisinopril ) . The odds ratios for developing DM with lisinopril ( 0.55 [ 95 % confidence interval , 0.43 - 0.70 ] ) or amlodipine ( 0.73 [ 95 % confidence interval , 0.58 - 0.91 ] ) vs chlorthalidone at 2 years were significantly lower than 1.0 ( P<.01 ) . There was no significant association of FG level change at 2 years with subsequent coronary heart disease , stroke , cardiovascular disease , total mortality , or end-stage renal disease . There was no significant association of incident DM at 2 years with clinical outcomes , except for coronary heart disease ( risk ratio , 1.64 ; P = .006 ) , but the risk ratio was lower and nonsignificant in the chlorthalidone group ( risk ratio , 1.46 ; P = .14 ) . CONCLUSIONS Fasting glucose levels increase in older adults with hypertension regardless of treatment type . For those taking chlorthalidone vs other medications , the risk of developing FG levels higher than 125 mg/dL ( 6.9 mmol/L ) is modestly greater , but there is no conclusive or consistent evidence that this diuretic-associated increase in DM risk increases the risk of clinical events In a joint Veterans Administration-National Heart , Lung , and Blood Institute study of mild hypertension , 1,012 men and women , 21 to 50 years of age and with diastolic pressure from 85 to 105 mm Hg , were r and omized into two double-blind treatment groups . Subjects in the active group received chlorthalidone or chlorthalidone plus reserpine , while the other subjects received matching placebo tablets . After one year of treatment , the chlorthalidone group had increases of 10.0 + /- 1.8 ( SE ) mg/dL in total cholesterol level , 9.8 + /- 5.2 mg/dL in triglyceride level , and 12.6 + /- 3.4 mg/dL in low-density lipoprotein-cholesterol level above the changes in the placebo group . There was no difference in high-density lipoprotein changes between the two groups ( 0.1 + /- 0.8 mg/dL ) . The possible net effect on risk of increasing lipid values while lowering pressure in the long-term treatment of mild hypertension with thiazides or related diuretics must be further evaluated We examined the biochemical changes and the efficacy of indapamide in the prevention of  calcium stone recurrences . Seventy-five patients with calcium nephrolithiasis and hypercalciuria were r and omly assigned to three different therapies : diet and fluid ( group A ) , diet and fluid plus indapamide 2.5 mg/day ( group B ) . and diet and fluid plus indapamide 2.5 mg/day plus allopurinol 300 mg/day ( group C ) . Before treatment and after 6 , 12 , 24 , and 36 months of therapy , we evaluated blood pressure , serum and urine risk parameters ( including relative supersaturations of calcium oxalate . calcium phosphate and uric acid ) , stone rate , and the proportion of calculi-free patients .  During the 3 years of treatment , urinary calcium greatly decreased in groups B and C. dropping to 50 % of the pretreatment values : urinary oxalate also significantly declined in group B ( - 24 % ) and group C ( -27 % ) . Relative supersaturations of calcium oxalate and calcium phosphate decreased to the same extent in groups B and C ( about one-half of the pretreatment value ) , and relative supersaturation of uric acid was particularly reduced in group C ( -65 % of the pretreatment value ) . The stone rate improved in all three groups ( p > 0.005 ) . but using actuarial analysis in the evaluation of calculi-free patients , indapamide , and indapamide plus allopurinol groups were found to have a significantly more favorable effect than diet and fluid treatment ( p > 0.02 ) , without any difference between the two drug groups . Because indapamide has fewer side effects than thiazide diuretics , we conclude that indapamide could be an interesting alternative to thiazides in the prevention of calcium stones in hypercalciuric patients OBJECTIVE To provide up date d , evidence -based recommendations for the therapy of hypertension in adults . OPTIONS For patients with hypertension , a number of antihypertensive agents may control blood pressure . R and omized trials evaluating first-line therapy with thiazides , beta-adrenergic antagonists , angiotensin-converting enzyme inhibitors , calcium channel blockers , alpha-blockers , central ly acting agents or angiotensin II receptor antagonists were review ed . OUTCOMES The health outcomes that were considered were changes in blood pressure , cardiovascular morbidity , and cardiovascular and /or all-cause mortality rates . Economic outcomes were not considered due to insufficient evidence . EVIDENCE MEDLINE was search ed for the period March 1999 to October 2001 to identify studies not included in the 2000 revision of the Canadian Recommendations for the Management of Hypertension . Reference lists were scanned , experts were polled , and the personal files of the subgroup members and authors were used to identify other published studies . All relevant articles were review ed and appraised , using prespecified levels of evidence , by content experts and method ological experts . VALUES A high value was placed on the avoidance of cardiovascular morbidity and mortality . BENEFITS , HARMS AND COSTS Various antihypertensive agents reduce the blood pressure of patients with sustained hypertension . In certain setting s , and for specific classes of drugs , blood-pressure lowering has been associated with reduced cardiovascular morbidity and /or mortality . RECOMMENDATIONS The present document contains detailed recommendations pertaining to treatment thresholds , target blood pressures , and choice of agents in various setting s in patients with hypertension . The main changes from the 2000 Recommendations are the addition of a section on the treatment of hypertension in patients with diabetes mellitus , the amalgamation of the previous sections on treatment of hypertension in the young and old into one section , increased emphasis on the role of combination therapies over repeated trials of single agents and expansion of the section on the treatment of hypertension after stroke . Implicit in the recommendations for therapy is the principle that treatment for an individual patient should take into consideration global cardiovascular risk , the presence and /or absence of target organ damage , and comorbidities . VALIDATION All recommendations were grade d according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group . Individuals with potential conflicts of interest relative to any specific recommendation were excluded from voting on that recommendation . Only those recommendations achieving high levels of consensus are reported here . These guidelines will continue to be up date d annually BACKGROUND No reduction in either coronary mortality or sudden cardiac death ( SCD ) has been demonstrated in overviews of r and omized trials of treatment of hypertension with diuretics . METHODS An overview was conducted of coronary mortality and SCD in r and omized controlled antihypertensive trials in which an  epithelial sodium channel ( ENaC ) inhibitor/ hydrochlorthiazide ( HCTZ ) combination was used . Secondarily , an analogous overview in which thiazide diuretic was used alone was performed . R and omized trials that used an ENaC inhibitor/ HCTZ combination ( or , alternatively , thiazide diuretic alone ) were identified from previous meta-analyses , search es of PubMed , search of the Cochrane Clinical Trials data base , and review of publications that addressed the consequences of treating hypertension . Trials in which participants were r and omized to either an ENaC inhibitor combined with a thiazide diuretic ( or to a thiazide diuretic alone ) or to control treatment for at least one year and in which coronary mortality was reported were included . Numbers of events in individual trials were abstract ed independently by 2 authors . RESULTS Significant reductions in both coronary mortality and SCD were observed in the overview of trials in which elderly patients received an ENaC inhibitor/ HCTZ combination . The odds ratio ( OR ) for coronary mortality was 0.59 ( 95 % confidence interval [ CI ] 0.44 , 0.78 ) and for SCD was 0.60 ( 95 % CI 0.38 , 0.94 ) . In contrast , an overview of the trials using thiazide diuretics alone showed no significant reductions of either coronary mortality ( OR 0.94 ; 95 % CI 0.81 , 1.09 ) or SCD ( OR 1.27 ; 95 % CI 0.93 , 1.75 ) . CONCLUSIONS Use of an ENaC inhibitor combined with HCTZ for treatment of hypertension in the elderly results in favorable effects on coronary mortality and SCD CONTEXT Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality , but the optimal first-step therapy is unknown . OBJECTIVE To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease ( CHD ) or other cardiovascular disease ( CVD ) events vs treatment with a diuretic . DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , active-controlled clinical trial conducted from February 1994 through March 2002 . SETTING AND PARTICIPANTS A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers . INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n = 15 255 ) ; amlodipine , 2.5 to 10 mg/d ( n = 9048 ) ; or lisinopril , 10 to 40 mg/d ( n = 9054 ) for planned follow-up of approximately 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome was combined fatal CHD or nonfatal myocardial infa rct ion , analyzed by intent-to-treat . Secondary outcomes were all-cause mortality , stroke , combined CHD ( primary outcome , coronary revascularization , or angina with hospitalization ) , and combined CVD ( combined CHD , stroke , treated angina without hospitalization , heart failure [ HF ] , and peripheral arterial disease ) . RESULTS Mean follow-up was 4.9 years . The primary outcome occurred in 2956 participants , with no difference between treatments . Compared with chlorthalidone ( 6-year rate , 11.5 % ) , the relative risks ( RRs ) were 0.98 ( 95 % CI , 0.90 - 1.07 ) for amlodipine ( 6-year rate , 11.3 % ) and 0.99 ( 95 % CI , 0.91 - 1.08 ) for lisinopril ( 6-year rate , 11.4 % ) . Likewise , all-cause mortality did not differ between groups . Five-year systolic blood pressures were significantly higher in the amlodipine ( 0.8 mm Hg , P = .03 ) and lisinopril ( 2 mm Hg , P<.001 ) groups compared with chlorthalidone , and 5-year diastolic blood pressure was significantly lower with amlodipine ( 0.8 mm Hg , P<.001 ) . For amlodipine vs chlorthalidone , secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine ( 10.2 % vs 7.7 % ; RR , 1.38 ; 95 % CI , 1.25 - 1.52 ) . For lisinopril vs chlorthalidone , lisinopril had higher 6-year rates of combined CVD ( 33.3 % vs 30.9 % ; RR , 1.10 ; 95 % CI , 1.05 - 1.16 ) ; stroke ( 6.3 % vs 5.6 % ; RR , 1.15 ; 95 % CI , 1.02 - 1.30 ) ; and HF ( 8.7 % vs 7.7 % ; RR , 1.19 ; 95 % CI , 1.07 - 1.31 ) . CONCLUSION Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive . They should be preferred for first-step antihypertensive therapy 1 . Although it is now easy to treat most patients with hypertension without producing troublesome side effects , a few patients remain refractory to conventional methods of treatment . These patients will progress to die of renal failure unless the blood pressure is controlled . 2 . Thiazides potentiate the effect of other hypotensive agents and this potentiation is probably independent of their diuretic action . Diazoxide actually produces salt and water retention at the same time as marked decrease in the blood pressure .  Spirono-lactone in a dose of 400 mg daily produced a highly significant reduction in blood pressure in an unselected group of patients with severe refractory hypertension . 3 . β-Adrenergic blocking agents either alone or in combination with other drugs may be useful in the control of severe hypertension . An increasing effect on the blood pressure was demonstrated with doses between 1 and 2 g per day . 4 . A new drug , prazosin hydrochloride , with properties somewhat similar to hydrallazine but with few side effects promises to be useful in the control of severe refractory hypertension particularly in combination with β-adrenergic blocking drugs BACKGROUND Hypertension is a common comorbidity in patients with type 2 diabetes mellitus and a major risk factor for microvascular and macrovascular disease . Although the blood pressure-lowering effects of sodium-glucose cotransporter 2 ( SGLT2 ) inhibitors are already established , guidance is needed on how to use these drugs in patients already receiving antihypertensive therapy . We aim ed to compare blood pressure and glycaemic effects of the SGLT2 inhibitor dapagliflozin with placebo in patients with inadequately controlled type 2 diabetes mellitus and hypertension . METHODS In this double-blind , placebo-controlled , phase 3 study we enrolled patients from 311 centres in 16 countries across five continents . Patients had uncontrolled type 2 diabetes ( HbA1c 7·0%-10·5 % ; 53 - 91 mmol/mol ) and hypertension ( systolic 140 - 165 mm Hg and diastolic 85 - 105 mm Hg at both enrolment and r and omisation , and a mean 24 h blood pressure of ≥130/80 mm Hg by ambulatory monitoring within 1 week of r and omisation ) and were receiving oral antihyperglycaemic drugs , insulin , or both  , plus a renin-angiotensin system blocker and an additional antihypertensive drug . Using an interactive voice-response system , we r and omly assigned ( 1:1 ) patients to dapagliflozin 10 mg once a day or to placebo , with r and omisation stratified by additional antihypertensive drug use and insulin use at baseline , in a block size of two . The co- primary endpoints were changes in seated systolic blood pressure and HbA1c measured in the full analysis set , which included all patients who received at least one dose of study drug and had both a baseline and at least one post-baseline measurement of efficacy . This trial is registered with Clinical Trials.gov , number NCT01195662 . FINDINGS Between Oct 29 , 2010 , and Oct 4 , 2012 , we r and omly assigned 225 patients to dapagliflozin and 224 to placebo . Seated systolic blood pressure was significantly reduced in the group assigned to dapagliflozin ( adjusted mean change from baseline -11·90 mm Hg [ 95 % CI -13·97 to -9·82 ] ) compared with those assigned to placebo ( -7·62 mm Hg [ -9·72 to -5·51 ] ; placebo-adjusted difference for dapagliflozin -4·28 mm Hg [ -6·54 to -2·02 ] ; p=0·0002 ) . Reductions in HbA1c concentrations were also significantly greater in patients assigned to dapagliflozin ( adjusted mean change from baseline -0·63 % [ 95 % CI -0·76 to -0·50 ] ) than in those assigned to placebo ( -0·02 % [ -0·15 to 0·12 ] ; placebo-adjusted difference -0·61 % [ -0·76 to -0·46 , ] ; p<0·0001 ) . In a post-hoc analysis , we found difference in blood pressure versus placebo was greater in patients receiving a β blocker ( -5·76 mm Hg [ 95 % CI -10·28 to -1·23 ] ) or a calcium-channel blocker ( -5·13 mm Hg , [ -9·47 to -0·79 ] ) as their additional antihypertensive drug than in those receiving a thiazide diuretic ( -2·38 mm Hg [ -6·16 to 1·40 ] ) . Adverse events were similar in the dapagliflozin and placebo groups ( 98 [ 44 % ] patients vs 93 [ 42 % ] , respectively , had at least one adverse event ) , with few adverse events related to renal function ( 1 % vs < 1 % ) or volume depletion ( < 1 % vs 0 % ) . INTERPRETATION Dapagliflozin 10 mg significantly improved blood pressure and HbA1c and was tolerated similarly to placebo . Its blood pressure-lowering properties were particularly favourable in patients already receiving a β blocker or calcium-channel blocker . Dapagliflozin could benefit patients with type 2 diabetes who need a diuretic-like effect to optimise control of blood pressure , adding meaningful efficacy to antihypertensive drug regimens . FUNDING Bristol-Myers Squibb , AstraZeneca The T allele of the C825 T polymorphism of the gene encoding the & bgr;3-subunit of G proteins has been associated with increased sodium-hydrogen exchange and low renin in patients with essential hypertension . To assess its association with blood pressure response to diuretic therapy , we measured the C825 T polymorphism in 197 blacks ( 134 men , 63 women ) and 190 non-Hispanic whites ( 76 men , 114 women ) with essential hypertension ( mean±SD age 48±7 years ) , who underwent monotherapy with hydrochlorothiazide for 4 weeks . Mean declines in systolic and diastolic blood pressures were 6±2 ( P < 0.001 ) and 5±1 ( P < 0.001 ) mm Hg greater , respectively , in TT than in CC homozygotes . Responses in heterozygotes were intermediate between the homozygous groups . Other univariate predictors of greater blood pressure responses included black race , female gender , higher pretreatment blood pressure , older age , lower waist-to-hip ratio , and measures of lower renin-angiotensin-aldosterone system activity . After the effects of the other predictors were considered , the TT genotype remained a significant predictor of greater declines in systolic and diastolic blood pressures . Thus , the C825 T polymorphism of the G protein & bgr;3-subunit may help identify patients with essential hypertension who are more responsive to diuretic therapy OBJECTIVE To examine the relationship of possible modifiable risk factors , including obesity , physical activity level , alcohol consumption , blood pressure , and thiazide diuretic use with the development of  non-insulin-dependent diabetes mellitus ( NIDDM ) requiring treatment among a large cohort of community-dwelling elderly . SETTING The East Boston Senior Health Project , one of four components of the National Institute on Aging-sponsored Established Population s for the Epidemiologic Study of the Elderly ( EPESE ) . PARTICIPANTS Residents of East Boston who were 65 years of age or older . MEASUREMENTS We performed a prospect i ve cohort study with follow-up over two consecutive 3-year time periods beginning in 1982 - 1983 . The main outcome measure was the occurrence of NIDDM , defined as new treatment with a hypoglycemic agent .  A total of 2737 study participants contributed 4682 3-year intervals for analysis . MAIN RESULTS NIDDM requiring hypoglycemic therapy  occurred in 185 participants over the duration of the study . High body mass index ( > 26 kg/m2 ) ( adjusted odds ratio 2.4 , 95 % confidence interval 1.3 - 4.4 ) and low physical activity level ( adjusted odds ratio 1.5 , 95 % confidence interval 1.0 - 2.1 ) were significant predictors of NIDDM in a multiple logistic regression model adjusting for age , sex , blood pressure , and self-report of " high blood sugar " moderate alcohol consumption ( 0.5-<1 ounce per day ) had an inverse relation to NIDDM of borderline significance ( adjusted odds ratio 0.4 , 95 % confidence interval 0.2 - 1.0 ) . Those receiving one or more non-thiazide antihypertensive agents had a higher risk of developing NIDDM in a model including age , sex , body mass index , various antihypertensive regimens , physical activity level , alcohol consumption , blood pressure , and self-report of " high blood sugar . " Thiazide diuretic therapy alone or in combination with another antihypertensive was not associated with NIDDM . CONCLUSIONS Our findings suggest a positive relationship of obesity and low physical activity level with the development of NIDDM requiring treatment in elderly persons . The inverse association of borderline significance between moderate alcohol use and NIDDM deserves further study . Thiazide diuretic therapy conferred no excess risk for developing NIDDM in this older population although selection factors in the choice of antihypertensive therapy may partially explain the absence of a thiazide effect The combination of angiotensin converting enzyme ( ACE ) inhibitor and thiazide diuretic has advantages over monotherapy for the treatment of hypertension . Previous study design s have often been inadequate to demonstrate the details of interactions between these antihypertensive agents . This study used a modified 4 x 4 factorial r and omized , double-blind , placebo-controlled , parallel group design to study the efficacy of 17 different doses of fosinopril ( Fos ) , a phosphinic acid derived ACE inhibitor , and hydrochlorothiazide ( HCTZ ) in 550 patients with mild to moderate hypertension . Data from these variables were fit to quadratic response surface models ( QRSM ) using polynomial functions in the doses of the two components . Using QRSM , seated systolic ( SeSBP ) and diastolic blood pressure ( SeDBP ) responses at 8 weeks were predicted for actual doses and interpolated for intermediate doses not studied . Fos and HCTZ alone and in combination produced a dose-related reduction in SeSBP and SeDBP . Using 10 mg Fos + 12.5 mg HCTZ reduced the adjusted mean SeDBP 6.3 mm Hg and 20 mg Fos + 12.5 mg HCTZ lowered the same measure 9.1 mm Hg . Coadministration of Fos and HCTZ produced an additive antihypertensive effect . This study of combination agents for hypertension using a factorial design with QRSM accurately predicts dose responses and is a valuable clinical trial methodology A r and omised , placebo-controlled , double-blind crossover study was conducted in 14 patients with mild essential hypertension comparing different regimens of administration of the " short-acting " diuretic , chlorothiazide and the " long-acting " diuretic , chlorthalidone . There were 6 r and omised treatment phases each of 5 weeks duration . For blood pressure recorded both at the Clinic and at home the most prominent effects were seen with st and ing blood pressure , for which significant reductions of mean blood pressure compared to the placebo phase were observed with chlorthalidone 25 mg once daily ( -5 + /- 1 ( SE ) mm Hg - p less than 0.05 ) , chlorthalidone 50 mg once daily ( -7 + /- 1 mm Hg - p less than 0.01 ) and chlorothiazide 500 mg twice daily ( -4 + /- 1 mm Hg - p less than 0.05 ) . Blood pressure reductions with chlorothiazide 500 mg once daily and 1000 mg once daily were not significant . About half of the patients completing the trial could be described as " non-responders " . The observed biochemical changes ( reduced plasma potassium and chloride concentrations and increased plasma bicarbonate and urate concentrations ) were most marked in the phases with the most prominent blood pressure effects . The result support the suggestion that a sustained diuretic effect is desirable when diuretics are used in the treatment of hypertension . This can be obtained by selection of the appropriate dosage regimen for a particular diuretic , such as once daily administration for " long-acting " and twice daily for " short-acting " thiazide-type diuretics To compare the effects of exercise training and hydrochlorothiazide on left ventricular ( LV ) geometry and mass , blood pressure ( BP ) , and hyperinsulinemia in older hypertensive adults , we studied 28 patients r and omized either to a group ( age 66.4 + /- 1.3 yr ; n = 16 ) that exercised or to a group ( age 65.3 + /- 1.2 yr ; n = 12 ) that received hydrochlorothiazide for 6 mo .  Endurance exercise training induced a 15 % increase in peak aerobic power . The reduction in systolic BP was twofold greater with thiazide than with exercise ( 26.6 + /- 12.2 vs. 11.5 + /- 10.9 mmHg ) . Exercise and thiazide reduced LV wall thickness , LV mass index ( 14 % in each group ) , and the LV wall thickness-to-radius ratio ( h/r ) similarly ( exercise : before 0.48 + /- 0.2 , after 0.42 + /- 0.01 ; thiazide : before 0.47 + /- 0.04 , after 0.40 + /- 0.04 ; P = 0.017 ) . The reductions in systolic BP and h/r were correlated in the exercise group ( r = 0.70 , P = 0.005 ) but not in the thiazide group . Exercise training reduced glucose-stimulated hyperinsulinemia ( before : 13.65 + /- 2.6 vs. 9.84 + /- 1.5 mU.ml(-1).min ; P = 0.04 ) and insulin resistance . Thiazide did not affect plasma insulin levels . The results suggest that although exercise is less effective in reducing systolic BP than thiazide , it can induce regression of LV hypertrophy similar in magnitude to thiazide . Unlike hydrochlorothiazide , exercise training can improve insulin resistance and aerobic capacity in older hypertensive people In the Hypertension Detection and Follow-up Program ( HDFP ) , elevated blood pressure ( BP ) was treated by rigorous , stepped care ( SC ) therapy among half the participants , while the other half were referred to usual sources of care ( referred care , RC ) . There was no program to reduce weight , however , some participants changed weight voluntarily over the first 2 yr , providing an opportunity to examine the role of weight change in the development of diuretic-induced hyperuricemia , hyperglycemia and hypercholesterolemia . There was a stepwise progression from decreased glucose , uric acid and cholesterol concentrations , and BP associated with maximum weight loss to increased values with maximum weight gain . In SC , systolic BP declined by 22.4 % among weight-losers and by 17.1 % among weight-gainers ; in RC , it was 14.4 and 8.1 % , respectively . The pattern in diastolic blood pressure and weight change was similar but not as marked . These findings suggest the potential importance of weight loss in enhancing effectiveness of antihypertensive drug treatment and attenuating increases in glucose , uric acid , and cholesterol associated with diuretic treatment of hypertension . The weight change analyses are based on postr and omization observations and do not reflect experimental changes Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes .  Dihydropyridine calcium channel blockers , however , may lower blood pressure but not albuminuria in these patients . Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics . We conducted a double blind r and omized controlled trial on 332 hypertensive , albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year . The trial employed a non-inferiority design . Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort . The percentage of patients progressing to overt proteinuria was similar for both groups . When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria . We conclude that initial treatment using benzaepril with a diuretic result ed in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker . In contrast , blood pressure reduction , particularly the diastolic component , favored the combination with amilodipine . The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure In a double blind placebo controlled r and omised parallel study the antihypertensive activity and adverse biochemical effects of three doses of cyclopenthiazide were evaluated in patients with mild essential hypertension that had been recently diagnosed or was being treated with a single drug . After a four week placebo washout period 53 patients with diastolic blood pressures between 90 - 110 mm Hg were r and omly assigned to 50 , 125 , or 500 micrograms cyclopenthiazide or matching placebo for an eight week period of treatment . Blood pressure was measured in the patients ' homes by the same observer every two weeks . Serum urea , electrolytes , urate , and creatinine concentrations and 24 hour urinary sodium excretion were monitored every four weeks and serum magnesium concentration and plasma renin activity at the end of the washout and treatment periods . After eight weeks of treatment systolic and diastolic blood pressures were significantly reduced in patients taking 125 and 500 micrograms cyclopenthiazide when compared with those taking placebo . The decrement in serum potassium concentration ( 0.6 mmol/l ) and increase in serum urate concentration 0.06 mmol/l ) were greatest with the 500 micrograms dose , the increase in serum urate concentration alone being significant . No change in serum magnesium concentration or 24 hour urinary sodium excretion was noted with any dose of cyclopenthiazide . Only the 500 micrograms dose of cyclopenthiazide significantly increased the mean plasma renin activity ( 1.8 ( 95 % confidence interval 0.2 to 3.4)-5.4 ( 3.9 to 6.8 ) nmol angiotensin I/l/h ) ; the other doses like the placebo had no effect . Cyclopenthiazide 125 micrograms , a dose lower than is currently marketed , produced a similar hypotensive response to 500 micrograms of the drug without up setting the biochemical profile The aim of the present analysis was to calculate the cost-effectiveness of metoprolol versus thiazide diuretics in middle-aged men with mild to moderate uncomplicated hypertension . The analysis was based on the Metoprolol Atherosclerosis Prevention in Hypertensives ( MAPHY ) study , a r and omised trial which showed a significantly lower risk for coronary events in patients taking metoprolol than in patients on thiazide diuretics .  The main analysis was based on Swedish costs , but the costs were also varied in a special sensitivity analysis . Metoprolol was shown to be cost-saving compared with thiazide diuretics when both direct and indirect costs of morbidity were included . When only direct costs were included , the cost per life-year gained was $ US2400 . The result of the present analysis suggests that metoprolol is to be preferred to thiazide diuretics from a cost-effectiveness st and point in the treatment of mild to moderate hypertension in middle-aged men . These findings regarding cost-effectiveness should , however , not be extrapolated to patient groups not included in the MAPHY trial BACKGROUND The efficacy of antihypertensive drugs newer than diuretics and beta-blockers has not been established . We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension . METHODS We did a prospect i ve , r and omised , double-blind trial in Europe and Israel in 6321 patients aged 55 - 80 years with hypertension ( blood pressure > or = 150/95 mm Hg , or > or = 160 mm Hg systolic ) . Patients had at least one additional cardiovascular risk factor . We r and omly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system ( GITS ) formulation ( n=3157 ) , or co-amilozide ( hydrochlorothiazide 25 mg [ corrected ] plus amiloride 2.5 mg ; n=3164 ) . Dose titration was by dose doubling , and addition of atenolol 25 - 50 mg or enalapril 5 - 10 mg . The primary outcome was cardiovascular death , myocardial infa rct ion , heart failure , or stroke . Analysis was done by intention to treat . FINDINGS Primary outcomes occurred in 200 ( 6.3 % ) patients in the nifedipine group and in 182 ( 5.8 % ) in the co-amilozide group ( 18.2 vs 16.5 events per 1000 patient-years ; relative risk 1.10 [ 95 % CI 0.91 - 1.34 ] , p=0.35 ) . Overall mean blood pressure fell from 173/99 mm Hg ( SD 14/8 ) to 138/82 mm Hg ( 12/7 ) . There was an 8 % excess of withdrawals from the nifedipine group because of peripheral oedema ( 725 vs 518 , p<0.0001 ) , but serious adverse events were more frequent in the co-amilozide group ( 880 vs 796 , p=0.02 ) . Deaths were mainly non-vascular ( nifedipine 176 vs co-amilozide 172 ; p=0.81 ) . 80 % of the primary events occurred in patients receiving r and omised treatment ( 157 nifedipine , 147 co-amilozide , difference 0.33 % [ -0.7 to 1.4 ] ) . INTERPRETATION Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications . The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy Abstract The objective of this study was to examine the cost-effectiveness of angiotensin-converting enzyme inhibitor (ACEI)-based treatment compared with thiazide diuretic-based treatment for  hypertension in elderly Australians considering diabetes as an outcome along with cardiovascular outcomes from the Australian government 's perspective . We used a cost – utility analysis to estimate the incremental cost-effectiveness ratio ( ICER ) per quality -adjusted life-year ( QALY ) gained . Data on cardiovascular events and new onset of diabetes were used from the Second Australian National Blood Pressure Study , a r and omized clinical trial comparing diuretic-based ( hydrochlorothiazide ) versus ACEI-based ( enalapril ) treatment in 6083 elderly ( age ≥65 years ) hypertensive patients over a median 4.1-year period . For this economic analysis , the total study population was stratified into 2 groups . Group A was restricted to participants diabetes free at baseline ( n = 5642 ) ; group B was restricted to participants with preexisting diabetes mellitus ( type 1 or type 2 ) at baseline ( n = 441 ) .  Data on utility scores for different events were used from available published literature s ; whereas , treatment and adverse event management costs were calculated from direct health care costs available from Australian government reimbursement data . Costs and QALYs were discounted at 5 % per annum . One-way and probabilistic sensitivity analyses were performed to assess the uncertainty around utilities and cost data .After a treatment period of 5 years , for group A , the ICER was Australian dollars ( AUD ) 27,698 ( & OV0556 ; 18,004 ; AUD 1–&OV0556 ; 0.65 ) per QALY gained comparing ACEI-based treatment with diuretic-based treatment ( sensitive to the utility value for new-onset diabetes ) . In group B , ACEI-based treatment was a dominant strategy ( both more effective and cost-saving ) . On probabilistic sensitivity analysis , the ICERs per QALY gained were always below AUD 50,000 for group B ; whereas for group A , the probability of being below AUD 50,000 was 85%.Although the dispensed price of diuretic-based treatment of hypertension in the elderly is lower , upon considering the potential enhanced likelihood of the development of diabetes in addition to the costs of treating cardiovascular disease , ACEI-based treatment may be a more cost-effective strategy in this population Objective To assess longitudinally the association of serum uric acid and its change due to diuretic treatment with  cardiovascular events in hypertensive patients . Design Cohort study in a r and omized trial . Setting Cohort of hypertensive patients . Participants A total of 4327 men and women , aged ≥ 60 years , with isolated systolic hypertension , r and omized to placebo or chlorthalidone  , with the addition of atenolol or reserpine if needed , were observed for 5 years . Main outcome measures Major cardiovascular events , coronary events , stroke and all-cause mortality . Results Cardiovascular event rates for quartiles of baseline serum uric acid were : I , 32.7 per 1000 person-years ; II , 34.5 per 1000 person-years ; III , 38.1 per 1000 person-years ; and IV , 41.4 per 1000 person-years ( P for trend = 0.02 ) . The adjusted hazard ratio ( HR ) , of cardiovascular events for the highest quartile of serum uric acid versus the lowest quartile was 1.32 ( 95 % CI , 1.03–1.69 ) . The benefit of active treatment was not affected by baseline serum uric acid . After r and omization , an increase of serum uric acid < 0.06 mmol/l ( median change ) in the active treatment group was associated with a HR of 0.58 ( 0.37–0.92 ) for coronary events compared with those with a serum uric acid increase ≥ 0.06 mmol/l . This difference was not explained by blood pressure effects . Those with a serum uric acid increase ≥ 0.06 mmol/l in the active treatment group had a similar risk of coronary events as the placebo group . Conclusions Serum uric acid independently predicts cardiovascular events in older persons with isolated systolic hypertension . Monitoring serum uric acid change during diuretic treatment may help to identify patients who will most benefit from treatment BACKGROUND Thiazides are recommended to initiate antihypertensive drug treatment in black subjects . OBJECTIVE To test the efficacy of this recommendation in a South African black cohort . METHODS Men and women ( N = 409 ) , aged 18 to 70 years , with a mean ambulatory daytime diastolic blood pressure between 90 and 114 mm Hg , were r and omized to 13 months of open-label treatment starting with the nifedipine gastrointestinal therapeutic system ( 30 mg/d , n = 233 ) , sustained-release verapamil hydrochloride ( 240 mg/d , n = 58 ) , hydrochlorothiazide ( 12.5 mg/d , n = 58 ) , or enalapril maleate ( 10 mg/d , n = 60 ) . If the target of reducing daytime diastolic blood pressure below 90 mm Hg was not attained , the first-line drugs were titrated up and after 2 months other medications were added to the regimen . RESULTS While receiving monotherapy ( 2 months , n = 366 ) , the patients ' systolic and diastolic decreases in daytime blood pressure averaged 22/14 mm Hg for nifedipine , 17/11 mm Hg for verapamil , 12/8 mm Hg for hydrochlorothiazide , and 5/3 mm Hg for enalapril . At 2 months the blood pressure of more patients treated with nifedipine was controlled : 133 ( 63.3 % , P</=.03 ) vs 20 ( 39.9 % ) receiving verapamil , 21 ( 40.4 % ) receiving hydrochlorothiazide , and 11 ( 20.8 % ) receiving enalapril . At 13 months ( n = 257 ) , more patients ( P<.001 ) continued receiving monotherapy with nifedipine ( 94/154 [ 61.0 % ] ) or verapamil ( 22/35 [ 62.9 % ] ) than hydrochlorothiazide ( 10/39 [ 25.6 % ] ) or enalapril ( 1/29 [ 3.4 % ] ) . A sustained decrease of left ventricular mass ( P<.001 ) with no between-group differences was achieved at 4 and 13 months . CONCLUSIONS In contrast to current recommendations , calcium channel blockers are more effective than thiazides as initial treatment in black subjects with hypertension . If treatment is started with thiazides or converting-enzyme inhibitors , combination therapy is more likely to be required to control blood pressure and reduce left ventricular mass Brinerdin ( S and oz ) , a combination of a diuretic ( clopamide 5 mg ) , a vasodilator ( dihydro-ergocristine 0.5 mg ) and reserpine ( 0.1 mg ) ( CDR ) was compared with methyldopa ( MD ) plus hydrochlorothiazide ( HCT ) for antihypertensive effect , adverse reactions , compliance and patient preference in an open cross-over trial . Eighteen patients completed both arms of the trial and 5 patients who completed the CDR arm were withdrawn while on the MD arm because of adverse effects in 4 and poor control in 1 . On HCT 50 mg daily the mean baseline systolic blood pressure was 163.9 + /- 16.3 mmHg and the diastolic blood pressure was 105.9 + /- 6.7 mmHg . On CDR these were reduced to systolic blood pressure 140.3 + /- 15.1 mmHg and diastolic blood pressure 87.8 + /- 9.3 mmHg . On MD + HCT the systolic blood pressure was reduced to 138.5 + /- 16.9 mmHg and the diastolic blood pressure to 88.9 + /- 10.3 mmHg . The differences between the two treatment periods in systolic blood pressure ( 1.8 mmHg ; 95 % confidence interval ( CI ) - 4.1 + 7.7 mmHg ) and diastolic blood pressure ( 1.1 mmHg ; 95 % CI - 4.6 + 2.4 mmHg ) were not significant with P values of 0.6 and 0.7 respectively . Compliance was 98.2 % for CDR and 94.7 % for MD + HCT ( P = 0.02 ) . Unusual sleepiness occurred more frequently in the MD arm ( P less than 0.01 ) . Thirteen patients chose to continue on CDR , 2 on MD + HCT and 3 had no preference ( P = 0.005 ) . CDR is similar in antihypertensive effect to MD + HCT but is better tolerated with fewer withdrawals , fewer adverse effects , better compliance and has more patients electing to continue taking it Osteoporosis is responsible for about 1.3 million fractures in the United States each year [ 1 ] . Further , recent research has shown that the risk for most types of fracture in elderly women is related to low bone mass ; thus , the public health impact of osteoporosis may , in fact , be much greater [ 2 ] and is projected to increase over the next several decades [ 3 ] . Postmenopausal estrogen replacement is the current recommended therapy for the prevention of osteoporosis [ 4 ] . However , the use of estrogen is not widespread among elderly women [ 5 ] . Clearly , more options for the prevention of osteoporosis and fracture need to be developed and explored . One option is the use of thiazide diuretics . Thiazide diuretics are known to reduce urinary excretion of calcium [ 6 , 7 ] and may also decrease bone resorption [ 6 ] and bone turnover [ 8 ] . The use of thiazide diuretics has been associated with a reduced risk for fracture , with risk ratios ranging from 0.3 to 0.8 [ 9 - 18 ] . For example , in a casecontrol study that excluded patients taking other drugs thought to affect bone mass , Ray and colleagues [ 15 ] found a 50 % reduction in the risk for hip fracture among patients who had used thiazide diuretics  for 6 years . In addition , LaCroix and colleagues [ 16 ] reported a 30 % lower risk for hip fracture in current users compared with nonusers . The Framingham Study also showed a lower risk for hip fracture among users of pure thiazide drugs when compared with those using agents that combined thiazide diuretics with other antihypertensive drugs [ 17 ] . However , all of these studies have been observational , which allows the possibility that users of thiazide diuretics have a lower risk for hip fracture because of other confounding factors . In addition , the more recent data of Heidrich and colleagues [ 19 ] conflict with these results . These investigators found a crude odds ratio for thiazide use and hip fracture of 1.1 , which is not statistically significant . However , when they adjusted for the potentially confounding effects of nursing-home residence ; previous hospitalizations ; history of stroke , alcoholism or organic brain syndrome ; body weight ; leg paralysis ; and use of phenobarbital , corticosteroids , or other diuretics , a significantly increased risk for hip fracture was found among women who reported current use of thiazide diuretics  [ 19 ] . No study has prospect ively evaluated the relation between thiazide diuretics and other types of fracture . The mechanism by which thiazide diuretics might protect against hip fracture is not known . Thiazide diuretics may decrease fracture risk by preserving bone mass [ 10 , 11 , 20 - 23 ] . Cross-sectional studies have shown that users of thiazide diuretics have slightly higher cortical and trabecular bone mass than nonusers . Two r and omized clinical studies of the effect of thiazide diuretics on bone loss had conflicting results [ 24 , 25 ] . If thiazide diuretics reduce the risk for hip fracture by slowing bone loss , then these agents should also protect against other types of fracture that are associated with reduced bone mass [ 2 ] . On the other h and , thiazide diuretics could increase the risk for fractures by increasing the risk for falls [ 26 ] . Thiazide diuretics might do this by causing dizziness or postural hypotension [ 27 ] , although the association of diuretic use with falling is not consistent [ 28 ] . More than 90 % of hip fractures are related to falls [ 29 ] . No previous study has included a comprehensive analysis of the effects of thiazide diuretics on bone mass , the risk for falls , and the risk for all fractures in a single population . In our prospect i ve study of 9704 women who were 65 years or older ( the Study of Osteoporotic Fractures ) , we assessed thiazide diuretic use and bone mass at baseline and conducted follow-up examinations every 4 months for the occurrence of fractures and falls . Methods Study Sample From September 1986 through October 1988 , women who were at least 65 years old were recruited for the Study of Osteoporotic Fractures in four areas of the United States : Portl and , Oregon ; Minneapolis , Minnesota ; Baltimore County , Maryl and ; and the Monongahela Valley region near Pittsburgh , Pennsylvania . Age-eligible women were recruited through several sources : health maintenance organizations ; lists of residents that had been compiled for other epidemiologic studies ; jury- selection lists ; voter- registration lists ; and lists of driver 's license holders [ 30 ] . We excluded black women because of their lower incidence of fractures , women who were unable to walk without the assistance of another person , and women who had bilateral hip replacements . Measurement of Bone Mass Bone mineral content ( g/cm ) and density ( g/cm2 ) were measured using single-photon absorptiometry ( OsteoAnalyzer , Siemens-Osteon , Wahiawa , Hawaii ) . Details of these methods have been reported elsewhere [ 30 ] . We scanned three sites : the distal radius , the proximal radius , and the calcaneus . The distal radius is composed of about 60 % cortical bone and 40 % trabecular bone , the proximal radius is about 99 % cortical bone [ 31 ] , and the calcaneus is about 97 % trabecular bone [ 32 ] . The reproducibility of the bone mass measurements , expressed as coefficients of variation , ranged from 1.3 % to 2.0 % among individuals and from 0.4 % to 1.2 % among scanners [ 30 ] . Diuretic Use Information on diuretic use was obtained at the baseline clinic interview . Participants were asked to bring all current medications to the clinic for verification . In addition , pictures of tablets were presented to participants to assist them in the re collection of previously prescribed diuretics . Diuretics , including combination drugs , were classified as thiazide diuretics according to the American Medical Association drug evaluations [ 33 ] . Separate histories were obtained from participants for use of thiazide and nonthiazide diuretics . Chlorthalidone was classified as a thiazide diuretic because its effects on calcium excretion are similar to those of thiazide diuretics . Analyses in which chlorthalidone was not considered as a thiazide diuretic yielded similar results . Women were asked whether they had ever taken diuretics ; at what age they had started taking diuretics ; whether they were currently using diuretics and , if not , when they had stopped ; whether they took diuretics the entire time or stopped for a few years ; and the name of the medication they were currently using . Duration of diuretic use was calculated as the total number of years that they reported using diuretics . No information was collected on dose at the baseline visit , but dose-related data were recorded at the first annual telephone interview . Information on duration of thiazide diuretic use was missing in 15 women . These women were excluded from all analyses . Other Measurements Reported health status , type of menopause , alcohol consumption , and cigarette smoking were assessed using a question naire that was review ed with the participant by a trained interviewer . Women were considered to have had a surgical menopause if they reported having had a bilateral oophorectomy at the age at which they stopped menstruating . Regarding alcohol consumption , participants were asked how much they had consumed during the past 30 days and how many times they had consumed three or more drinks per day and five or more drinks per day during the past 30 days . The measure of alcohol consumption used in our study was drinks per week , which was adjusted for atypical drinking , particularly heavy drinking over the last 30 days .  Dietary calcium  was assessed by a food frequency question naire and an interview using st and ardized food models to estimate portion sizes [ 34 ] . In our study , total calcium intake included dietary and supplemental calcium . Women were also asked if they had ever taken the following medications : thyroid hormones , medicine for seizures , vitamin D or multivitamins containing vitamin D , TUMS , calcium supplements , antacids , prednisone , cortisone , other steroid pills , birth control pills , estrogen pills , estrogen skin patches , estrogen vaginal cream or suppositories , estrogen injections , and progestins . Information was obtained on current use , duration of use , and specific drug and dosage used for the longest period . Functional status was measured by a respondent 's answers to questions about her ability to perform six instrumental activities of daily living by herself and without using special aids or equipment . These activities were as follows : walking two or three blocks outside on level ground ; climbing up 10 steps without stopping ; walking down 10 steps ; preparing one 's own meals ; doing heavy housework ; and doing one 's own shopping for groceries or clothes . The measure used in these analyses is the total number of activities ( ranging from 0 to 6 ) that a woman reported she was unable to do or had difficulty doing . Additionally , women were asked to rate their health status as very good , good , fair , poor , or very poor . During the clinic examination , body weight was measured ( after removal of shoes and heavy outer clothing ) using a balance beam scale . Height was measured ( after removal of shoes ) using a Harpenden stadiometer ( Holtain , Ltd. , Dyved , United Kingdom ) . Height and weight were used to calculate the body mass index ( kg/m2 ) . Ascertainment of Prevalent Vertebral Deformities The prevalence of vertebral deformities as shown by lateral thoracic and lumbar spine films was obtained on 2992 women ( 31 % of the cohort ) who were between 65 and 70 years old . The methods used to identify vertebral deformities have been described previously [ 35 ] . In summary , six points for each vertebral body , T4 through L4 , were marked with a translucent digitizer . We calculated three heights ( anterior , posterior , and middle ) and three ratios : anterior-to-posterior height ( wedge ) ; mid-to-posterior height ( endplate ) ; and the posterior height of each vertebra to the posterior height of the adjacent vertebrae ( crush ) . We classified a vertebral body The antihypertensive effects of telmisartan 80 mg versus valsartan 160 mg , both combined with hydrochlorothiazide ( HCTZ ) 25 mg , were assessed in a pooled analysis from two large trials with identical study design s in patients with stage 1–2 hypertension . The trials were double-blind with a 4:4:1 r and omization scheme to compare once-daily telmisartan 80 mg and HCTZ 25 mg versus once-daily valsartan 160 mg and HCTZ 25 mg versus once-daily placebo on reductions in clinic blood pressure ( BP ) . The primary end point was changes from baseline in BP at the end of 8 weeks . In total , 2121 patients were r and omized ( telmisartan – HCTZ , 942 , valsartan – HCTZ , 952 , and placebo , 227 ) and had baseline seated BPs of 154/102 and 155/102 mm Hg in the two studies , respectively .  Changes from baseline in BP after administration of telmisartan – HCTZ ( −24.5/−18.0 mm Hg ) were significantly greater than for both placebo ( −4.1/−6.5 mm Hg ) and valsartan – HCTZ ( −22.3/−16.8 mm Hg ) ( versus placebo , P<0.0001 for systolic and diastolic BP ; versus valsartan – HCTZ , P=0.0004 for systolic BP and P=0.0019 for diastolic BP ) . Adverse event rates were higher in the placebo group than in the active treatment groups ( placebo , 41 % , telmisartan – HCTZ , 30 % , and valsartan – HCTZ , 30 % , P<0.05 ) . These data confirm that telmisartan – HCTZ at doses of 80/25 mg lowered systolic and diastolic BP to a greater extent than valsartan – HCTZ at doses of 160/25 mg in stage 1–2 hypertension . The magnitude of the BP-lowering effect provides support for the use of angiotensin receptor blockers with higher doses of a thiazide diuretic ( 25 mg ) to improve hypertension control Fifty-five patients with mild to moderate , renal or essential hypertension were admitted to a double blind cross-over trial of 18 weeks , involving treatment periods with placebo , the thiazide bendrofluazide ( 15 mg daily ) and the beta blocker atenolol ( 600 mg daily ) . Compared to the placebo period ( 190/117 mm Hg ) the hypotensive effect of atenolol ( -24/16 mm Hg ) was more pronounced than the hypotensive effect of bendrofluazide ( -17/6 mm Hg ) . Arguments in favor of initiating antihypertensive drug therapy with beta blocker were its more powerful hypotensive effect , the quicker onset of its action , less metabolic disturbance , decreased frequency of complaints and patient 's preference . On thiazides body weight and the frequency of swollen ankles decreased . Plasma renin concentration was not found to have a strong predicting power for the hypotensive effect of atenolol or bendrofluazide but low renin patients showed a more pronounced blood pressure decrease on bendrofluazide and high renin patients , especially essential hypertensives , on atenolol . While these points can be a guide to therapy today , the preference of one drug over the other must eventually be based on their relative efficacy in decreasing morbidity and mortality from the hypertensive disease Context Previously published results of this r and omized , double-blind trial showed that hypertensive patients treated with doxazosin rather than chlorthalidone more often developed heart failure . Did differences in blood pressure control or treatment with other drugs explain these findings ? Contribution This analysis shows that the slightly worse blood pressure control achieved with doxazosin did not explain higher risks for heart failure . Risks with doxazosin versus chlorthalidone were highest among patients who received monotherapy ( relative risk , 3.10 ) and lowest among patients who received stepped care with additional drugs ( relative risk , 1.42 ) . Implication s Increased risks for heart failure with doxazosin versus chlorthalidone are attenuated but not eliminated when additional antihypertensive drugs are used . The Editors The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , multicenter clinical trial including 42 418 participants at 623 clinical sites , is design ed to determine whether treatment begun with a calcium-channel blocker ( amlodipine ) , an angiotensin-converting enzyme inhibitor ( lisinopril ) , or an -adrenergic blocker ( doxazosin ) compared to treatment with a diuretic ( chlorthalidone ) reduces the incidence of fatal coronary heart disease or nonfatal myocardial infa rct ion in high-risk patients with hypertension ( 1 ) . Secondary end points are all-cause mortality , stroke , and other cardiovascular events . A lipid-lowering trial in a subset of 10 356 participants is design ed to determine whether decreasing cholesterol levels with a hydroxymethyl glutamyl coenzyme A reductase inhibitor ( pravastatin ) compared with usual care reduces all-cause mortality in older , moderately hypercholesterolemic patients . In January 2000 , the doxazosin arm of the trial was discontinued ( 2 ) because major cardiovascular disease ( relative risk , 1.25 [ 95 % CI , 1.17 to 1.33 ] ; P < 0.001 ) , especially heart failure ( relative risk , 2.04 [ 95 % CI , 1.79 to 2.32 ] ; P < 0.001 ) , was significantly increased compared with the chlorthalidone arm . Equally important , a low probability existed that doxazosin would show benefit over chlorthalidone for the primary end point by the scheduled study end , given the lack of difference ( relative risk , 1.02 [ 95 % CI , 0.90 to 1.17 ] ; P > 0.2 ] at that time . These intention-to-treat analyses compared patients assigned to chlorthalidone with patients assigned to doxazosin . In this article , we analyze how treatment changes may have affected the comparison of doxazosin with chlorthalidone in terms of heart failure . Our major objectives are to ascertain to what extent the relative risk with doxazosin versus chlorthalidone depends on 1 ) whether the assigned drugs were used as monotherapy or in combination with other agents and 2 ) the difference in decreases in systolic and diastolic blood pressure . Methods Study Design The rationale and design of ALLHAT are described in detail elsewhere ( 1 ) . In brief , eligible participants were men and women 55 years of age or older who had systolic or diastolic hypertension ( 140/90 mm Hg or hypertension controlled with medication ) plus at least one additional risk factor for coronary heart disease events . The risk factors included previous ( > 6 months ) myocardial infa rct ion or stroke , left ventricular hypertrophy on electrocardiography or echocardiography , history of type 2 diabetes , current cigarette smoking , and a low high-density lipoprotein cholesterol level . Persons with a history of hospitalized or treated symptomatic heart failure or a known ejection fraction less than 0.35 were excluded . Unless the drug regimen required tapering for safety , participants who had been taking antihypertensive medications continued to do so until the day of r and omization , at which point they stopped taking all previous medications . On the day after r and omization , treatment with the study drug was initiated . Enrollment occurred from February 1994 through January 1998 . The original reported number of 42 448 participants and 625 sites changed because 30 patients with poor documentation of informed consent were excluded ( 2 ) . Participants were assigned by a computer-generated r and omization schedule in a ratio of 1.7:1 to receive chlorthalidone or doxazosin . R and omization was stratified by center and blocked over time to maintain the ratio . All participants gave written informed consent , and all centers obtained institutional review board approval . Ascertainment of Outcomes At each clinic visit , occurrence of study end points was assessed by the clinical investigator . A hospital discharge summary was required for each hospitalized study outcome , and a death certificate was required for each death . ALLHAT defined symptomatic heart failure as clear-cut signs or symptoms of left or right ventricular dysfunction that can not be attributed to other causes . A patient had to have at least one symptom ( paroxysmal nocturnal dyspnea , dyspnea at rest , New York Heart Association class III dyspnea or other symptoms [ on less than ordinary exertion ] , or orthopnea ) and one sign ( rales , ankle edema , tachycardia , cardiomegaly or characteristic pulmonary pattern on chest radiography , S3 gallop , or jugular venous distention ) ( 3 ) . Symptoms and signs were determined by the clinic investigator through patient history , chart review , or consultation with the treating physician , but such data were not collected central ly . A one-time sample of 24 hospitalized or fatal heart failure events was review ed in a blinded manner by the ALLHAT Endpoints Subcommittee ; 20 of 24 ( 83 % ) were deemed to have complete data for a definitive diagnosis . Of the 20 cases , the agreement rate between the subcommittee and the clinic investigators was 90 % ( 18 of 20 ) and similar in both treatment groups . Details on the validity of diagnosis of heart failure will be provided in a future report . Measurement and Treatment of Blood Pressure The ALLHAT protocol specified a stepped-care treatment program for hypertension . Trained observers using st and ardized techniques measured blood pressures during the trial ( 1 , 2 ) . All blood pressures were calculated as the average of two measurements obtained with a 30-second interval between them . The blood pressure goal in all four study arms was less than 140/90 mm Hg . This level was to be achieved with the lowest possible dose of blinded first-line drug , with addition of second- and third-line open-label therapy as needed after reaching the maximal dose of first-line drug . Chlorthalidone and doxazosin were to be taken once daily in the morning . By design , doses were selected to achieve equivalent blood pressure control in the treatment groups . The first , second , and third dosage levels were 12.5 mg/d , 12.5 mg/d ( sham titration ) , and 25 mg/d , respectively , for chlorthalidone and 2 mg/d , 4 mg/d , and 8 mg/d for doxazosin . Double-blinded 1-mg and 12.5-mg doses of doxazosin and chlorthalidone , respectively , were used for the first week to minimize the frequency of postural hypotension associated with doxazosin . The identity of drugs was masked at each dosage level , but dosage level was not . After r and omization , patients were seen for dose titration as needed at 1 and 3 months per the protocol , but they could return more often until target blood pressure was reached . Subsequently , required visits occurred at 3-month intervals during the first year and at 4-month intervals thereafter . Open-label second-step drugs were added as needed and tolerated . These agents were reserpine ( 0.05 to 0.2 mg/d ) , clonidine ( 0.1 to 0.3 mg twice daily ) , and atenolol ( 25 to 100 mg/d ) . The choice of second-step drug was at the discretion of the treating clinician-investigator . The third-step agent was hydralazine ( 25 to 100 mg twice daily ) . Details of these therapies are provided elsewhere ( 1 ) . Investigators could choose to prescribe open-label antihypertensive drugs other than those provided by the study . However , use of the drug classes under study thiazide diuretics , calcium antagonists , angiotensin-converting enzyme inhibitors , and -adrenergic blockerswas strongly discouraged to avoid dilution of treatment comparisons . When clinical conditions other than uncontrolled hypertension ( for example , angina or heart failure ) were present , drugs from any study class could be used . If a step 1 drug was specifically required for blood pressure control while blinded drug treatment was continued , the step 1 drug could be added as open-label therapy but the dose could not exceed one half the maximum recommended by the Fifth Joint National Committee ( 4 ) . In most such cases , unblinding the patient or the investigator to treatment assignment was not necessary . ( Overall , < 1 % of drug identities were provided to either participant or investigator . ) Any of nine possible open-label drug typesdiuretic , calcium-channel blocker , angiotensin-converting enzyme inhibitor , -adrenergic blocker , atenolol , reserpine , clonidine , hydralazine , and other antihypertensive drug ( which could include nonatenolol -blockers , although drug name was not logged)could be recorded at each visit . Because diuretics , angiotensin-converting enzyme inhibitors , and -blockers are beneficial in preventing or treating heart failure , we call these antihypertensive heart failure drugs . Data on  antihypertensive drug use before study enrollment were collected , but not by drug class . Statistical Analysis Data were analyzed for use of additional drugs according to participants ' r and omized treatment assignments and regardless of continuation of blinded study treatment . The outcomes all heart failure ( treated outside hospital , hospitalized , or fatal ) and hospitalized or fatal heart failure were examined by treatment group for the entire cohort . The time to event for the previously published as-r and omized analyses was the interval from r and omization to first diagnosis of heart failure for patients who had an outcome , or from r and omization to Objective To compare the incidence of stroke and other cardiovascular events in hypertensive patients receiving a low-dose diuretic and low-dose calcium antagonist combination with those receiving low-dose diuretic monotherapy  , and assess the effects of a small blood pressure difference at achieved levels lower than those achieved in previous placebo-controlled trials . Methods The Felodipine Event Reduction ( FEVER ) trial was an investigator- design ed , prospect i ve , multicentre , double-blind , r and omized , placebo-controlled , parallel group trial . It enrolled 9800 Chinese patients , of either sex , aged 50–79 years , with one or two additional cardiovascular risk factors or disease , whose blood pressure , 6 weeks after switching from previous antihypertensive therapy to low-dose ( 12.5 mg a day ) hydrochlorothiazide , was in the range 140–180 mmHg ( systolic ) or 90–100 mmHg ( diastolic ) . These patients were r and omly assigned either to low-dose felodipine extended release or placebo , and followed at 3-month intervals for an average of 40 months . Results The intention-to-treat analysis included 9711 r and omly selected patients with only 30 ( 0.3 % ) lost to follow-up . A total of 31 842 patient-years of follow-up were accumulated , with 85.9 % of patients remaining on blinded r and omized treatment . Add-on therapy was given to 33.9 % of the hydrochlorothiazide – felodipine patients and to 42.3 % of the hydrochlorothiazide – placebo patients . In the felodipine  group , systolic blood pressure (SBP)/diastolic blood pressure ( DBP ) decreased ( from r and omization to study end ) from 154.2/91.0 to 137.3/82.5 mmHg , and in the placebo group from 154.4/91.3 to 142.5/85.0 mmHg , with an average difference throughout the trial of 4.2/2.1 mmHg . In the felodipine group , the primary endpoint ( fatal and non-fatal stroke ) was reduced by 27 % ( P = 0.001 ) . Among secondary endpoints , all cardiovascular events were reduced by 27 % ( P < 0.001 ) , all cardiac events by 35 % ( P = 0.012 ) , death by any cause by 31 % ( P = 0.006 ) , coronary events by 32 % ( P = 0.024 ) , heart failure by 30 % ( P = 0.239 ) , cardiovascular death by 33 % ( P = 0.019 ) , cancer by 36 % ( P = 0.017 ) in the felodipine group . No significant differences were found in new-onset diabetes . Both treatments were very well tolerated . Conclusions In moderately complicated hypertensive patients from China even a difference in SBP/DBP as small as 4/2 mmHg , such as that induced by adding low-dose felodipine to low-dose hydrochlorothiazide , is associated with very substantial reductions in the incidence of most types of cardiovascular events . As the SBP achieved in the felodipine group was below the recommended goal of less than 140 mmHg , and SBP in the placebo group was slightly above that level , FEVER provides the required evidence in support of the guidelines recommended goal , even for a hypertensive population not entirely consisting of patients with diabetes or previous cardiovascular events OBJECTIVES The aim of this study was to test the hypothesis that the angiotensin II type 1 receptor blocker ( ARB ) c and esartan can reduce the risk of stroke in elderly patients with isolated systolic hypertension ( ISH ) . BACKGROUND Isolated systolic hypertension is the predominant form of hypertension in the elderly , and stroke is the most common cardiovascular ( CV ) complication . METHODS In the Study on Cognition and Prognosis in the Elderly ( SCOPE ) , 4,964 patients age 70 to 89 years were r and omly assigned to double-blind c and esartan or placebo with open-label antihypertensive therapy ( mostly thiazide diuretics ) added as needed to control blood pressure . Of the 4,964 patients , 1,518 had ISH ( systolic blood pressure > 160 mm Hg and diastolic blood pressure < 90 mm Hg ) . The present study is a predefined subgroup analysis of outcome results in the ISH patients . RESULTS Of the ISH patients , 754 were r and omized to the c and esartan group and 764 to the control group . Over the study period , blood pressure was reduced by 22/6 mm Hg in the c and esartan group and by 20/5 mm Hg in the control group ( difference between treatments 2/1 mm Hg ; p = 0.101 and 0.064 ) . A total of 20 fatal/non-fatal strokes occurred in the c and esartan group ( 7.2/1,000 patient-years ) and 35 in the control group ( 12.5/1,000 patient-years ) ; relative risk ( RR ) was 0.58 ( 95 % confidence interval 0.33 to 1.00 ) , that is , a RR reduction of 42 % ( p = 0.050 unadjusted , p = 0.049 adjusted for baseline risk ) . There were no marked or statistically significant differences between the treatment groups in other CV end points or all-cause mortality . CONCLUSIONS In elderly patients with ISH , antihypertensive treatment based on the ARB c and esartan result ed in a significant 42 % RR reduction in stroke in comparison with other antihypertensive treatment , despite little difference in blood pressure reduction The antihypertensive effect of indapamide ( 2.5 mg/day ) was compared to that obtained with a placebo in a controlled trial carried out by 11 physicians in their private practice . Thirty-one patients with uncomplicated essential hypertension were included . After a run-in period of 3 weeks without any treatment , either indapamide ( n = 16 ) or a placebo ( n = 15 ) were administered for 8 weeks in double-blind fashion . Blood pressure decreased in both groups . In patients treated with indapamide , systolic pressure was significantly lower than in those given the placebo at 3 out of the 4 follow-up visits ; diastolic pressure , however , was significantly lower only at the end of the trial . Both the active drug and the placebo were well tolerated . No significant change in body weight , plasma potassium and uric acid occurred during the study in either group of patients . It appears therefore that indapamide , at a dose which apparently has no major diuretic effect , may be useful for practitioners in managing patients with mild to moderate hypertension Low-dose combination therapy has been proposed as a rational first-line approach to hypertension treatment . We compared the efficacy and tolerability of the fixed combination of reserpine ( 0.1 mg ) plus the thiazide clopamid ( 5 mg ) with its single components and the calcium-antagonist nitrendipine ( 20 mg ) in a r and omized , double-blind , parallel study of 273 hypertensive patients with diastolic blood pressure ( BP ) between 100 and 114 mm Hg . The four groups did not differ regarding baseline characteristics ( mean age , 58 years ; 51 % men ; mean BP after a 2-week placebo period , 158 to 160/103 to 104 mm Hg ) . After 6 weeks of treatment with one capsule daily , mean reductions in sitting BP from baseline at 24 hours after dosing in the reserpine-clopamid combination , reserpine , clopamid , and nitrendipine groups were -23.0/-17.1 , -14.0/-11.7 , -13.6/-11.9 , and -11.6/-12.3 mm Hg , respectively ( 2P < .01 ) . The corresponding normalization rates ( diastolic BP < 90 mm Hg ) were 55 % , 40 % , 36 % , and 33 % ( 2P = .11 ) . All patients whose BP had not been normalized at this point received two capsules of the respective medication once daily from weeks 7 to 12 . At week 12 , mean BP reductions were -25.7/-18.1 , -14.6/-12.2 , -17.7/-13.4 , and -14.9/-15.3 mm Hg in the four groups , respectively ( 2P < .01 ) . The respective normalization rates were 69 % , 35 % , 39 % , and 45 % ( 2P < .0001 ) . Linear regression modeling indicated that reserpine and clopamid combined acted more than additively . As regards tolerability , adverse experiences were observed in 27 % , 28 % , 29 % , and 48 % of patients , respectively ( 2P < .05 ) . The respective rates of premature discontinuation because of adverse effects were 3 % , 3 % , 7 % , and 13 % ( 2P = .06 ) . In conclusion , a low-dose combination of reserpine and clopamid lowered BP significantly more than both the components alone and nitrendipine . Moreover , the combination was tolerated as well as its components and significantly better than nitrendipine . Thus , the use of this low-dose reserpine-thiazide combination appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension Background : The increased risk of cardiovascular morbidity and mortality associated with arterial hypertension is particularly pronounced in patients with type 2 diabetes mellitus .  Blood pressure control is , therefore , decisively important but often not sufficiently achieved . Objective : The primary objective of this study was to evaluate the antihypertensive effect of low dose spironolactone added to triple therapy for resistant hypertension in patients with type 2 diabetes measured by ambulatory monitoring . Secondary objectives were to evaluate the effects on glycaemic control and urinary albumin excretion as well as adverse effects . Methods : In a multicentre , double-blind , r and omized , placebo-controlled study 119 patients with blood pressure at or above 130/80 mmHg despite triple antihypertensive therapy were included . One tablet of 25 mg spironolactone or placebo was added to previous treatment and increased to two if blood pressure below 130/80 mmHg was not achieved after 4 weeks . Blood pressure was measured by ambulatory monitoring at baseline and after 16 weeks . Results : The study was completed by 112 patients , 57 r and omized to spironolactone  and 55 to placebo .  Average daytime placebo-corrected blood pressure was reduced by 8.9 (4.7–13.2)/3.7 ( 1.5–5.8 ) mmHg . Also office blood pressure , night-time , 24-h and pulse pressures were reduced significantly . Urinary albumin/creatinine ratio was significantly reduced in the spironolactone group . Glycaemic control remained unchanged . Hyperkalemia was the most frequent adverse event leading to dose reduction in three cases and discontinuation in one , whereas gynaecomastia was not reported . Conclusion : Low dose spironolactone exerts significant BP and urinary albumin creatinine ratio lowering effects in high-risk patients with resistant hypertension and type 2 diabetes mellitus OBJECTIVE --To determine the effect of thiazide diuretic drugs on rates of bone mineral loss . DESIGN --Longitudinal , observational study with a mean follow up of five years . SETTING --Hawaii Osteoporosis Center , Honolulu . SUBJECTS--1017 Japanese-American men born between 1900 and 1920 , of whom 378 were treated for hypertension ( study group ) and 639 did not have hypertension ( control group ) . INTERVENTION -- Thiazide diuretics were taken by 325 men for a mean of 11.9 years ; 53 men took antihypertensive drugs other than thiazides . MAIN OUTCOME MEASURE -- Rate of bone loss estimated from serial photon absorptiometric scanning at three skeletal sites ( calcaneus , distal radius , and proximal radius ) . RESULTS --Rates of bone loss at all three sites were significantly reduced among thiazide users when compared with controls . The reductions in loss rate ranged from 28.8 % ( p = 0.02 ) ( distal radius ) to 49.2 % ( p = 0.0005 ) ( calcaneus ) relative to the controls . At all three sites the men taking other antihypertensive drugs had faster loss rates ( 22.6 - 43.1 % ) than those of the controls but the difference was significant only for the distal radius . CONCLUSION --Thiazide diuretics slow the rate of bone loss in elderly men This study compared the efficacy and safety of fixed-dose combinations ( FDCs ) of the angiotensin II receptor blocker azilsartan medoxomil ( AZL-M ) and the thiazide-like diuretic chlorthalidone ( CLD ) with the individual monotherapies in a double-blind factorial study . A total of 1714 patients with clinic systolic blood pressure ( SBP ) 160 mm Hg to 190 mm Hg inclusive were r and omized to AZL-M 0 mg , 20 mg , 40 mg , or 80 mg and /or chlorthalidone 0 mg , 12.5 mg , or 25 mg . The primary efficacy end point was change from baseline to 8 weeks in trough ( hour 22 - 24 ) SBP by ambulatory blood pressure ( BP ) monitoring ( ABPM ) .  Patients ' mean age was 57 years ; 47 % were men and 20 % were black .  Baseline trough BP was approximately 165/95 mm Hg and 151/91 mm Hg by clinic and ABPM measurements , respectively . For the pooled AZL-M/CLD 40/25-mg and 80/25-mg FDC groups , SBP reduction by ABPM at trough was 28.9 mm Hg and exceeded AZL-M 80 mg and CLD 25 mg monotherapies by 13.8 mm Hg and 13 mm Hg , respectively ( P<.001 for both comparisons ) . Discontinuation rates and elevations in serum creatinine were dose-dependent and occurred more often in the AZL-M/CLD groups . In patients with stage 2 hypertension , treatment with the combination of AZL-M and CLD result ed in substantially greater SBP reduction compared with either agent alone In a double-blind study , thirty patients having mild to moderate essential hypertension were r and omly assigned to a six week regimen of either tienilic acid , hydrochlorothiazide , or placebo .  Blood pressure was significantly reduced with tienilic acid and hydrochlorothiazide although more so with tienilic acid .  Serum uric acid declined strikingly with tienilic acid and increased significantly with hydrochlorothiazide .  Serum potassium declined slightly with tienilic acid but more so with hydrochlorothiazide .  Serum creatinine and blood urea nitrogen increased slightly more with tienilic acid than with hydrochlorothiazide . There were no clinical adverse effects to any of the medications during this study . Twenty-four months of continuous administration of tienilic acid revealed maintenance of blood pressure effect , but with slight increases in blood urea nitrogen , serum creatinine and uric acid and slight decreases in serum potassium as compared to six weeks administration . Tienilic acid appears to be a useful new antihypertensive agent . The hypouricaemic effect is profound and strongly suggests the need for continuing evaluation of this compound because of its unique combination of diuretic , antihypertensive and hypouricaemic properties Hypertensive patients over the age of 60 years were admitted to a double-blind placebo-controlled trial . Patients in the actively treated group received a combined potassium-losing and -sparing diuretic ( triamterene 50 mg plus hydrochlorothiazide 25 mg ; n = 416 ) ; this dose could be doubled and methyldopa ( up to 2 g , daily ) was added in 35 % of patients when blood pressure remained high . The placebo group ( n = 424 ) received matching capsules and tablets . Adverse effects were assessed in the double-blind period of the trial by calculating the incidence of abnormal biochemical results , investigator reports of diseases and prescriptions of concomitant therapy and a self-administered symptom question naire completed by patients . In 1000 hypertensive subjects over 60 years of age , 1 year of active treatment would prevent 11 fatal cardiac events , 6 fatal and 11 non-fatal strokes and 8 cases of severe congestive heart failure . No unexpected adverse treatment effects were observed . A significant excess incidence rate ( per 1000 person years ) was found in the active group compared with placebo for : ( 1 ) impaired renal function , a serum creatinine greater than 180 mumol/l ( 2.0 mg/dl ) ; ( 2 ) mild hypokalaemia , a serum potassium less than 3.5 mmol/l ; ( 3 ) reports of gout ; and ( 4 ) an elevated serum uric acid greater than 0.52 mmol/l in men or greater than 0.46 in women . Elevated blood sugar and prescriptions for hypoglycaemic drugs tended to be more frequent in the actively treated group , but this difference was not statistically significant . In both groups , there was a low incidence ( less than 7 per 1000 person years ) of anaemia and depression and diseases of the liver , gall bladder or pancreas . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE To investigate the patterns of electrolyte abnormalities result ing from thiazide administration and whether they cause ventricular arrhythmias , and to help resolve the controversy over whether clinicians should routinely prescribe potassium-conserving therapy to all patients treated with thiazides .  DESIGN Double-blind , r and omized controlled trial . PARTICIPANTS A total of 233 hypertensive men aged 35 to 70 years . INTERVENTIONS Participants were withdrawn from prior diuretic treatment and were replenished with oral potassium chloride and magnesium oxide . They were then r and omized to 2 months of treatment with ( 1 ) hydrochlorothiazide ; ( 2 ) hydrochlorothiazide with oral potassium ; ( 3 ) hydrochlorothiazide with oral potassium and magnesium ; ( 4 ) hydrochlorothiazide and triamterene ; ( 5 ) chlorthalidone ; or ( 6 ) placebo . MAIN OUTCOME MEASURES Ventricular arrhythmias on 24-hour Holter monitoring and serum and intracellular potassium and magnesium levels . RESULTS Of the 233 participants , 212 ( 91 % ) completed the study .  Serum potassium levels were 0.4 mmol/L lower in the hydrochlorothiazide group than in the placebo group ( P less than 0.01 ) , and this mean difference was not affected by supplementation with potassium , with potassium and magnesium , or with triamterene . However , the supplements did prevent the occasional occurrence of marked hypokalemia ; all 12 of the men who developed serum potassium levels of 3.0 mmol/L or less were among the 90 who received diuretics without supplementation ( P less than 0.01 ) . Similarly , the overall proportion of men with ventricular arrhythmias was not affected by r and omized treatment , but there was a twofold increase in the proportion with arrhythmias among the 12 men with serum potassium levels of 3.0 mmol/L or less ( P = .02 ) . Serum magnesium and intracellular potassium and magnesium levels were not reduced by hydrochlorothiazide , nor were they related to ventricular arrhythmias . CONCLUSIONS In the majority of hypertensive patients , treatment with 50 mg/d of hydrochlorothiazide does not cause marked hypokalemia or ventricular arrhythmias . However , because some individuals will develop hypokalemia after starting diuretic therapy , serum potassium levels should be monitored and potassium-sparing strategies should be used when indicated This r and omised , double-blind study was design ed to investigate the efficacy of a once-daily ( OD ) combination of the AT1 receptor blocker , eprosartan 600 mg , and the thiazide diuretic , hydrochlorothiazide ( HCTZ ) 12.5 mg , in patients with mild to moderate hypertension ( sitting diastolic blood pressure ( sitDBP ) ⩾98 mm Hg and ⩽114 mm Hg ) not adequately controlled with eprosartan 600 mg OD . A total of 494 patients entered the open-label monotherapy run-in phase , which consisted of eprosartan 600 mg OD for 3 weeks . Patients who responded to monotherapy were not eligible to enter the r and omised phase of the study and were withdrawn . The remaining 309 patients were then r and omised to either eprosartan 600 mg plus HCTZ 12.5 mg OD or to continue on eprosartan 600 mg OD . In the eprosartan plus HCTZ combination group , both sitDBP and sitting systolic blood pressure ( sitSBP ) were significantly reduced compared with the eprosartan monotherapy group . In addition , the response rate was higher in the combination group compared with the monotherapy group . There were no significant effects on reduction of sitDBP due to gender , prior use of antihypertensives or baseline severity of hypertension . The tolerability profile for the combination group was similar to that for the monotherapy group . Headache was the most frequent adverse event in both treatment groups . The majority of adverse events were mild to moderate in intensity . In this study of patients who were unresponsive to eprosartan monotherapy for 3 weeks , a combination product of eprosartan 600 mg and HCTZ 12.5 mg was shown to be an effective and well tolerated treatment The object of this study was to determine the clinical ly relevant dose of bendrofluazide for the treatment of arterial hypertension . A material of 257 male and female subjects , age 25 - 70 years , with sitting diastolic blood pressures between 100 - 120 mmHg after six weeks of placebo treatment participated in this r and omized , double-blind placebo-controlled parallel group study . The patients were treated with either 0 , 1.25 , 2.5 , 5.0 or 10 mg bendrofluazide daily for 12 weeks . Blood pressure was measured with a r and om zero sphygmomanometer and a Tricuff . Compliance was checked by tablet counts . The mean decreases in diastolic blood pressure were 3.5 , 9.8 , 10.8 , 10.1 and 10.8 mmHg in the five treatment groups respectively . The heart rates were unchanged in all groups . Dose-effect relations were demonstrated for potassium , urate , glucose , cholesterol and apolipoprotein B. The lowest dose of bendrofluazide , 1.25 mg , affected only urate , whereas all of the mentioned biochemical variables were affected by the highest dose of 10 mg . It can be concluded that the optimal dose of bendrofluazide for aterial hypertension is 1.25 mg daily . Increase in the dose beyond this level only results in more pronounced adverse biochemical effects including the lipid-metabolism and subjective adverse events As sub studies of the Medical Research Council 's trials of treatment of mild hypertension and of hypertension in the elderly , two studies were carried out comparing the effects of different doses of two diuretics on blood pressure , concentrations of some biochemical variables , and the incidence of subjective adverse reactions . In one study , in which 484 patients with mild hypertension participated , daily doses of bendrofluazide 5 mg and 10 mg , with and without oral potassium supplements , were compared . In the second , involving 701 elderly patients with hypertension , daily doses of hydrochlorothiazide 25 mg together with amiloride 2.5 mg were compared with hydrochlorothiazide 50 mg together with amiloride 5 mg . The mean ( + /- SD ) duration s of treatment were 35 + /- 17 months in the first study and 10 + /- 7 months in the second . Neither study showed any significant difference in blood pressure response to the two doses of diuretic , whereas biochemical changes and the reported incidence of subjective adverse reactions were dose-related . In the first study , potassium supplementation with potassium chloride 16.8 or 33.6 mmol did not have a significant effect on the fall in serum potassium level , which was only slightly reduced , and did not have any significant effect on the antihypertensive effect of either dose of bendrofluazide The European Working Party on High Blood Pressure in the Elderly study ( EWPHE ) was a placebo-controlled , double-blind , inter-patient assessment of diuretic treatment in hypertensive patients aged 60 years or more . Of the 840 patients included in the study 247 had isolated systolic hypertension ( systolic blood pressure greater than or equal to 160 and diastolic blood pressure less than or equal to 95 mmHg ) . In those ( n = 120 ) r and omized to active treatment ( diazide-hydrochlorothiazide with triamterene + /- methyldopa )  blood pressure after 3 years was , on average , 19/8 mmHg lower than in the placebo group ( n = 119 ) and after 5 years the difference was 9/7 mmHg . Data on mortality and morbidity were insufficient for firm conclusions to be drawn . The data are presented here only to communicate the trends observed and to provide information that may be useful in the design of future trials . The trends observed for cardiac mortality , terminating non-fatal events ( including severe heart failure ) and combined fatal and non-fatal cardiovascular events follow a similar pattern to that observed in the trial overall , in that active treatment appeared to confer benefit . However , in the case of isolated systolic hypertension none of these differences between active and placebo treatment achieved statistical significance . We conclude that , given the epidemiological data incriminating systolic hypertension as a risk factor and the data presented here , a rigorous assessment of the value of treating isolated systolic hypertension is justified Serum glucose levels , triglyceride levels , and body weight are reported from a controlled drug trial in men , aged 40 to 49 , with uncomplicated mild hypertension . The drug treatment started with hydrochlorothiazide alone , and methyldopa was added when necessary . If side effects occurred , methyldopa was replaced by propranolol . No detailed advice about diet , smoking , or weight reduction was given to any group . The untreated control subjects had a small increase in serum glucose levels during five years , from 6.08 to 6.21 mmol/liter . Those treated with hydrochlorothiazide alone and those treated with hydrochlorothiazide plus methyldopa had a small increase in serum glucose levels of the same order as that in the control subjects . However , those receiving the thiazide/propranolol combination experienced a sizeable increase in glucose levels , from 5.96 to 6.53 mmol/liter ( p less than 0.001 ) . This increase was significantly greater than the increase in the other groups ( p less than 0.001 ) . The thiazide/propranolol group also showed a significant increase in serum triglyceride levels ( p less than 0.05 ) . There was no difference in serum potassium levels in the different drug groups . The results indicate that moderate thiazide doses do not have significant effects on serum glucose levels in this age group . Propranolol in combination with thiazide seems to increase the level of serum glucose BACKGROUND The chronic low- grade metabolic acidosis that occurs in various renal disorders and in normal people , and that is related both to dietary net acid load and age-related renal functional decline , may contribute to osteoporosis by increasing urine calcium excretion . Administration of potassium ( K ) alkali salts neutralizes acid and lowers urine calcium excretion . Urine calcium excretion also can be reduced by the administration of thiazide diuretics , which are often given with supplemental K to avoid hypokalemia . We determined whether the K alkali salt potassium bicarbonate ( KHCO3 ) and the thiazide diuretic hydrochlorothiazide ( HCTZ ) combined is more effective in reducing urinary calcium than KHCO3 alone or HCTZ combined with the conventionally coadministered nonalkalinizing K salt potassium chloride ( KCl ) . METHODS Thirty-one healthy men and women aged 50 or greater were recruited for a four-week , double-blind , r and omized study . After a baseline period of 10 days with three 24-hour urine and arterialized blood collection s , subjects were r and omized to receive either HCTZ ( 50 mg ) plus potassium ( 60 mmol daily ) as either the chloride or bicarbonate salt . Another 19 women received potassium bicarbonate ( 60 mmol ) alone . After two weeks , triplicate collection s of 24-hour urines and arterialized bloods were repeated . RESULTS Urinary calcium excretion decreased significantly in all groups . KHCO3 alone and HCTZ + KCl induced similar decreases ( -0.70 + /- 0.60 vs. -0.80 + /- 1 . 0 mmol/day , respectively ) . Compared with those treatments , the combination of HCTZ + KHCO3 induced more than a twofold greater decrease in urinary calcium excretion ( -1.8 + /- 1.2 mmol/day , P < 0 . 05 ) . Both HCTZ + KHCO3 and KHCO3 alone reduced net acid excretion significantly ( P < 0.05 ) to values of less than zero . CONCLUSIONS KHCO3 was superior to KCl as an adjunct to HCTZ , inducing a twofold greater reduction in urine calcium excretion , and completely neutralizing endogenous acid production so as to correct the pre-existing mild metabolic acidosis that an acid-producing diet usually induces in older people . Accordingly , for reducing urine calcium excretion in stone disease and osteoporosis , the combination of HCTZ + KHCO3 may be preferable to that of HCTZ + KCl BACKGROUND It is expected that the treatment of hypertension in patients with renal disease decreases the risk of cardiovascular events , but the evidence in these patients is lacking . OBJECTIVE To assess the effect of diuretic-based treatment on cardiovascular events in patients with isolated systolic hypertension and renal dysfunction . METHODS A total of 4336 persons aged 60 years and older with systolic blood pressures of 160 mm Hg and higher and diastolic blood pressures of less than 90 mm Hg were r and omly assigned to receive either placebo or chlorthalidone ( 12.5 - 25.0 mg/d ) , with the addition of atenolol ( 25 - 50 mg/d ) or reserpine ( 0.05 - 0.10 mg/d ) if needed , and observed for 5 years . The risk of first-occurring cardiovascular events , including stroke , transient ischemic attack , myocardial infa rct ion , heart failure , coronary artery bypass surgery , angioplasty , aneurysm , endarterectomy , sudden death , or rapid death , was stratified according to baseline serum creatinine levels ( 35.4 - 84.0 , 84.1 - 101.6 , 101.7 - 119.3 , and 119.4 - 212.2 micromol/L [ 0.4 - 0.9 , 1.0 - 1.1 , 1.2 - 1.3 , and 1.4 - 2.4 mg/dL ] ) . RESULTS Systolic blood pressure reduction was not affected by baseline serum creatinine levels . Active treatment did not affect the risk of serum creatinine levels becoming elevated during follow-up . The risk of hypokalemia with active treatment decreased significantly with increasing baseline serum creatinine levels . In the 4 baseline serum creatinine groups , the relative risk ( 95 % confidence interval ) of cardiovascular events developing with active treatment was 0.73 ( 0.54 - 0.97 ) , 0.63 ( 0.49 - 0.82 ) , 0.62 ( 0.44 - 0.87 ) , and 0.59 ( 0.38 - 0.91 ) . The results were similar for the outcomes of stroke or coronary artery events and in analyses stratified by sex or age . CONCLUSION Diuretic-based treatment of patients with isolated systolic hypertension prevents the development of cardiovascular events in older persons with mild renal dysfunction The antihypertensive efficacy of a 1.5-mg sustained-release formulation ( SR 1.5 ) of indapamide , a diuretic related to thiazide , has been pointed out by using conventional sphygmomanometric measurement 24 h after dosing in clinic , in two large European r and omized , double-blind , controlled studies ( 2 and 3 months ) . One of these studies was then extended to 12 months , as a complementary open study .  Quality -controlled ambulatory blood pressure monitoring ( ABPM ) data for a total of 216 patients from these studies are presented , including subgroups of hypertensives and responders .  Indapamide SR 1.5 achieves an adequate 24-h blood pressure control by significantly reducing the 24-h , diurnal , and nocturnal blood pressures versus baseline , confirming the sphygmomanometric data . The benefit at 2 and 3 months is maintained at 1 year , which confirms the long-term efficacy of SR 1.5 mg . The trough-to-peak ratio -- not previously calculated for a diuretic according to international guidelines --meets Food and Drug Administration requirements and confirms the 24-h efficacy of indapamide SR 1.5 BACKGROUND The apparent shortfall in prevention of coronary heart disease ( CHD ) noted in early hypertension trials has been attributed to disadvantages of the diuretics and beta blockers used . For a given reduction in blood pressure , some suggested that newer agents would confer advantages over diuretics and beta blockers . Our aim , therefore , was to compare the effect on non-fatal myocardial infa rct ion and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril . METHODS We did a multicentre , prospect i ve , r and omised controlled trial in 19 257 patients with hypertension who were aged 40 - 79 years and had at least three other cardiovascular risk factors . Patients were assigned either amlodipine 5 - 10 mg adding perindopril 4 - 8 mg as required ( amlodipine-based regimen ; n=9639 ) or atenolol 50 - 100 mg adding bendroflumethiazide 1.25 - 2.5 mg and potassium as required ( atenolol-based regimen ; n=9618 ) . Our primary endpoint was non-fatal myocardial infa rct ion ( including silent myocardial infa rct ion ) and fatal CHD . Analysis was by intention to treat . FINDINGS The study was stopped prematurely after 5.5 years ' median follow-up and accumulated in total 106 153 patient-years of observation . Though not significant , compared with the atenolol-based regimen , fewer individuals on the amlodipine-based regimen had a primary endpoint ( 429 vs 474 ; unadjusted HR 0.90 , 95 % CI 0.79 - 1.02 , p=0.1052 ) , fatal and non-fatal stroke ( 327 vs 422 ; 0.77 , 0.66 - 0.89 , p=0.0003 ) , total cardiovascular events and procedures ( 1362 vs 1602 ; 0.84 , 0.78 - 0.90 , p<0.0001 ) , and all-cause mortality ( 738 vs 820 ; 0.89 , 0.81 - 0.99 , p=0.025 ) . The incidence of developing diabetes was less on the amlodipine-based regimen ( 567 vs 799 ; 0.70 , 0.63 - 0.78 , p<0.0001 ) . INTERPRETATION The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen . On the basis of previous trial evidence , these effects might not be entirely explained by better control of blood pressure , and this issue is addressed in the accompanying article . Nevertheless , the results have implication s with respect to optimum combinations of antihypertensive agents Background Prehypertension is associated with higher  cardiovascular risk ,  target organ damage , and incidence of hypertension . The Prevention of Hypertension in Patients with PreHypertension ( PREVER‐Prevention ) trial aim ed to evaluate the efficacy and safety of a low‐dose diuretic for the prevention of hypertension and end‐organ damage . Methods and Results This r and omized , parallel , double‐blind , placebo‐controlled trial was conducted in 21 Brazilian academic medical centers . Participants with prehypertension who were aged 30 to 70 years and who did not reach optimal blood pressure after 3 months of lifestyle intervention  were r and omized to a chlorthalidone/amiloride combination pill or placebo and were evaluated every 3 months during 18 months of treatment . The primary outcome was incidence of hypertension . Development or worsening of microalbuminuria , new‐onset diabetes mellitus , and reduction of left ventricular mass were secondary outcomes . Participant characteristics were evenly distributed by trial arms . The incidence of hypertension was significantly lower in 372 study participants allocated to diuretics compared with 358 allocated to placebo ( hazard ratio 0.56 , 95 % CI 0.38–0.82 ) , result ing in a cumulative incidence of 11.7 % in the diuretic arm versus 19.5 % in the placebo arm ( P=0.004 ) . Adverse events ; levels of blood glucose , glycosylated hemoglobin , creatinine , and microalbuminuria ; and incidence of diabetes mellitus were no different between the 2 arms . Left ventricular mass assessed through Sokolow‐Lyon voltage and voltage‐ duration product decreased to a greater extent in participants allocated to diuretic therapy compared with placebo ( P=0.02 ) . Conclusions A combination of low‐dose chlorthalidone and amiloride effectively reduces the risk of incident hypertension and beneficially affects left ventricular mass in patients with prehypertension . Clinical Trial Registration URL : http://www . Clinical Trials.gov , www.ensaiosclinicos.gov . Unique identifiers : NCT00970931 , RBR‐74rr6s OBJECTIVE --To determine the relevant dose of bendrofluazide for treating mild to moderate hypertension . DESIGN --Double blind parallel group trial of patients who were given placebo for six weeks and then r and omly allocated to various doses of bendrofluazide ( 1.25 , 2.5 , 5 , or 10 mg daily ) or placebo for 12 weeks . SETTING --General practice s in Zeal and , Denmark . PATIENTS --257 Patients with newly diagnosed or previously treated hypertension , aged 25 - 70 , who had a mean diastolic blood pressure of 100 - 120 mm Hg after receiving placebo for six weeks . MAIN OUTCOME MEASURES --Reduction in diastolic blood pressure and changes in biochemical variables ( potassium , urate , glucose , fructosamine , total cholesterol , apolipoprotein A I , apolipoprotein B , and triglyceride concentrations ) . RESULTS --All doses of bendrofluazide significantly reduced diastolic blood pressure to the same degree ( 10 - 11 mm Hg ) . Clear relations between dose and effect were shown for potassium , urate , glucose , total cholesterol , and apolipoprotein B concentrations . The 1.25 mg dose increased only urate concentrations , whereas the 10 mg dose affected all the above biochemical variables . CONCLUSION --The relevant range of doses of bendrofluazide to treat mild to moderate hypertension is 1.25 - 2.5 mg a day . Higher doses caused more pronounced adverse biochemical effects including adverse lipid effects . Previous trials with bendrofluazide have used too high doses The therapeutic and biochemical effects of two commonly employed diuretic preparations were compared in a double-blind fashion in 32 patients with congestive heart failure . At the doses employed , furosemide and a fixed combination of spironolactone and hydrochlothiazide maintained control of the clinical manifestations of congestive heart failure to about the same degree . However , significant biochemical changes in the renin-aldosterone system were found in patients receiving the spironolactone/thiazide combination therapy . A significant increase in plasma renin activity and a significantly greater increase in aldosterone excretion were found in the spironolactone/thiazide group compared to the furosemide group . No significant differences were observed in serum potassium levels or 24-hour potassium excretion rates in patients treated with the two diuretic preparations OBJECTIVE To assess the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal ( total ) stroke in isolated systolic hypertension . DESIGN Multicenter , r and omized , double-blind , placebo-controlled . SETTING Community-based ambulatory population in tertiary care centers . PARTICIPANTS 4736 persons ( 1.06 % ) from 447,921 screenees aged 60 years and above were r and omized ( 2365 to active treatment , 2371 to placebo ) . Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was less than 90 mm Hg . Of the participants , 3161 were not receiving antihypertensive medication at initial contact , and 1575 were . The average systolic blood pressure was 170 mm Hg ; average diastolic blood pressure , 77 mm Hg . The mean age was 72 years , 57 % were women , and 14 % were black . INTERVENTIONS -- Participants were stratified by clinical center and by antihypertensive medication status at initial contact . For step 1 of the trial , dose 1 was chlorthalidone , 12.5 mg/d , or matching placebo ; dose 2 was 25 mg/d . For step 2 , dose 1 was atenolol , 25 mg/d , or matching placebo ; dose 2 was 50 mg/d . MAIN OUTCOME MEASURES Primary . Nonfatal and fatal ( total ) stroke . Secondary . Cardiovascular and coronary morbidity and mortality , all-cause mortality , and quality of life measures . RESULTS Average follow-up was 4.5 years . The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the active treatment group , and the 5-year average diastolic blood pressure was 72 and 68 mm Hg , respectively . The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo . The relative risk by proportional hazards regression analysis was 0.64 ( P = .0003 ) . For the secondary end point of clinical nonfatal myocardial infa rct ion plus coronary death , the relative risk was 0.73 . Major cardiovascular events were reduced ( relative risk , 0.68 ) . For deaths from all causes , the relative risk was 0.87 . CONCLUSION In persons aged 60 years and over with isolated systolic hypertension , antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36 % , with 5-year absolute benefit of 30 events per 1000 participants . Major cardiovascular events were reduced , with 5-year absolute benefit of 55 events per 1000 Two recent , multicenter , double-blind , placebo-controlled studies established the efficacy and safety of low-dose bisoprolol/hydrochlorothiazide ( HCTZ ) in patients with mild to moderate essential hypertension .  Bisoprolol , a cardioselective beta-blocker , was used in a dose of 2.5 mg , 5 mg , or 10 mg . HCTZ was used at a dose of 6.25 mg . This low-dose compound was developed to minimize dose-related adverse effects . The addition of HCTZ to each of the doses of bisoprolol was compared with monotherapy and placebo . Results of both studies demonstrated that this once-a-day , low-dose option effectively reduced sitting diastolic and systolic blood pressure measured at the end of the 24-hour dosing period . Drug-related adverse effects , including those generally associated with traditional beta-blocker therapy , were infrequent in individuals who received the low-dose bisoprolol/HCTZ regimen . Dose-related side effects were minimized because of the low doses of the two agents used together . There were no significant changes in mean total cholesterol , triglycerides , or serum glucose with bisoprolol/HCTZ 6.25 mg therapy versus placebo ( analysis of variance statistical methods ) . The incidence of treatment-induced hypokalemia with bisoprolol/HCTZ 6.25 mg was not significant ; uric acid elevations were minimized , and the incidence of hyperuricemia was significantly ( P < 0.01 ) less with bisoprolol/HCTZ 6.25 mg than with 25 mg of HCTZ . Once-a-day dosing with the low-dose agent controlled ( defined as a sitting diastolic blood pressure < or = 90 mmHg and /or a decrease from baseline > or = 10 mmHg ) blood pressure in up to 80 % of patients for a full 24 hours after dosing . ( ABSTRACT TRUNCATED AT 250 WORDS SIR — It is estimated that 25–40 % of adults aged 65 years and over use diuretics [ 1 ] . The three major classes of diuretics have different effects on renal calcium balance .  Loop diuretics increase renal calcium excretion [ 2 ] , while thiazide and potassium-sparing diuretics exert a hypocalciuric effect . Thiazides facilitate the reabsorption of calcium in the early segment of the convoluted distal tubule , and potassium-sparing diuretics promote reabsorption of calcium in the late segment of the distal tubule [ 3–5 ] . Epidemiological data [ 6–14 ] and results from r and omised controlled trials [ 15–17 ] suggest that thiazide diuretic use is associated with a small increase in bone mineral density ( BMD ) or a decreased rate of bone loss . However , these associations were observed primarily among women . There are few data regarding the effects of loop diuretics on BMD and findings are not consistent across studies [ 18 , 19 ] . Although some studies have shown that loop diuretic use may be associated with an increased risk of hip and osteoporotic fractures [ 20–22 ] , it is uncertain whether this possibly elevated fracture risk was mediated by the effect of loop diuretics on bone or rather on fall-related mechanisms , such as dizziness and orthostasis . To our knowledge , no studies have specifically examined whether potassium-sparing diuretics have an independent effect on BMD . Therefore , we conducted a cross-sectional study among participants in the Osteoporotic Fractures in Men ( MrOS ) study , an ongoing prospect i ve study of community-dwelling men , to investigate the association between current diuretic use and BMD at multiple skeletal sites . We hypothesised that compared with diuretic non-users , loop diuretic users would have a lower mean BMD , while thiazide and potassium-sparing diuretic users would have a higher mean BMD In guidelines , a combination therapy of two or more antihypertensives is recommended for treatment of hypertension where monotherapy is ineffective . Although diuretics or calcium channel blockers are commonly used as add-ons to angiotensin receptor blocker ( ARB ) , the most effective and safe combination has not been established . In this r and omized 4-month study , the efficacy and safety were compared between an ARB/diuretics ( losartan/hydrochlorothiazide [ HCTZ ] ) combination and the most prescribed combination , ARB/calcium channel blocker ( c and esartan/amlodipine ) in hypertensive patients for whom 8 mg/day of c and esartan proved ineffective . After 36 patients were recruited and allocated into two groups , changes in blood pressure ( BP ) and laboratory values were analyzed in 31 patients : 16 patients received losartan ( 50 mg/day)/HCTZ ( 12.5 mg/day ) ( L/H group ) , and 15 patients received c and esartan ( 8 mg/day)/amlodipine ( 5 mg/day ) ( C/A group ) after 5 patients were withdrawn . After 4 months , L/H significantly ( p<0.001 ) reduced mean systolic BP (SBP)/diastolic BP ( DBP ) from baseline 160/89±13/11 mmHg to 140/80±9/8 mmHg , and C/A reduced BP from 161/90±10/11 mmHg to 141/79±10/7 mmHg . The efficacy in reducing BP was similar between the two combination therapies . L/H significantly reduced serum potassium , but within the normal range , and did not increase serum uric acid or serum triglyceride . With L/H , the percentage of patients who attained the BP goal in SBP was higher in elderly patients than in younger patients . As L/H is more cost-effective than c and esartan/amlodipine and has fewer adverse effects on uric acid and other metabolic parameters than diuretic monotherapy , it is concluded to be useful for the management of hypertension The 2014 Evidence -Based Guideline for the Management of  High Blood Pressure In Adults : Report From the Panel Members Appointed to the Eighth Joint National Committee ( JNC 8) recommends several major changes from the JNC 7 report ( 1 , 2 ) . The 2014 guideline is based on a systematic review of r and omized , controlled trials ( RCTs ) by a multidisciplinary panel using a process informed by Institute of Medicine recommendations for guideline development ( 3 ) . Although there was almost unanimous agreement on nearly all recommendations , a minority of the panel ( the authors of this commentary ) disagreed with the recommendation to increase the target systolic blood pressure ( SBP ) from 140 to 150 mm Hg in persons aged 60 years or older without diabetes mellitus ( DM ) or chronic kidney disease ( CKD ) . This target guides both the initiation of therapy and treatment goals . Although this issue has major clinical and public health implication s , the guideline only briefly summarized the concerns underlying the minority opinion to maintain the target of less than 140 mm Hg . The Institute of Medicine recommendation for guideline development encourages guidelines to provide a description and explanation of any differences of opinion regarding the recommendation ( 3 ) . This summarizes the evidence and rationale underlying the minority opinion to maintain the SBP target of 140 mm Hg or lower in persons aged 60 years or older until there is greater certainty of the risks and benefits of a higher target . First , increasing the target will probably reduce the intensity of antihypertensive treatment in a large population at high risk for cardiovascular disease ( CVD ) ( Table 1 ) . The higher SBP goal would apply to some of the groups at highest cardiovascular risk , such as African Americans , hypertensive patients with multiple CVD risk factors other than DM or CKD , and those with clinical CVD . Second , the evidence supporting increasing the SBP target from 140 to 150 mm Hg in persons aged 60 years or older was insufficient and inconsistent with the evidence supporting the panel 's recommendations for an SBP target of less than 140 mm Hg in persons younger than 60 years and those aged 60 years or older with DM or CKD . Third , the higher SBP goal in individuals aged 60 years or older may reverse the decades-long decline in CVD , especially stroke mortality ( 4 ) . In the absence of definitive evidence defining the optimum SBP target , observational studies and RCT data that the panel did not systematic ally review more strongly support the SBP goal of less than 140 mm Hg , especially in high-risk individuals . Other recent guideline groups review ing similar evidence have recommended a goal of less than 140 mm Hg , particularly in persons aged 80 years or younger ( 59 ) . Table 1 . U.S. Cardiovascular Disease Death Rates for Persons Younger and Older Than 65 y Persons Aged 60 Years or Older With Hypertension and SBP Controlled to 140 mm Hg or Lower More than half of the 72 million persons with hypertension in the United States are aged 60 years or older ( 10 , 11 ) . Among these individuals , the 2014 guideline recommends the SBP goal of 140 mm Hg or lower only for those with DM and those younger than 70 years with CKD ( 2 ) . Although the prevalence of hypertension in this age group ( 65 % to 67 % ) did not change between 1999 and 2010 , the percentage with adequate blood pressure control increased from 27.4 % ( 19992000 ) to 50.5 % ( 20112012 ) , with 82.2 % now receiving antihypertensive medications ( 10 , 12 ) . Data from NHANES ( National Health and Nutrition Examination Survey ) from 2001 to 2008 show that among treated and untreated hypertensive adults aged 60 years or older , median SBPs were 136 mm Hg and 152 mm Hg , respectively ( 13 ) , and SBPs have been decreasing in this age group over the past 5 decades ( Figure ) ( 4 ) . Thus , a target of less than 150 mm Hg would likely increase blood pressures in the treated hypertensive population and would suggest that nearly half of the untreated hypertensive patients in this age range should remain untreated . The large population at high risk for CVD , with most currently at an SBP of 140 mm Hg or lower , creates concern that a higher SBP target will adversely affect public health . Figure . Smoothed weighted frequency distribution , median , and 90th percentile of systolic blood pressure for persons aged 60 to 74 y : United States , 19592010 . Reproduced from Lackl and and colleagues ( 4 ) . NHANES = National Health and Nutrition Examination Survey ; NHES = National Health Examination Survey . High Risk in Persons With the Higher Goal Age substantially increases risk for cardiovascular events ( Table 1 ) , so differences in cardiovascular risk do not justify different targets for patients older and younger than 60 years . The risk range for white and African American men aged 60 years is 9 % to 30 % , depending on risk factor profile . For men of both ethnicities who are aged 70 years or older and have SBP controlled to 140 mm Hg , even without clinical CVD or DM , the 10-year risk exceeds 20 % ( 14 ) . Thus , on the basis of absolute risk , using an age threshold of 60 years to define eligibility for less aggressive treatment lacks consistency . Persons aged 60 to 79 years are at higher risk than those who are younger , even if the younger persons have DM . Insufficient Evidence for Differential Hypertension Treatment Benefit for Patients Older and Younger Than 60 Years The 2014 guideline panel failed to identify evidence of differential benefits or harms of treatment using an SBP goal of 140 mm Hg with an age threshold of 60 years . There is little RCT evidence of risk or benefit in treating persons younger than 60 years to this target , except in those with diastolic hypertension . The guideline indicates that no qualifying evidence was found comparing an SBP less than 140 mm Hg to any other SBP goal for persons younger than 60 years ( 2 ) . However , in persons aged 60 years or older , the SHEP ( Systolic Hypertension in the Elderly Program ) trial showed benefit of treating hypertension to an SBP goal between 140 and 145 mm Hg ( Table 2 ) ( 15 ) . HYVET ( Hypertension in the Very Elderly Trial ) found a benefit of an SBP target of less than 150 mm Hg on health outcomes , including mortality in persons aged 80 years or older ( 16 ) . Patients in the HYVET treatment group achieved an SBP of 144 mm Hg at 2 years compared with 159 mm Hg in the control group , and blood pressures continued to decrease in both groups until the end of the trial . Therefore , HYVET and the SHEP trial provide evidence that reducing SBP to around 140 mm Hg has substantial benefit without major harm in older persons . Thus , the best evidence available for an SBP target around 140 mm Hg , which meets the guideline RCT criteria , is in persons older than 60 years . The lack of benefit seen in 2 Japanese trials in older individuals ( JATOS [ Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients ] [ 17 ] and the VALISH [ Valsartan in Elderly Isolated Systolic Hypertension ] trial [ 18 ] ) was cited by some to rationalize the higher SBP target , but these trials were underpowered ( Table 2 ) . The SHEP trial and HYVET together reported 365 strokes and more than 285 coronary heart disease events , whereas JATOS and the VALISH trial only had a combined total of 125 strokes and 67 coronary heart disease events . In addition , the much larger FEVER ( Felodipine Event Reduction ) trial ( 19 ) did not meet criteria for inclusion in the panel 's deliberation ( Table 2 ) . This trial , which was conducted in a Chinese population ( age range , 50 to 79 years ; mean age , 62 years ) , reported a significant 27 % reduction in its primary outcome , as well as significant reductions in all CVD , total mortality , coronary heart disease , and heart failure in patients treated to an SBP of 137 mm Hg with a thiazide diureticcalcium-channel blocker combination versus 143 mm Hg with a thiazide diuretic plus placebo ( 19 ) . Table 2 . Trials Comparing Different Systolic Blood Pressure Thresholds In addition , generalizability of the Japanese trials to other population s of patients older than 60 years , such as African Americans , is uncertain . African Americans are at highest risk for all complications of hypertension and are historically undertreated . Thus , we believe that recommending less aggressive targets in this or other high-risk population s requires stronger justification than the guideline cites . Three recent guidelines from other countries have concluded that the appropriate cut point for an age-related differential SBP goal is 80 years or older ( 57 ) . We agree that this higher treatment target in frail hypertensive patients aged 80 years or older better reflects existing evidence . Safety and Adverse Event Risk in Hypertensive Patients Aged 60 Years or Older Despite the limited number of end points in JATOS and the VALISH trial , their size and duration provide evidence of safety of the SBP target of less than 140 mm Hg . The VALISH investigators concluded that this target was safe in relatively healthy patients aged 70 years or older with isolated systolic hypertension ( 18 ) . In JATOS , adverse events requiring treatment discontinuation were reported in only 36 patients , with no differences in discontinuation rate between groups ( 17 ) . This evidence and the favorable results at slightly higher blood pressures in the SHEP trial and HYVET provide reassurance of the safety of an SBP goal of less than 140 mm Hg in older , nonfrail persons . Other Trial Evidence of Benefit of Treatment at an SBP of 140 mm Hg or Lower Results of the SPS3 ( Secondary Prevention of Small Subcortical Strokes ) trial indicated that an SBP target of less than 130 mm Hg versus 144 mm Hg in 3020 patients ( mean age , 63 years ) reduced subsequent strokes by 19 % ( P= 0.08 ) and hemorrhagic strokes by nearly 50 % ( P < 0.01 ) ( 20 ) . Of note , the FEVER trial reported a 44 % ( P < 0.001 ) reduction in all strokes in a subgroup analysis of patients older than 65 years ( 17 ) . Finally , 2 meta-analyses Ten patients with low-renin hypertension were treated with high doses of a diuretic and a mineralocorticoid antagonist in a double-blind crossover study . Hydrochlorothiazide-induced volume depletion had a beneficial hypotensive response . However , despite comparable diuretic response , the hypotensive response observed with spironolactone was significantly greater . Renin responsiveness was seen to increase — but to submaximal levels — with thiazide therapy ; while spironolactone therapy restored normal renin responsiveness . The differential response to thiazide and spironolactone is similar to the response observed when these agents are used in primary aldosteronism , a hypertensive disease where mineralocorticoid excess is clearly identified as the cause of both the hypertension and low plasma renin activity . The fact that mineralocorticoid blockade induced by spironolactone corrects the hypertension and restores normal renin responsiveness suggests that mineralocorticoid excess may be responsible for the hypertension and low plasma renin activity The efficacy and safety of the novel calcium antagonist Amlodipine ( Pfizer Laboratories , New York , New York ) and hydrochlorothiazide were evaluated and compared in a r and omized , single-blind , parallel group study in black Africans with essential hypertension . Twenty Nigerians with newly diagnosed mild to moderate essential hypertension were r and omized to receive ascending doses of Amlodipine ( 5 mg and 10 mg ) or hydrochlorothiazide ( 25 mg or 50 mg ) , and blood pressure and heart rate were measured at baseline and at 2 , 4 , and 6 weeks of therapy . Both Amlodipine and hydrochlorothiazide significantly reduced supine and erect blood pressure . Supine blood pressure on Amlodipine fell from a mean of 190/104 mm Hg to 150/79 mm Hg , and on thiazide from 180/103 mm Hg to 141/84 mm Hg . There was , however , no significant difference between both drugs in antihypertensive efficacy . Neither drug induced a reflex increase in heart rate . The fall in blood pressure on both agents was associated with an increase in plasma urea .  Amlodipine induced no change in plasma potassium , but hydrochlorothiazide caused hypokalemia . Both agents were well tolerated , and Amlodipine should undergo further study in the treatment of hypertension in blacks OBJECTIVES The goal of this study was to determine if a low-dose combination of the angiotensin-converting enzyme inhibitor perindopril ( Per ) and the diuretic indapamide ( Ind ) reduces central ( thoracic aorta , carotid artery ) as well as brachial systolic blood pressure ( SBP ) more than the beta-blocker atenolol and to determine the hemodynamic factors influencing independently brachial and central SBP : pulse wave velocity ( PWV ) and pattern of wave reflections . BACKGROUND In high cardiovascular risk population s , angiotensin blockade improves survival without affecting brachial SBP and diastolic blood pressure ( DBP ) . Whether central SBP , which is physiologically lower than brachial SBP , is significantly reduced has never been investigated . METHODS This study was a double-blind r and omized trial for one year in patients with essential hypertension . RESULTS For a similar DBP reduction , Per/Ind decreased SBP significantly more than atenolol , with a more pronounced reduction for central than for brachial SBP . After one year , the difference between brachial and central SBP was maintained by Per/Ind ( 8.28 + /- 1.53 mm Hg ) and significantly attenuated by atenolol ( 0.29 + /- 1.61 mm Hg ) . Under atenolol , the principal factor modulating SBP reduction was mean blood pressure . Under Per/Ind , this parameter played a minor role , and the central SBP reduction implied a major role for disturbed PWV and wave reflections . CONCLUSIONS Under Per/Ind , but not atenolol , normalization of brachial SBP is achieved with a significantly greater reduction of central SBP . This hemodynamic profile reflects changes of wave reflections issued from distal arterial and arteriolar territory , where Per/Ind , but not atenolol , is known to improve vessel wall structure & NA ; Several imperatives drive the need to establish the merit of treating isolated systolic hypertension in the elderly . These include its higher prevalence with age , the associated excess cardiovascular risks , and the rapid aging of the population . The Systolic Hypertension in the Elderly Program demonstrated a significant reduction in stroke incidence ( fatal and nonfatal ) ( 36 % , equivalent to preventing 30 strokes per 1,000 participants per 5 years ) . A 27 % reduction in coronary heart disease incidence and a 32 % reduction in all major cardiovascular events were also achieved ( equivalent to the prevention of 16 and 55 events per 1,000 participants per 5 years , respectively ) . These results were associated with a treatment regimen in which the primary agent was low‐dose chlorthalidone . The benefits accrued to all subgroups identified based on baseline age , race and sex , blood pressure , serum cholesterol levels , and electrocardiographic abnormalities . The reduction in coronary disease is consistent with predictions based on prospect i ve epidemiological studies and is concordant with other recent intervention trials . It is a reasonable inference from the Systolic Hypertension in the Elderly Program findings that middle‐aged as well as older people with isolated systolic hypertension , and people with less severe degrees of this condition , particularly when other risk factors are present , would benefit from such therapy . Another reasonable implication of the trial relates to the matter of preferred drug treatment regimens for diastolic hypertension , in middle‐aged as well as older people . A low‐dose diuretic regimen is clearly the initial treatment of choice for most hypertensive patients , based on demonstrated reduction in risk for major cardiovascular events , including coronary heart disease , and its safety , patient acceptance , and low cost . ( Hypertension 1993;21:335‐343 The association of serum uric acid with cardiovascular disease  has been appreciated for nearly half a century ( 1 ) . Several prospect i ve studies have shown an association between baseline hyperuricemia and incident coronary heart disease , cardiovascular disease , and death ( 2 - 10 ) . Despite the strength of these associations , uric acid has not been established as a causal risk factor for cardiovascular disease . Instead , uric acid seems inextricably linked to hypertension , dyslipidemia , and disordered glucose metabolism , which play a causal role in the pathogenesis of cardiovascular disease . As such , uric acid may be merely a marker of risk for cardiovascular disease . Several recent reports , however , have attempted to dispel this notion ( 3 , 9 , 11 - 14 ) . Using data from the First National Health and Nutrition Examination Study ( NHANES I ) , Freedman and colleagues ( 3 ) demonstrated that each 60-mol/L increment in uric acid level was associated with a 48 % increase in risk for  incident ischemic heart disease among women . Furthermore , a growing body of laboratory and clinical evidence suggests that uric acid plays a role in platelet adhesiveness ( 15 - 17 ) , formation of free radicals ( 18 ) , and oxidative stress ( 19 , 20 ) . As a result of this growing controversy , we revisited this question in the Framingham Heart Study sample . Longer and more contemporary follow-up and more outcome events allowed us to exp and on a previous Framingham report [ 2 ] . In this paper , we describe the relation of baseline serum uric acid level to 1 ) incident coronary heart disease events [ death from coronary heart disease , recognized myocardial infa rct ion , and coronary insufficiency ] , 2 ) death from cardiovascular disease , and 3 ) death from all causes . Because previous studies ( 2 , 3 , 7 , 21 ) have suggested that uric acid is more strongly associated with adverse events in women than in men , we chose a priori to perform sex-specific analyses . Methods Study Sample The selection criteria and study design of the Framingham Heart Study and the Framingham Offspring Study have been described elsewhere ( 22 , 23 ) . Original participants of the Framingham Heart Study who took part in the 13th biennial examination ( 1972 to 1976 ) and adult participants in the first examination of the Framingham Offspring Study ( 1971 to 1975 ) were eligible for this investigation ( n=7940 ) . Blood sample s for uric acid measurement were obtained in 7650 ( 96.3 % ) persons . Participants were excluded ( n=887 ) for the following reasons : use of more than 2 g of salicylates per day ( n=17 ) , missing covariate or follow-up data ( n=117 ) , and prevalent cardiovascular disease ( n=753 ) . The remaining 6763 participants were followed prospect ively until 1994 . Baseline Measurements and Definitions Medical histories and physical examinations were performed for each participant at every clinic visit . Systolic and diastolic blood pressure were measured twice in the left arm of seated participants by using a mercury-column sphygmomanometer positioned near eye level . The average of the two readings was used for each blood pressure variable . The diagnosis of hypertension was based on a systolic blood pressure of 140 mm Hg or higher , a diastolic blood pressure of 90 mm Hg or higher , or the current use of antihypertensive drugs ( 24 ) . Height and weight were measured at each examination , and body mass index was calculated as the weight in kilograms divided by the square of the height in meters . Participants who reported smoking at least one cigarette per day during the year before the examination were classified as current smokers . Alcohol use was ascertained by self-report and was categorized as ounces of ethanol consumed per week . Menopause was defined as the absence of menses for 1 year or more . Diabetes was defined on the basis of a nonfasting blood glucose level of 11.1 mmol/L ( 200 mg/dL ) or greater , a fasting blood glucose level of 7.8 mmol/L ( 140 mg/dL ) or greater , or the use of insulin or an oral hypoglycemic agent . Serum uric acid levels were measured with an autoanalyzer that used a phosphotungstic acid reagent ( 25 ) . Cholesterol levels were determined according to the Abell-Kendall method ( 26 ) . Outcome Events The primary outcome measures were incident coronary heart disease events , death from cardiovascular disease ( coronary heart disease , congestive heart failure , stroke , or other cardiovascular disease ) , and death from all causes . Coronary heart disease events included the following : death from coronary heart disease ( available information suggested coronary heart disease as the probable cause ) , recognized myocardial infa rct ion ( serial electrocardiographic changes leading to development of new pathologic Q waves , characteristic increase and decrease in serum myocardial markers with a suggestive clinical history , or evidence at necropsy of new or recent infa rct ion ) , and coronary insufficiency ( prolonged ischemic chest discomfort associated with transient repolarization abnormality , without criteria for myocardial infa rct ion ) . Events that were more equivocal , such as unrecognized myocardial infa rct ion and angina pectoris , were not included as coronary heart disease events for this analysis . A panel of three physicians determined the outcome events according to previously published criteria ( 27 ) after review ing Framingham Heart Study and outside hospital and physician records . Statistical Analysis Separate analyses were performed for men and women . All participants were divided according to sex-specific uric acid quintiles . Crude event rates were calculated for each quintile . Cox proportional-hazards regression models ( 28 ) were used to examine the relations of uric acid quintiles ( with quintile 1 as the reference category ) and the relation of uric acid level as a continuous variable to incidence of coronary heart disease events , cardiovascular disease mortality rates , and all-cause mortality rates . For comparative purpose s , hazard ratios were calculated without adjustment . For inferential purpose s , hazard ratios were calculated with adjustment for age only and also with adjustment for age and other clinical variables associated with uric acid level or atherosclerotic events : body mass index ( kg/m2 ) , diabetes ( yes/no ) , systolic blood pressure ( mm Hg ) , current diuretic use ( yes/no ) , use of antihypertensive medications other than diuretics ( yes/no ) , left ventricular hypertrophy shown on electrocardiography ( yes/no ) , total cholesterol level ( mmol/L ) , smoking status ( yes/no ) , alcohol use ( ounces consumed per week ) , and menopausal status in women ( yes/no ) . Post hoc subgroup analyses were done to determine any possible relations between quintiles of uric acid and the outcome events in participants stratified according to diuretic use and hypertension status . All analyses were performed on a Sun UltraSPARC computer ( Sun Microsystems , Mountain View , California ) using SAS software ( SAS Institute , Cary , North Carolina ) ( 29 ) . A two-sided P value less than 0.05 was the criterion for statistical significance . Results Participant Characteristics Table 1 shows the baseline clinical characteristics for men and women . The mean uric acid level was 379 mol/L in men ( range , 119 to 738 mol/L ) and 285 mol/L in women ( range , 24 to 696 mol/L ) . The effect of age on mean serum uric acid level is illustrated in the Figure . In men , uric acid levels changed minimally with age . In women , mean serum uric acid levels gradually increased from the fourth to the seventh decades of life . Furthermore , among women 30 to 54 years of age , the mean serum uric acid level was 5 to 13 mol/L greater in those who were postmenopausal ( data not shown ) . Table 1 . Baseline Clinical Characteristics Figure . Mean serum uric acid level by sex and 5-year age group .  Uric Acid Level and Outcome Events There were 117 376 person-years of follow-up . In men , 394 coronary heart disease events , 232 deaths due to cardiovascular disease , and 729 deaths from all causes occurred . As a continuous variable , baseline uric acid level was not associated with increased risk for any end point in men . In fully adjusted Cox models , for every 60-mol/L increase in serum uric acid level , hazard ratios were as follows : 0.91 ( 95 % CI , 0.83 to 0.99 ) for coronary heart disease , 0.95 ( CI , 0.86 to 1.06 ) for death from cardiovascular disease , and 0.97 ( CI , 0.91 to 1.03 ) for death from all causes . In men , baseline quintile of serum uric acid level was also not associated with increased risk for any outcome measure . Uric acid level was inversely related to coronary heart disease in the full multivariable adjusted model ( Table 2 ) . Table 2 . Relations of Serum Uric Acid Level to Coronary Heart Disease , Death from Cardiovascular Disease , and Death from All Causes  In women , 223 coronary heart disease events , 197 deaths from cardiovascular disease , and 731 deaths from all causes occurred . From quintile 1 to quintile 5 , crude rates increased more than threefold for coronary heart disease ( from 1.9 to 7.5 per 1000 person-years ) , death from cardiovascular disease ( from 1.3 to 7.0 per 1000 person-years ) and death from all causes ( from 6.3 to 21.8 per 1000 person-years ) ( Table 2 ) . In unadjusted Cox models in which quintile 1 was the reference category , risk significantly increased with increasing uric acid quintile for all three outcome measures ( P<0.001 for trend ) . This trend diminished after adjustment for age but remained significant for coronary heart disease ( P=0.002 ) , death from cardiovascular disease ( P=0.009 ) , and death from all causes ( P=0.03 ) . In fully adjusted Cox models , baseline uric acid level was no longer associated with increased risk for coronary heart disease ( P>0.2 for trend ) , death from cardiovascular disease ( P=0.23 ) , or death from all causes ( P>0.2 ) . Similar relations were found when baseline uric acid level was assessed as a continuous variable . In the fully adjusted models , hazard ratios for every 60-mol/L increase in serum uric acid level were as follows : 1.05 ( CI , 0.94 to 1.17 ) for Summary 1 . A total of 450 hypertensive patients above the age of 60 years have entered the double-blind multicentre trial of the European Working Party on High blood pressure in Elderly ( EWPHE ) . After stratification and r and omization half were treated with one capsule daily containing 25 mg of hydrochlorothiazide and 50 mg of triamterene and half were given placebo . In those receiving active treatment , if blood pressure control was not adequate they were given a second capsule and if necessary up to 2 g of methyldopalday . 2 . No significant differences between the groups were present before r and omization . A significant blood pressure difference of 25/10 mmHg was obtained between the groups and maintained during 4 years of follow-up . No major disturbances in serum potassium or serum sodium were noted with the present drug combination . 3 . During the initial phase an increase in serum creatinine and serum uric acid was noted in the actively treated group , which was maintained during the later years . This increase in serum creatinine in the actively treated group was related ( P = 0.003 and r = -0.247 ) to the decrease in sitting systolic blood pressure . Changes in serum uric acid were ( r = 0.3 and P = 0 - 003 ) correlated with the changes in serum creatinine both in the placebo and in the actively treated group , but Correspondence : Professor Dr A. Amery , Hypertension and Cardiovascular Rehabilitation Unit , Academic Hospital , St Raphael , Kapucijnenvoer 35 , B-3000 Leuven , Belgium . independent of the change in creatinine ; the serum uric acid was on average 1 mg higher in the actively treated than in the placebo group . 4 . Fasting blood glucose did not change significantly in the placebo-treated group but in the active treatment group the rise was statistically signficant . 5 . A favourable influence on prognosis by active treatment can be expected on the basis of the blood pressure reduction and in the absence of major electrolytes disturbances . However , the balance between this decreased risk and the increased risk produced by the rise in blood glucose and the other treatment effects remains to be determined . Therefore the trial continues and more patients are being admitted Low-dose thiazide-type diuretics are recommended as initial therapy for most hypertensive patients .  Chlorthalidone has significantly reduced stroke and cardiovascular end points in several l and mark trials ; however , hydrochlorothiazide remains favored in practice . Most clinicians assume that the drugs are interchangeable , but their antihypertensive effects at lower doses have not been directly compared . We conducted a r and omized , single-blinded , 8-week active treatment , crossover study comparing chlorthalidone 12.5 mg/day ( force-titrated to 25 mg/day ) and hydrochlorothiazide 25 mg/day ( force-titrated to 50 mg/day ) in untreated hypertensive patients . The main outcome , 24-hour ambulatory blood pressure ( BP ) monitoring , was assessed at baseline and week 8 , along with st and ard office BP readings every 2 weeks . Thirty patients completed the first active treatment period , whereas 24 patients completed both . An order – drug – time interaction was observed with chlorthalidone ; therefore , data from only the first active treatment period was considered . Week 8 ambulatory BPs indicated a greater reduction from baseline in systolic BP  with chlorthalidone 25 mg/day compared with hydrochlorothiazide 50 mg/day ( 24-hour mean = −12.4±1.8 mm Hg versus −7.4±1.7 mm Hg ; P=0.054 ; nighttime mean = −13.5±1.9 mm Hg versus −6.4±1.8 mm Hg ; P=0.009 ) . Office systolic BP reduction was lower at week 2 for chlorthalidone 12.5 mg/day versus hydrochlorothiazide 25 mg/day ( −15.7±2.2 mm Hg versus −4.5±2.1 mm Hg ; P=0.001 ) ; however , by week 8 , reductions were statistically similar ( −17.1±3.7 versus −10.8±3.5 ; P=0.84 ) . Within recommended doses , chlorthalidone is more effective in lowering systolic BPs  than hydrochlorothiazide , as evidence d by 24-hour ambulatory BPs . These differences were not apparent with office BP measurements The efficacy of thiazide-like chlorthalidone , 50 mg , plus reserpine , 0.25 mg , was compared with that of hydrochlorothiazide , 50 mg , plus reserpine , 0.125 mg , in a six-week double-blind study of 57 patients with essential hypertension unresponsive to diet control and diuretic ( step 1 ) therapy . An average decrease in diastolic pressure of 17.0 mm Hg was attained at the end of week 6 by the chlorthalidone/reserpine group ; the average drop in the hydrochlorothiazide/reserpine group was 18.6 mm Hg . Both treatment groups displayed greater blood pressure control each week than the preceding week ; and , at the end of week 6 , both groups attained control of at least 5 mm Hg below the diastolic goal pressure of 90 mm Hg . The chlorthalidone/reserpine-treated group required fewer titrations than the hydrochlorothiazide/reserpine-treated group . There were no reports of frequent or severe side effects with either drug Context Despite evidence showing that even mild elevation of blood pressure above 140/90 mm Hg puts patients at risk for cardiovascular complications , many patients who are treated for hypertension still have high blood pressure . Contribution The authors sought to improve the blood pressure of patients using a health systems approach .  They r and omly assigned providers caring for hypertensive patients to receive a Web link to the Seventh Report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ; the Web link and a computer alert notifying them of the patient 's blood pressure ; or the Web link , computer alert , and a letter educating the patient about ways to control his or her blood pressure .  Patients of providers r and omly assigned to the third group had greater decreases in blood pressure and were more likely to have a systolic blood pressure less than 140 mm Hg . Caution s The study took place in a Veterans Affairs setting , follow-up blood pressure measures were missing for many patients , and the study was not design ed to detect a mechanism for any observed changes . Implication s A health systems approach that gave providers feedback about their patients ' blood pressure and that gave patients information about ways to control it improved blood pressure control compared with provider education alone . The Editors Currently , more than 50 million persons in the United States have hypertension ( 1 ) . The Seventh Report of the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC 7 ) promotes blood pressure goals of less than 140/90 mm Hg ( 25 ) . Providers , however , often delay changes in therapy or use higher blood pressure thresholds for the treatment of hypertension ( 2 , 4 , 6 , 7 ) , which leads to a variance in guideline adherence that contributes to a quality gap in care . Despite widespread guideline promotion , 65 % of persons in the United States have poorly controlled hypertension ( 1 , 6 , 8 , 9 ) . Factors contributing to the achievement of hypertension goals include provider decision making and patient adherence to antihypertensive treatment . These factors can be influenced by other factors , such as patient interactions with clinicians , commercial influences , and patient participation in treatment decisions ( 6 , 1017 ) . A review of hypertension goal attainment in primary care ( 18 ) found that interventions with the largest positive change were complex , multifactorial , and involved 4 areas : activities directed at changing clinician behavior , changes to the organization , information enhancement , and educational programs directed at patients . Although these findings suggest opportunities to achieve effective intervention by directing a change at each component ( 2 , 17 , 1923 ) , the impact of each component is less well known . Our aim was 1 ) to improve the quality of care of patients with hypertension at our facility while examining the relative contribution of each aspect of a multifactorial intervention design ed to improve care and 2 ) to show the effects of physician-level clustering on quality assessment . We conducted a cluster r and omized , controlled study to evaluate common components of a multifactorial intervention in veterans with essential hypertension . Methods Study Design and Setting This project was a cluster r and omized , controlled trial design ed to examine the relative contribution of 3 quality improvement interventions of increasing intensity in improving blood pressure control in veterans . This study was the evaluation component of a Veterans Integrated Service Network campaign to improve blood pressure control in patients who are treated in the Tennessee Valley Healthcare System . The health care system comprises 2 teaching hospitals , 2 large community-based outpatient clinics , and 6 small community-based outpatient clinics . There were 523659 outpatient visits made by 69928 veterans during fiscal year 2004 . The institutional review board of V and erbilt University and the VA Tennessee Valley Healthcare System research and development committee for human subjects protection approved this study . Inclusion Criteria We first identified eligible patients and then r and omly assigned providers caring for at least 1 of those patients to receive study interventions . Patients were eligible for inclusion in the study if they were 21 to 90 years of age , filled their medications at Veterans Administration ( VA ) pharmacies , had at least 2 uncontrolled blood pressure measurements in the 6-month baseline period ( systolic blood pressure > 140 mm Hg or diastolic blood pressure 90 mm Hg ) , and were only taking 1 antihypertensive medication . We restricted our study sample to patients with uncontrolled hypertension who were only taking 1 antihypertensive medication because the JNC 7 guidelines propose that most patients with hypertension will require 2 or more medications to achieve their blood pressure goals ( 5 , 12 ) . Therefore , this sample includes patients for whom the quality of hypertension care could be improved . Eligible patients were identified between July and December 2003 by search ing data from the Mid-South Quality Improvement Data warehouse , which are downloaded monthly from Veterans Health Information System and Technology Architecture . The search initially identified 4648 patients with a primary care visit who had a diagnosis of hypertension indicated by International Classification of Diseases , Ninth Revision , Clinical Modification ( ICD-9-CM ) codes 401.1 or 401.9 and who were prescribed only 1 antihypertensive medication ( Figure ) . We excluded 2821 ( 60 % ) patients because they had at least 1 recorded blood pressure reading between July and December 2003 that was at goal ( systolic blood pressure 140 mm Hg and diastolic blood pressure < 90 mm Hg ) . We mailed an assent letter to the remaining 1827 patients in January 2004 asking permission to review their electronic medical record and indicating that their primary provider would potentially receive suggestions to improve their hypertension care . Another 486 patients were excluded after r and omization because they declined chart review ( n= 222 ) or were taking more than 1 antihypertensive medication at the time of chart review ( n= 264 ) . Figure . Study flow diagram . * Excluded providers who cared for patients who declined chart review or those who were taking more than 1 medication at the time of chart review after r and omization . Providers were eligible for r and omization if they provided care for at least 1 patient who fulfilled the eligibility criteria . Providers were classified as attending physicians , resident physicians , or nonphysician clinicians ( nurse practitioner or physician assistant ) and were stratified into providers with at least 30 eligible patients and those with less than 30 eligible patients to help balance the number of patients in each study group . One hundred eighty-two providers were r and omly assigned to study interventions ; after r and omization , 23 providers were additionally excluded because the patients they cared for declined chart review or were taking more than 1 antihypertensive medication at the time of chart review ( Figure ) . Interventions Providers were r and omly assigned to 1 of 3 study groups : provider education only ; provider education and alert ; or provider education , alert , and patient education . All interventions were performed during the week of 14 June through 18 June 2004 , and follow-up continued through 31 December 2004 . Provider Education All providers in the 3 study groups received an e-mail message that explained the planned intervention . Providers who received only the e-mail message were controls for those who received the other 2 more intensive interventions . The e-mail informed providers that they might receive electronic alerts in the computerized patient record requesting reevaluation of a patient 's antihypertensive regimen . It also reported that a letter was being sent to selected patients advocating medication adherence and lifestyle modification to lower blood pressure . The e-mail message included a Web link to the JNC 7 guidelines for the treatment of hypertension ( www.nhlbi.nih.gov/ guidelines /hypertension/jnc7full.pdf ) . The message was sent by the supervisory pharmacist at the VA Tennessee Valley Healthcare System and was signed by the medical director of the network . Provider Education and Alert In the second study group , an alert was added to provider education . The alert was a 1-time patient-specific electronic notification that was sent by the pharmacy to the prescribing provider through each eligible patient 's electronic medical record over a 1-week period in June 2004 . Each time providers signed on to a computer , any medical record that contained an alert was brought to their attention . The alert gave a brief outline of the JNC 7 recommendations ( 5 ) and reminded providers that goal blood pressure should be 140/90 mm Hg or less . It included date s and values of the patient 's last 3 recorded blood pressure measurements and offered the following options : addition of a thiazide or thiazide combination diuretic , addition of another antihypertensive medication , or continuation of current medications and dosages . The alert reminded providers of the available thiazides on the VA formulary and stated that thiazides were contraindicated in patients with renal insufficiency or allergies to sulfa medications . Provider Education , Alert , and Patient Education The third study group combined the provider education and alert described previously with a patient education component . We sent a personalized letter that contained educational information concerning hypertension to each eligible patient in this study group . The letter was labeled Notice : To Veterans with High Blood Pressure and was design ed at an eighth- grade reading level . The letter recommended the use of behavioral strategies , such as medication adherence , low-sodium diet , and exercise , BACKGROUND Antihypertensive agents differentially influence the plasma adiponectin concentration and the effects of fixed-dose combination regimens remain unclear . The influence of a combination of an angiotensin-converting enzyme inhibitor ( ACEI ) and a thiazide-type diuretic or an ACEI alone on plasma adiponectin concentrations in patients with essential hypertension was evaluated in the present study . METHODS AND RESULTS After a 2-week placebo run-in phase , 30 patients with essential hypertension were r and omized to receive preterax ( 2 mg perindopril/0.625 mg indapamide ) or cilazapril ( 2.5 mg ) once daily for 12 weeks . Plasma adiponectin and insulin concentrations were measured before and after treatment . Insulin resistance was measured by homeostasis assessment index ( HOMA-IR ) . Treatment with preterax ( P=0.003 ) and cilazapril ( P=0.031 ) significantly reduced systolic blood pressure ( BP ) , but only preterax reduced diastolic BP ( P=0.024 ) . Cilazapril treatment significantly increased the plasma adiponectin concentration ( P=0.025 ) and reduced plasma triglycerides ( P=0.041 ) , whereas preterax treatment increased the plasma insulin concentration ( P=0.041 ) and tended to increase HOMA-IR . CONCLUSIONS The combination of an ACEI and indapamide improved BP control , but attenuated the beneficial effects of ACE inhibition on plasma adiponectin in patients with essential hypertension . Such a combination may be best reserved for improved BP control rather than for metabolic protection in clinical hypertension Although the use of antihypertensive medications has been associated with reduced risk of Alzheimer 's disease ( AD ) , it remains unclear which class provides the most benefit . The Cache County Study of Memory Health and Aging is a prospect i ve longitudinal cohort study of dementing illnesses among the elderly population of Cache County , Utah . Using waves I to IV data of the Cache County Study , 3417 participants had a mean of 7.1 years of follow-up . Time-varying use of antihypertensive medications including different class of diuretics , angiotensin converting enzyme inhibitors , β-blockers , and calcium channel blockers was used to predict the incidence of AD using Cox proportional hazards analyses . During follow-up , 325 AD cases were ascertained with a total of 23,590 person-years . Use of any antihypertensive medication was associated with lower incidence of AD ( adjusted hazard ratio [ aHR ] , 0.77 ; 95 % confidence interval [ CI ] , 0.61 - 0.97 ) . Among different classes of antihypertensive medications , thiazide ( aHR , 0.7 ; 95 % CI , 0.53 - 0.93 ) , and potassium-sparing diuretics ( aHR , 0.69 ; 95 % CI , 0.48 - 0.99 ) were associated with the greatest reduction of AD risk . Thiazide and potassium-sparing diuretics were associated with decreased risk of AD . The inverse association of potassium-sparing diuretics confirms an earlier finding in this cohort , now with longer follow-up , and merits further investigation The Systolic Hypertension in the Elderly Program ( SHEP ) is a r and omized , blinded test of the efficacy of antihypertensive drug treatment . In a large feasibility trial , 551 men and women who had isolated systolic hypertension and were at least 60 years old received chlorthalidone ( 25 to 50 mg/day ) or matching placebo as the step I drug . After 1 year , 83 % of the chlorthalidone group and 80 % of the placebo group were still taking SHEP medications . Of those still taking chlorthalidone , 88 % had reached goal blood pressure ( BP ) without requiring a step II drug , and most had responded to the lower dose ( 25 mg/day ) . The BP response was similar in all age , sex and race subgroups , with an overall mean difference between r and omized groups of 17 mm Hg for systolic BP ( p less than 0.001 ) and 6 mm Hg for diastolic BP ( p less than 0.001 ) . The only common adverse effects were asymptomatic changes in the serum levels of potassium ( 0.5 mEq/liter lower in the chlorthalidone group , p less than 0.001 ) , uric acid ( 0.9 mg/dl higher , p less than 0.001 ) and creatinine ( 0.08 mg/dl higher , p = 0.02 ) . This study indicates that chlorthalidone is effective for lowering BP in elderly patients with systolic hypertension and sets the stage for a larger trial of the effects of such treatment on the incidence of cardiovascular disease OBJECTIVES We sought to determine the efficacy of isradipine in reducing left ventricular ( LV ) mass and wall thickness in hypertensive patients . BACKGROUND LV hypertrophy on the echocardiogram is a strong predictor of cardiovascular events . Reduction of LV mass may be a desirable goal of drug therapy for hypertension . However , although thiazide diuretic drugs have been advocated as first-line therapy for hypertension , their efficacy in reducing LV mass has been question ed . METHODS Patients with mild to moderate diastolic hypertension and LV mass in excess of 1 SD of normal values were r and omized to isradipine ( n = 89 ) or hydrochlorothiazide therapy ( n = 45 ) . Evaluations were obtained at baseline , after 3 and 6 months of treatment and 2 weeks after treatment was stopped . RESULTS At 6 months , LV mass decreased by 43 + /- 45 g ( mean + /- SD ) with hydrochlorothiazide ( p < 0.001 ) but only by 11 + /- 48 g with isradipine ( p = NS ; between-group comparison , p < 0.001 ) . Two weeks after drug therapy was stopped , LV mass remained 24 + /- 41 g lower than that at baseline in the hydrochlorothiazide group ( p = 0.003 ) but only 7 + /- 50 g lower in the isradipine group ( p = NS ) . Septal and posterior wall thicknesses were significantly and equally reduced with both isradipine and hydrochlorothiazide . Greater LV mass reduction with hydrochlorothiazide was related to a 2.8 + /- 3.3-mm reduction of LV cavity size with hydrochlorothiazide but no reduction with isradipine . At 6 months of treatment , diastolic blood pressure ( BP ) by design was equally reduced in both treatment groups . At 3 months , systolic BP was reduced by 17 + /- 15 mm Hg with isradipine and by 26 + /- 15 and 25 + /- 17 mm Hg at 3 and 6 months , respectively , with hydrochlorothiazide ( p = 0.003 , between-group comparison ) . However , on stepwise multivariable regression analysis , treatment selection ( partial r2 = 0.082 , p = 0.001 ) , change in average 24-h systolic BP ( partial r2 = 0.032 , p = 0.029 ) and change in average sitting systolic BP ( partial r2 = 0.017 , p = 0.096 ) were predictive of LV mass reduction . CONCLUSIONS Despite an equivalent reduction of diastolic BP , 6 months of therapy with hydrochlorothiazide is associated with a substantial reduction of LV mass , greater than that with isradipine . The superior efficacy of hydrochlorothiazide for LV mass reduction is associated with a greater reduction of systolic BP as well as drug selection itself . These data may have important therapeutic implication Objectives The International Nifedipine GITS Study Intervention as a Goal in Hypertension Treatment ( INSIGHT ) showed , by means of office blood pressure measurements , that long-term treatment with nifedipine GITS is as effective as diuretics in preventing cardiovascular and cerebrovascular complications . However , since office blood pressure measurements reflect to a limited extent blood pressure outside the office , a side-arm INSIGHT study in which patients underwent both office measurement and 24 h ambulatory blood pressure monitoring was also performed . Design and methods The study had a r and omized , double-blind , parallel group design . After 4 weeks of placebo , mild-to-moderate essential hypertensive patients were r and omized to nifedipine GITS 30 mg or amiloride 2.5 + hydrochlorothiazide  5 mg for 3.1 years . Dose titration was performed by dose doubling and addition of atenolol 25–50 mg or enalapril 5–10 mg , or other drugs when needed . Analysis was carried out by intention-to-treat and included computation of 24 h , day and night ambulatory blood pressure and heart rate values . Additional analyses included computation of the trough-to-peak ratio and the smoothness index ( the ratio between the average of the 24-hourly blood pressure reductions after treatment and its st and ard deviation ) . Results A total of 151 patients were recruited and 149 were valid for analysis : 78 patients had 24 h ambulatory recordings both at baseline and during treatment and 134 during treatment . Office , 24 h and day and night blood pressures were all significantly and similarly reduced by both treatments . Office and ambulatory heart rate was left unchanged by diuretics , while it was slightly reduced by nifedipine . Median trough-to-peak ratios were always > 0.5 and superimposable between the two treatment groups . Similarly , smoothness indices of systolic and diastolic blood pressures were comparably high for nifedipine and diuretics , thus demonstrating a similar well-balanced antihypertensive response to both drugs . No significant differences were observed between the two treatment groups in the number of cardiovascular events ( 17 in the nifedipine-based and 26 in the diuretics-based treatment group ) . Conclusions In the INSIGHT study , the long-term antihypertensive effect on 24 h blood pressure and the cardiovascular protection of nifedipine was similar to that of diuretics Background : Aldosterone antagonists have proven efficacy for management of resistant hypertension and proteinuria reduction ; however , they are not widely used due to risk of hyperkalemia . This study assesses the risk factors for hyperkalemia in patients with chronic kidney disease ( CKD ) and resistant hypertension whose blood pressure ( BP ) is reduced to a guideline goal . Methods : This is a two-center study conducted in university-based hypertension clinics directed by clinical hypertension specialists . Forty-six patients with resistant hypertension and stages 2 or 3 CKD ( mean estimated glomerular filtration rate ( eGFR ) 56.5 ± 16.2 ml/min/1.73 m2 ) were evaluated for safety and efficacy of aldosterone blockade added to preexisting BP-lowering regimens . All patients were on three mechanistically complementary antihypertensive agents including a diuretic and a renin-angiotensin system blocker . Patients were evaluated after a median of 45 treatment days . The primary endpoint was change in systolic BP . Secondary endpoints included change in serum potassium , creatinine , eGFR , diastolic BP and tolerability . Results : The mean age of the patients studied was 64.9 ± 10.7 years , all were obese and 86 % had type 2 diabetes , with 82 % being African-American . Addition of aldosterone antagonism yielded a further mean reduction in systolic BP of 14.7 ± 5.1 mm Hg ( p = 0.001 ) . Females with BMI > 30 and those with a baseline systolic BP > 160 mm Hg were more likely to have a greater BP reduction to aldosterone antagonism . In total , 39 % of the patients had a > 30 % decrease in eGFR when the BP goal was achieved . The mean increase in serum potassium was 0.4 mEq/l above baseline ( p = 0.001 ) , with 17.3 % manifesting hyperkalemia , i.e. serum potassium > 5.5 mEq/l . Predictors of hyperkalemia included a baseline eGFR of ≤45 ml/min/1.73 m2 in whom serum potassium was > 4.5 mEq/l on appropriately dosed diuretics . Contributing risks in this subgroup included a systolic BP reduction of > 15 mm Hg associated with an eGFR fall of > 30 % . Conclusion : Aldosterone antagonism is effective and safe for achieving a BP goal among people with diabetic nephropathy when added to a triple antihypertensive regimen that includes a blocker of the renin-angiotensin system and an appropriately selected and dosed diuretic . Caution is advised when using aldosterone blockade for BP control in people with advanced stage 3 nephropathy with a serum potassium of > 4.5 mEq/l for safety reasons Objective : To compare the blood pressure‐lowering efficacy , the frequency of side effects and changes in laboratory values of three & bgr;‐blockers and a potassium‐sparing diuretic combination in elderly hypertensive patients . Design : The Swedish Trial in Old Patients with Hypertension ( STOP‐Hypertension ) was a prospect i ve , r and omized , double‐blind , multicentre trial comparing active antihypertensive treatment with placebo in patients aged 70‐84 years . Methods : The study group consisted of 1627 elderly hypertensive patients ( mean ± SD age 75.7 ± 3.7 years ; 37 % males , 63 % females ) . Supine and st and ing blood pressure , heart rate and side effects were recorded at each visit . Blood was drawn for routine analysis . The mean length of follow‐up was 25 months ( range 6‐65 ) . No patient was lost to follow‐up . Results : After 2‐months ' single‐drug therapy , all four active drugs were found to be equally effective in reducing diastolic blood pressure ( DBP ) . However , there were differences in their efficacy in reducing systolic blood pressure ( SBP ) ; the diuretic was significantly more effective than the & bgr;‐receptor blockers . The results of a series of multiple linear regression analyses showed that the observed differences in effect on SBP could not be explained by the different effects of the drugs on heart rate . More than two‐thirds of the patients were given supplementary treatment , most of them already by the 2‐month visit , after which there was no significant difference in blood pressure among the treatment regimens . The changes in laboratory values and in the prevalence of symptoms were minor for all four regimens . Conclusion : Metoprolol ( controlled release ) , atenolol , pindolol and the combination hydrochlorothiazide + amiloride were equally effective as single drugs in reducing DBP . There were differences in their efficacy in reducing SBP , the diuretic being more effective than the & bgr;‐blockers . After addition of supplementary treatment ( & bgr;‐blocker to diuretic , or vice versa ) there were no significant differences in blood pressure reduction among the groups . The changes in laboratory values and in the prevalence of symptoms were minor for all active treatment regimens . Thus , the satisfactory effect on cardiovascular morbidity and mortality was not impaired by low tolerability of the drugs Antihypertensive medications are used extensively in children despite a paucity of r and omized , placebo-controlled trials . This study was among the first r and omized , controlled pediatric antihypertensive medication trials , in which the combination drug bisoprolol fumarate/hydrochlorothiazide ( B/HT ) was compared with placebo . The study comprised a 2-week single-blind placebo screening period , a 6-week double-blind dose titration period , a 4-week double-blind dose maintenance period , and a 2-week double-blind dose-tapering period . One hundred and forty subjects were enrolled to achieve 94 r and omized subjects treated either with B/HT ( n=62 ) or placebo ( n=32 ) . B/HT induced significant reductions compared with placebo for average sitting systolic blood pressure ( SiSBP ) ( 9.3 vs. 4.9 mmHg , P<0.05 ) and sitting diastolic blood pressure ( SiDBP ) ( 7.2 vs. 2.7 mmHg , P<0.05 ) . The placebo-subtracted BP reductions were greater in younger children and those with more-severe baseline hypertension . The percentage of subjects with BP less than the 90th percentile at study completion was 45 % for B/HT and 34 % for placebo ( P = NS ) . Although the study demonstrated that B/HT  reduced BP safely compared with placebo , the large placebo effect and failure of most subjects to achieve target BP control make it uncertain whether B/HT is appropriate first-line therapy for pediatric hypertension , particularly in adolescents with mild-to-moderate BP elevation Although diuretics are recommended for the treatment of hypertension , decreased diuretic use and increased calcium antagonist use necessitate a comparison of the efficacy of these drugs in preventing cardiovascular events .  Patients > /=60 years of age with systolic blood pressure of 160 to 220 mm Hg and diastolic blood pressure < 115 mm Hg were enrolled . Patients were r and omly assigned to 20 mg of sustained-release nicardipine hydrochloride twice daily or 2 mg of trichlormethiazide once daily by the double-dummy method and followed up for 5 years . A total of 414 patients were analyzed : 204 in the nicardipine group and 210 in the diuretic group .  Blood pressure  at entry was 172/94 mm Hg and 173/93 mm Hg , respectively , and decreased to 147/81 mm Hg and 147/79 mm Hg , respectively . Cardiovascular morbidity rates per 1000 persons per year were similar in the nicardipine and diuretic groups ( 27.8 and 26.8 , respectively ; P=0.923 ) . The sex- and age-adjusted risk ratio for the nicardipine group was 0.973 ( 95 % confidence interval , 0.514 to 1.839 , P=0.932 ) . The calcium antagonist and diuretic groups had a similarly decreased rate of cardiovascular events AIM Our objective was to investigate the effects and tolerability of fixed-dose combination therapy on blood pressure and LDL in adults without elevated blood pressure or lipid levels . METHODS This was a double-blind r and omised placebo-controlled trial in residents of Kalaleh , Golestan , Iran . Following an 8-week placebo run-in period , 475 participants , aged 50 to 79 years , without cardiovascular disease , hypertension or hyperlipidaemia were r and omised to fixed-dose combination therapy with aspirin 81 mg , enalapril 2.5 mg , atorvastatin 20 mg and hydrochlorothiazide 12.5 mg ( polypill ) or placebo for a period of 12 months . The primary outcomes were changes in LDL-cholesterol , systolic and diastolic blood pressure and adverse reactions . Analysis was by intention-to-treat basis . RESULTS At baseline , there were differences in systolic blood pressure ( 6 mmHg ) . Taking account of baseline differences , at 12 months , polypill was associated with statistically significant reductions in blood pressure ( 4.5/1.6 mmHg ) and LDL-cholesterol ( 0.46 mmol/l ) . The study drug was well tolerated , but result ed in the modest reductions in blood pressure and lipid levels . CONCLUSION The effects of the polypill on blood pressure and lipid levels were less than anticipated , raising questions about the reliability of the reported compliance . There is a case for a fully powered trial of a polypill for the prevention of cardiovascular disease Thiazide diuretic agents lower the urinary excretion of calcium . Their use has been associated with increased bone density , but their role in preventing hip fracture has not been established . We prospect ively studied the effect of thiazide diuretic agents on the incidence of hip fracture among 9518 men and women 65 years of age or older residing in three communities . At base line , 24 to 30 percent of the subjects were  thiazide users . In the subsequent four years , 242 subjects had hip fractures . The incidence rates of hip fracture were lower among thiazide users than nonusers in each community ; the Mantel-Haenszel relative risk of hip fracture , adjusted for community and age , was 0.63 ( 95 percent confidence interval , 0.46 to 0.86 ) . The protective effect of the use of thiazides was independent of sex , age , impaired mobility , body-mass index , and current and former smoking status ; the multivariate adjusted relative risk of hip fracture was 0.68 ( 95 percent confidence interval , 0.49 to 0.94 ) . Furthermore , the protective effect was specific to thiazide diuretic agents , since there was no association between the use of antihypertensive medications other than thiazides and the risk of hip fracture . These prospect i ve data suggest that in older men and women the use of thiazide diuretic agents is associated with a reduction of approximately one third in the risk of hip fracture Effects of once‐daily doses of 50 mg triamterene with 25 mg hydrochlorothiazide and 5 mg amiloride with 50 mg hydrochlorothiazide were compared in a r and omized , multicenter study of 84 adult subjects with mild to moderate hypertension ( diastolic blood pressure 90 to 114 mm Hg ) . After a 3‐wk placebo lead‐in period , the subjects entered a 6‐wk treatment period . The two drug regimens were compared with respect to antihypertensive effects and effects on serum potassium and magnesium levels during the final week of drug therapy , with the use of the last week of placebo therapy as a covariate . Both drug regimens substantially reduced mean supine systolic and diastolic blood pressures to well within normal limits ; there was no significant difference between the two groups . Twenty‐four of the 41 subjects receiving triamterene‐hydrochlorothiazide ( 59 % ) and 29 of the 43 patients receiving amiloride‐hydrochlorothiazide ( 67 % ) had diastolic blood pressure < 90 mm Hg at week 9 . Five subjects receiving amiloride‐hydrochlorothiazide ( 12 % ) and two subjects receiving triamterene‐hydrochlorothiazide ( 5 % ) had hypokalemia ( serum potassium level < 3.5 mEq/l ) at week 9 . The average decrease in serum potassium levels  during amiloride‐hydrochlorothiazide therapy ( −0.33 ± 0.08 mEq/l ) was greater than that after triamterene‐hydrochlorothiazide ( −0.08 ± 0.07 mEq/l ) . Serum magnesium levels were not changed by either regimen . Weight loss was greater in the amiloride‐hydrochlorothiazide group than in the triamterene‐hydrochlorothiazide group . It is reasonable to assume that the greater potassium loss during amiloride‐hydrochlorothiazide therapy than during triamterene‐hydrochlorothiazide therapy was a consequence of the larger dose of hydrochlorothiazide in the former ( 50 mg ) compared with the latter ( 25 mg ) . Although the effect on lowering blood pressure by amiloride‐hydrochlorothiazide was slightly greater than that by triamterene‐hydrochlorothiazide ( also consistent with the larger dose of hydrochlorothiazide ) , the difference was small and not significant . Triamterene‐hydrochlorothiazide at low doses is effective in the treatment of hypertension
Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available : bendrofluazide , chlorthalidone , cyclopenthiazide , metolazone or indapamide .
This is based on an informal indirect comparison of results observed in other Cochrane review s on ACE inhibitors , ARBs and renin inhibitors compared with placebo , which used similar inclusion /exclusion criteria to the present review .Thiazides reduced potassium , increased uric acid and increased total cholesterol and triglycerides .
These effects were dose-related and were least for hydrochlorothiazide .
Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides .
This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect .
Thiazides reduced potassium , increased uric acid and increased total cholesterol and triglycerides
BACKGROUND Hypertension is a modifiable cardiovascular risk factor .
Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity , the dose-related effect of thiazides in decreasing blood pressure has not been subject to a rigorous systematic review .
It is not known whether individual drugs within the thiazide diuretic class differ in their blood pressure-lowering effects and adverse effects .
OBJECTIVES To determine the dose-related decrease in systolic and /or diastolic blood pressure due to thiazide diuretics compared with placebo control in the treatment of patients with primary hypertension .
Secondary outcomes included the dose-related adverse events leading to patient withdrawal and adverse biochemical effects on serum potassium , uric acid , creatinine , glucose and lipids .