South African hypertension guideline 2011. Results of combination anti-hypertensive therapy after failure of each of the components. Department of Veterans Affairs Cooperative Study Group on Anti-hypertensive Agents. Influence of diabetes and type of hypertension on response to antihypertensive treatment. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic 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 A prospective evaluation of persistence on antihypertensive treatment with different antihypertensive drugs in clinical practice Management of hypertension and the core services guidelines: results from interviews with 100 Auckland general practitioners. Medical treatment of hypertension in Switzerland. The 2009 Swiss Hypertension Survey (SWISSHYPE). Genome-wide response to antihypertensive medication using home blood pressure measurements: a pilot study nested within the HOMED-BP study. 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Renoprotective Effect and Cost-Effectiveness of Using Benidipine, a Calcium Channel Blocker, to Lower the Dose of Angiotensin Receptor Blocker in Hypertensive Patients with Albumiuria Antihypertensive efficacy and safety of olmesartan medoxomil and ramipril in elderly patients with mild to moderate essential hypertension: the ESPORT study First‐Line Treatment of Left Ventricular Failure Complicating Acute Myocardial Infarction: A Randomised Evaluation of Immediate Effects of Diuretic, Venodilator, Arteriodilator, and Positive Inotropic Drugs on Left Ventricular Function Tolerability and safety of a calcium channel blocker in comparison with a diuretic in the treatment of elderly patients with hypertension: secondary analysis of the NICS-EH. Remikiren (Ro 42-5892)--an orally active renin inhibitor in essential hypertension. Effects on blood pressure and the renin-angiotensin-aldosterone system. Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer Chlorthalidone does not increase the hypotensive effect of nifedipine in essential hypertensives: a crossover multicentre study. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): Practical Implications Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic. A 10-year controlled trial with bendroflumethiazide. Quantitative effects of timolol and hydrochlorothiazide on blood pressure, heart rate and plasma renin activity: results of a double-blind factorial trial in patients with essential hypertension. Twenty-four hour ambulatory blood pressure in the International Nifedipine GITS Study Intervention as a Goal in Hypertension Treatment (INSIGHT) Hypertension and Its Treatment in Postmenopausal Women: Baseline Data from the Women’s Health Initiative Effect of different antihypertensive drug classes on central aortic pressure. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. A Simplified Approach to the Treatment of Uncomplicated Hypertension: A Cluster Randomized, Controlled Trial The risk of myocardial infarction associated with antihypertensive drug therapies. The effects of nonsteroidal anti-inflammatory drugs on blood pressures of patients with hypertension controlled by verapamil. Comparison of the antihypertensive activities of xipamide and chlorthalidone: a double-blind, randomized, crossover trial. Direct Renin Inhibition With Aliskiren in Obese Patients With Arterial Hypertension Empirical modified sequential therapy containing levofloxacin and high-dose esomeprazole in second-line therapy for Helicobacter pylori infection: a multicentre clinical trial. Treatment of hypertension with enalapril and hydrochlorothiazide or enalapril and atenolol: contrasts in hypotensive interactions. A randomised crossover comparison of reserpine and sustained-release nifedipine in hypertension. The relationship of weight change to changes in blood pressure, serum uric acid, cholesterol and glucose in the treatment of hypertension. Additional Antihypertensive Effect of Drugs in Hypertensive Subjects Uncontrolled on Diltiazem Monotherapy: A Randomized Controlled Trial Using Office and Home Blood Pressure Monitoring Feedback on prescribing rate combined with problem-oriented pharmacotherapy education as a model to improve prescribing behaviour among general practitioners Conservation of first-line antiretroviral treatment regimen where therapeutic options are limited. Angiotensin-II receptor antagonist combined with calcium channel blocker or diuretic for essential hypertension Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis The 2007 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2 - therapy. Mayo regimen plus three different second-line chemotherapy regimens in sequential therapy in patients with advanced colorectal cancer (ACRC). The effect of antihypertensive agents on sleep apnea: protocol for a randomized controlled trial The Combination of Chlorthalidone with Nifedipine Does Not Exert an Additive Antihypertensive Effect in Essential Hypertensives: A Crossover Multicenter Study Comparative study of high dose mono-therapy of amlodipine or telmisartan, and their low dose combination in mild to moderate hypertension. Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study Cost-Effectiveness of Immune Checkpoint Inhibition in BRAF Wild-Type Advanced Melanoma. Combination of hydrochlorothiazide or benazepril with valsartan in hypertensive patients unresponsive to valsartan alone Prevention of hypertension in patients with pre-hypertension: protocol for the PREVER-prevention trial Diet or diuretic? Treatment of newly diagnosed mild to moderate hypertension in the elderly Bismuth-containing quadruple therapy as second-line treatment for Helicobacter pylori infection: effect of treatment duration and antibiotic resistance on the eradication rate in Korea. The Eurevie Study: contrasting effect of piretanide and thiazides in mild to moderate hypertension. Testing a TheoRY-inspired MEssage ('TRY-ME'): a sub-trial within the Ontario Printed Educational Message (OPEM) trial Comparison of lafutidine and rabeprazole in 7-day second-line amoxicillin- and metronidazole-containing triple therapy for Helicobacter pylori: a pilot study. [Treatment of hypertension with indapamide 1.5 mg sustained-release form: synthesis of results]. Antihypertensive effects of amlodipine and hydrochlorothiazide in elderly patients with ambulatory hypertension. Physician-pharmacist co-management and 24-hour blood pressure control. Looking inside the black box: a theory-based process evaluation alongside a randomised controlled trial of printed educational materials (the Ontario printed educational message, OPEM) to improve referral and prescribing practices in primary care in Ontario, Canada Second-Line Rescue Therapy With Levofloxacin After H. pylori Treatment Failure: A Spanish Multicenter Study of 300 Patients Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs Effect of withdrawal of antihypertensive drug on depressive mood. 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 Oslo Hypertension Study 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. Patterns of anti-malarial drug treatment among pregnant women in Uganda Relaxation therapy for hypertension. Comparison of effects with concomitant placebo, diuretic, and beta-blocker. The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: the Nephros Study. Chlorthalidone Alone or in Fixed Combination with Slow-Release Metoprolol in the Management of Arterial Hypertension: A Long-Term Study of 545 Patients Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) Double-blind comparison of indapamide with a placebo in hypertensive patients treated by practicing physicians. Monotherapy with Nifedipine for Essential Hypertension in Adult Blacks A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial Thermal biofeedback as an effective substitute for sympatholytic medication in moderate hypertension: A failure to replicate Treatment of Hypertensive Urgencies with Oral Nifedipine, Nicardipine, and Captopril Calcium channel blockers and cardiac mortality in the treatment of hypertension: a report from the Department of Health Hypertension Care Computing Project (DHCCP) Long-term Methotrexate for Crohn's Disease: Safety and Efficacy in Clinical Practice A 3-month double-blind cross-over study of the effect of benazepril and hydrochlorothiazide on functional class in symptomatic mild heart failure. The effect of spironolactone (Aldactone) and methyldopa in low and normal renin hypertension. Evaluation of the Efficacy and Tolerability of a Low-Dose Combination of Isradipine and Spirapril in the First-Line Treatment of Mild to Moderate Essential Hypertension Effectiveness of Add-On Low-Dose Diuretics in Combination Therapy for Hypertension: Losartan/Hydrochlorothiazide vs. Candesartan/Amlodipine Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. Blood pressure screening, management and control in England: results from the health survey for England 1994
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 We r and omised ambulatory men with diastolic blood pressure ( BP ) 95 - 109 mmHg without anti-hypertensive medication to single drug treatment with either  hydrochlorothiazide 12.5 - 50 mg/day , atenolol 25 - 100 mg/day , captopril 25 - 100 mg/day , clonidine 0.2 - 0.6 mg/day , diltiazem-SR 120 - 360 mg/day , prazosin 4 - 20 mg/day or placebo in a double-blind prospect i ve trial . The assigned drug was titrated to a goal BP of < 90 mm Hg . Patients not achieving goal BP were rer and omised to an alternative single active drug . Non-responders to the second drug received the first drug in combination with the second . Of the 102 non-responders to both drugs who qualified for the combination , 59 ( 57.8 % ) responded . The combination pairs that included a diuretic achieved diastolic goal BP in 69 % and < 140 mm Hg systolic in 77 % compared with 51 % and 46 % , respectively , for those combinations without a diuretic ( P = 0.067 ; P = 0.002 ) . Six of the eight terminations due to adverse drug reactions were in combinations containing prazosin ; three of these six were hypotensive reactions . We conclude that two single drugs of insufficient efficacy to control BP individually have a high probability of achieving goal BP when combined , especially if the combination contains a diuretic The aim of our investigation was to determine whether the presence of additional risk factors or type of hypertension ( diastolic or isolated systolic ) influences blood pressure ( BP ) response to treatment . The International Nifedipine GITS Study : Intervention as a Goal in Hypertension Treatment ( INSIGHT ) study is a double-blinded outcome comparison of calcium channel blockade with diuretics in high-risk patients aged 55 to 80 years . Dynamic r and omization between nifedipine once daily and hydrochlorothiazide/amiloride was performed to ensure that approximately equal numbers of patients in the 2 groups had each of the major cardiovascular risk factors . Patients with isolated systolic hypertension were also separately r and omized . Atenolol or enalapril was the m and atory second-line drug . In 5669 patients who completed the 18-week titration , BP fell from 172+/-15/99+/-9 mm Hg ( mean+/-SD ) while receiving placebo to 139+/-12/82+/-7 mm Hg . Twenty-six percent of patients required 2 drugs , and 4 % required 3 drugs . Patients with diabetes were the most resistant to treatment , requiring second and third drugs 40 % and 100 % more frequently than patients without diabetes and achieving marginally the highest final BP , for any risk group , of 141+/-13/82+/-8 mm Hg . Age , smoking , gender , hypercholesterolemia , left ventricular hypertrophy , and existing atherosclerosis had little ( < 1 mm Hg ) or no influence on BP at the end of titration , but all except smoking slightly reduced the initial response of either systolic or diastolic BP . Patients with isolated systolic hypertension were slightly more responsive than average to treatment . Our findings suggest that in patients at high absolute risk of cardiovascular complications from hypertension , the risk factors themselves do not prevent the recommended BP targets from being achieved 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 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 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 Persistence on treatment affects the efficacy of antihypertensive treatment . We prospect ively investigated the persistence on therapy and the extent of  blood pressure ( BP ) control  in 347 hypertensive patients ( age 59.4 ± 6 years ) r and omly allocated to a first-line treatment with : angiotensin-converting enzyme ( ACE ) inhibitors , calcium-channel blockers ( CCBs ) , ß-blockers , angiotensin-II receptor blockers ( ARBs ) , or diuretics and followed-up for 24-months . Persistence on treatment was higher in patients treated with ARBs ( 68.5 % ) and ACE inhibitors ( 64.5 % ) vs CCBs ( 51.6 % ; p < 0.05 ) , β-blockers ( 44.8 % , p < 0.05 ) , and diuretics ( 34.4 % , p < 0.01 ) . No ARB , ACE inhibitor , β-blocker , or diuretic was associated with a higher persistence in therapy compared with the other molecules used in each therapeutic class . The rate of persistence was significantly higher in patients treated with lercanidipine vs others CCBs ( 59.3 % vs 46.6 % , p < 0.05 ) . Systolic and diastolic BP was decreased more successfully in patients treated with ARBs ( −11.2/−5.8 mmHg ) , ACE inhibitors ( −10.5/−5.1 mmHg ) , and CCBs ( −8.5/−4.6 mmHg ) compared with ß-blockers ( −4.0/−2.3 mmHg p < 0.05 ) and diuretics ( −2.3/−2.1 mmHg , p < 0.05 ) . No ARB , ACE inhibitor , β-blocker , or diuretic was associated with a higher BP control compared with the other molecules used in each therapeutic class . A trend toward a better BP control was observed in response to lercanidipine vs other CCBs ( p = 0.059 ) . The present results confirm the importance of persistence on treatment for the management of hypertension in clinical practice AIM To determine if the management of a hypothetical case of essential hypertension by general practitioners conforms with the Report to the National Advisory Committee on Core Health and Disability Services guidelines on the Management of Raised Blood Pressure in New Zeal and ( Core Services Report on Hypertension ) sent to all general practitioners in November 1992 . METHOD A cross-sectional survey of a r and om sample of 100 Auckl and general practitioners using a st and ard case of a 60 year old man with essential hypertension . Seventy interviews were conducted by a face-to-face interview and 30 by telephone interview . The main outcome measures were . Initial choice of medication and levels at which blood pressure would require treatment . RESULTS Forty one percent of the interviewed doctors had read the Core Services report on hypertension . Fifty percent of the doctors indicated they would use the recommended first line antihypertensive medication ( ie , diuretic or beta blocker ) . Doctors who prescribed beta blockers had been graduated a significantly longer time than those who did not . The majority of doctors indicated that they would initiate pharmacological treatment at lower blood pressures in younger patients than older patients contrary to the recommendation of the report . CONCLUSIONS Current reported practice is only partially consistent with that suggested by the Core Services report on hypertension . Approximately half of the doctors interviewed were prescribing the recommended first line medication . Treatment was more likely to be initiated at lower levels in younger patients than in older patients in spite of the higher absolute risk and potential absolute benefit in the latter group . Adherence to the guidelines could see a shift from overtreatment of younger patients to an increase in treatment for older patients who are at higher risk of blood pressure related disease . More specific graduate educational measures will be needed if the Core Services report on hypertension are to be implemented OBJECTIVES Despite a broad and efficient pharmacological antihypertensive armamentarium , blood pressure ( BP ) control is suboptimal and heterogeneous throughout Europe . Recent representative data from Switzerl and are limited . The goal of the present survey was therefore to assess the actual control rate of high BP in Switzerl and in accordance with current guidelines . The influence of risk factors , target organ damage and medication on BP levels and control was also evaluated . METHODS A cross-sectional visit-based survey of ambulatory hypertensive patients was performed in 2009 in Switzerl and . 281 r and omly selected physicians provided data on 5 consecutive hypertensive patients attending their practice s for BP follow-up . Data were anonymously collected on demographics , comorbidities and current medication , and BP was recorded . Subsequent modification of pharmacological antihypertensive therapy was assessed . RESULTS Data from 1376 patients were available . Mean age was 65 ± 12 years , 53.9 % were male subjects . 26.4 % had complicated hypertension . Overall , BP control ( < 140/90 mm Hg for uncomplicated and < 130/80 mm Hg for complicated hypertension ) was achieved in 48.9 % . Compared to patients with complicated hypertension , BP control was better in patients with uncomplicated hypertension ( 59.4 % vs. 19.2 % , p < 0.001 ) . As a monotherapy the most prescribed drug class were angiotensin receptor blockers ( ARB , 41 % ) , followed by angiotensin converting enzyme ( ACE ) inhibitors ( 21.5 % ) , betablockers ( 20.8 % ) and calcium channel blockers ( CCB , 10.8 % ) . The most prescribed drug combinations were ARB + diuretic ( 30.1 % ) and ACE inhibitors + diuretic ( 15.3 % ) . 46 % were receiving a fixed drug combination . In only 32.7 % of patients with uncontrolled hypertension was a change in drug therapy made . CONCLUSION This representative survey on treated adult hypertensive patients shows that , compared to earlier reports , the control rate of hypertension has improved in Switzerl and for uncomplicated but not for complicated , particularly diabetes-associated hypertension . ARBs and ACE inhibitors are the most prescribed antihypertensive drugs for monotherapy , whereas diuretics and ARBs were the most used for combination therapy BACKGROUND Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were r and omly allocated to first-line treatment with a calcium channel blocker ( CCB ) , angiotensin-converting enzyme inhibitor ( ACEI ) or angiotensin II receptor blocker ( ARB ) . METHODS We recruited 265 ( 93 for CCB , 71 for ACEI and 101 for ARB ) patients who completed the genomic study .  Home blood pressure was measured for 5 days off-treatment before r and omization and for 5 days after 2 - 4 weeks of r and omized drug treatment . Genotyping was performed by 500 K DNA microarray chips . The blood pressure responses to the three drugs were analyzed separately as a quantitative trait . For replication of SNPs with p < 10(-4 ) , we used the multicenter GEANE study , in which patients were r and omized to valsartan or amlodipine . RESULTS SNPs in PICALM , TANC2 , NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication . CONCLUSION Our approach , the first based on high-fidelity phenotyping by home blood pressure measurement , might be a step in moving towards the personalized treatment of hypertension Objective In accordance with international recommendations on the need to decrease doses of antihypertensive drugs , a low-dose ( 1.5 mg ) sustained-release ( SR ) formulation of indapamide was developed to optimize the drug 's efficacy : safety ratio . The aim of this work was to evaluate the benefit of a low-dose diuretic by consolidating the efficacy and safety results of two clinical trials with a similar design . Patients and methods Clinical data were obtained in two European r and omized double-blind studies with 690 mild to moderate hypertensive patients ( 95 mmHg ≤ supine diastolic blood pressure ≤ 114 mmHg using a mercury sphygmomanometer ) treated respectively for 2 and 3 months , with a mean age of 53 and 57 years , 44 and 57 % males , mean supine diastolic blood pressure of 100.6 and 102.5 mmHg and mean supine systolic blood pressure of 161.0 and 164.5 mmHg . Results The first study , a dose-finding study with indapamide SR at 1.5 , 2 and 2.5 mg versus placebo and the immediate-release ( IR ) formulation of indapamide , showed that the 1.5 mg dosage of the new indapamide formulation had an improved antihypertensive efficacy : safety ratio . The second study confirmed the equivalence of blood pressure reductions with 1.5 mg indapamide SR and 2.5 mg indapamide IR , and better acceptability with 1.5 mg indapamide SR , particularly in the number of patients with serum potassium levels < 3.4 mmol/l , which was reduced by more than 50 % . The long-term efficacy of 1.5 mg indapamide SR was observed through a 9-month open-treatment follow-up to the second study . Conclusion The 1.5 mg SR formulation of indapamide has an improved antihypertensive efficacy : safety ratio , which is in accordance with international recommendations for the use of low-dose antihypertensive drugs and diuretics in first-line therapy of hypertension The antihypertensive efficacy of the new dihydro-pyridine derivative nilvadipine given once daily was compared in two r and omized , double-blind studies with that of hydrochlorothiazide/triamterene ( HCT/T ) and of enalapril . In the first study , arterial pressures were compared after 4 weeks of therapy with nilvadipine ( 16 mg q.d . ) or HCT/T ( 25/50 mg q.d . ) in patients with mild-to-moderate hypertension in a parallel-group design . The combination of both treatments was administered after 4 weeks if diastolic arterial pressures were < 90 mm Hg . The blood pressure ( BP ) in the nilvadipine group ( n = 125 ) was 161/102 ± 17/7 ( mean ± SD ) mm Hg after a 2-week placebo period and decreased after 4 weeks by – 16/– 13 ± 22/12 mm Hg . The BP decreased in the HCT/T group ( n = 124 ) compared to the nilvadipine group to a similar degree ( p = 0.91 , n.s . ) from 160/103 ± 17/8 mm Hg by −17/-13 ± 18/11 mm Hg . A combination therapy was started after 4 weeks in 39 patients in the nilvadipine group and in 34 patients in the HCT/T group . This led independently of the treatment sequence , to a similar decrease in BP in the nilvadipine group ( – 17/7 ± 16/10 mm Hg ) and in the HCT/T group ( -12/9 ± 16/9 mm Hg ) . In the second study , the antihypertensive effect of nilvadipine ( 1 x 8 mg ) was compared with that of enalapril ( 1x10 mg ) in a r and omized , double-blind , crossover design . Sixty-one patients with essential hypertension ( WHO I – II ) were treated over two 4-week periods following placebo periods of 2 weeks . Nonresponders ( BP < 90 mm Hg ) were subsequently treated for an additional 4 weeks with a combination of both drugs given at the same dosage . The BP decreased to a similar degree after 4 weeks on nilvadipine from 175/108 ± 13/7 mm Hg by −19/-13 mm Hg and from 176/107 ± 13/6 mm Hg by −21/-13 mm Hg after 4 weeks on enalapril to 156/95 + 14/ 9 mm Hg and 155/94 ± 16/10 mm Hg , respectively . Goal diastolic BPs < 90 mm Hg were not achieved with monotherapy in 27 patients , but 15 of these 27 patients responded favorably to a combination of nilvadipine and enalapril  with diastolic BPs < 90 mm Hg . Combination therapy caused a decrease in the diastolic BP of −14/-13 mm Hg . In conclusion , nilvadipine administered once daily was as effective as  hydrochlorothiazide or enalapril  in lowering the BP . In combination with a diuretic , the sequence of treatments , i.e. , diuretic first or nilvadipine first , had no influence on antihypertensive efficacy . The combination of calcium antagonist and diuretic was as effective as that of the calcium antagonist with enalapril The importance of number of tablets for patient compliance was investigated in 160 patients with mild-moderate essential hypertension treated with a beta-adrenoceptor blocker and a thiazide diuretic . Mean BP at entry 146 + /- 16/92 + /- 8 mm Hg . All patients were given pindolol 10 mg and clopamide 5 mg in one combination tablet or in separate tablets for 4 months respectively . Approximately 90 % of the patients took greater than 90 % of the prescribed dose throughout the study . Mean BP decreased progressively and heart rate increased slightly . Side effects were more frequently reported during the first month of the study than previously , and 30 patients discontinued the treatment . No differences in this respect were seen between 1 and 2 tablets daily . Approximately 75 % of the patients preferred 1 tablet daily , but combining two drugs in one tablet had no effect upon compliance While monotherapy sometimes controls blood pressure ( BP ) , it is often essential to add a second drug for adequate control . This study examined in a factorial fashion the interaction of enalapril with some commonly used antihypertensive therapies .  There were between 10 and 16 patients in each study , and the patients had responded in part to the two drugs used .  Enalapril and sodium restriction lowered BP 12 + /- 3/11 + /- 2 and 4 + /- 2/3 + /- 1 mm Hg , respectively . The effects of the two therapies were additive , and there was no interaction . Enalapril and hydrochlorothiazide  lowered BP 11 + /- 3/8 + /- 3 and 8 + /- 2/6 + /- 2 mm Hg , respectively . The effect of the two drugs together indicated a positive interaction of 4 + /- 2/3 + /- 1 mm Hg ( p less than 0.05 ) . Enalapril and nifedipine both lowered BP ( 10 + /- 2/8 + /- 1 and 11 + /- 3/8 + /- 1 mm Hg ) . The two drugs combined had a strongly positive interaction of 10 + /- 3/7 + /- 2 mm Hg ( p less than 0.001 ) . Enalapril can be used with the other therapeutic methods tested . If a converting enzyme inhibitor does not reduce BP adequately , it appears appropriate to add a thiazide diuretic or a slow-channel calcium-blocking drug . The mechanism of the positive interaction with diuretics probably reflects an effect on the renin-angiotensin system , but the explanation for the synergism with slow-channel calcium-blocking drugs is unclear 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 Diuretic-based therapy is less effective in reducing the cardiac complications of hypertension than the risk of stroke and may be less effective in reducing left ventricular ( LV ) mass than is therapy with angiotensin converting enzyme ( ACE ) inhibition . In view of the strong association of LV hypertrophy with cardiovascular risk , this study was design ed to compare the impact of therapy with a diuretic and ACE inhibition on cardiac and vascular structure . Fifty essential hypertensives ( 74 % male , 88 % nonwhite ) participated in a double-blind study for 6 months and were r and omized to either ramipril or hydrochlorothiazide ( HCTZ ) . Echocardiography , carotid ultrasonography  , and  ambulatory blood pressure ( BP ) monitoring were performed at baseline and 3 and 6 months after initiation of therapy . The 22 ramipril patients were comparable to the 28 HCTZ patients at baseline in age , race , and 24-h BP . Although HCTZ result ed in a greater reduction in 24-h BP , only treatment with ramipril result ed in a decrease in LV mass ( 193 to 179 g , P < .005 , v 184 to 182 g , P = NS ) , attributable to a reduction in wall thicknesses but not in chamber diameter . In multivariate analysis , both change in BP and treatment group were independent predictors of change in LV mass . Importantly , although neither drug reduced carotid artery cross-sectional area , relative wall thickness increased due to a tendency for vessel diameter to decrease and wall thickness to increase , particularly in the diuretic group . Ramipril caused a sustained fall in plasma angiotensin II , whereas HCTZ increased angiotensin II levels . Although diuretic therapy was more effective in lowering ambulatory BP in this predominantly nonwhite population , only therapy with ACE inhibition was associated with regression of LV mass . Vascular geometry was altered consistent with the reduction in distending pressure result ing in vascular remodelling OBJECTIVE To evaluate whether the additional antihypertensive efficacy of the nifedipine-thiazide combination depends on the sequence of drug administration and whether the natriuretic effect of thiazide persists when co-administered with nifedipine . METHODS Double blind , r and omised , crossover , placebo-controlled study , in 12 salt-sensitive hypertensive black patients ( SSH ) . Evaluation of the antihypertensive ( 24 h ambulatory monitoring ) and natriuretic effects of placebo ( PL ) , of nifedipine-GITS ( NIF , 30 mg/d ) and of hydrochlorothiazide ( HCTZ , 25 mg/d ) given alone and in combination within two separate therapeutic sequences : PL-->NIF-->NIF + HCTZ and PL-->HCTZ-->HCTZ + NIF ( 1 month for each therapeutic regimen ) . RESULTS NIF induced greater ( p < 0.04 ) reduction of 24 h mean arterial pressure ( MAP ) ( -15.9 + /- 1.9 mm Hg , v PL ) than HCTZ ( -9.0 + /- 1.3 mm Hg ) . The association of NIF to HCTZ induced a greater ( p < 0.05 ) additional reduction of MAP-24 h ( 9.7 + /- 2.2 mm Hg ) than that produced by the association of HCTZ to NIF ( 4.1 + /- 1.3 mm Hg ) . NIF alone and in combination did not modify the diuresis-natriuresis observed with the previous treatment , whereas HCTZ alone and in combination always increased diuresis ( by 25 % ) and natriuresis ( by 53 % ) . There was a significant negative correlation ( r = -0.71 , p < 0.001 ) between blood pressure ( BP ) reduction induced by the drug administered first ( NIF or HCTZ ) and the additional BP reduction obtained by the association of the second drug . CONCLUSIONS In most of the SSH the NIF-GITS was more potent than HCTZ . NIF did not modify the diuretic-natriuretic effect of PL and of HCTZ . The greater potency of NIF may explain why in most patients the combination HCTZ to NIF induced a lower hypotensive effect than that of the association of NIF to HCTZ . Independently of the sequence of the drug administration , the lower the hypotensive effect of the drug administered first the greater the additional hypotensive effect that was observed by adding the second drug 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 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 Spironolactone is recommended as fourth-line therapy for essential hypertension despite few supporting data for this indication . We evaluated the effect among 1411 participants in the Anglo-Sc and inavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm who received spironolactone mainly as a fourth-line antihypertensive agent for uncontrolled blood pressure and who had valid BP measurements before and during spironolactone treatment . Among those who received spironolactone , the mean age was 63 years ( SD : ±8 years ) , 77 % were men , and 40 % had diabetes .  Spironolactone was initiated a median of 3.2 years ( interquartile range : 2.0 to 4.4 years ) after r and omization and added to a mean of 2.9 ( SD : ±0.9 ) other antihypertensive drugs . The median duration of spironolactone  treatment was 1.3 years ( interquartile range : 0.6 to 2.6 years ) . The median dose of spironolactone was 25 mg ( interquartile range : 25 to 50 mg ) at both the start and end of the observation period . During spironolactone therapy , mean blood pressure fell from 156.9/85.3 mm Hg ( SD : ±18.0/11.5 mm Hg ) by 21.9/9.5 mm Hg ( 95 % CI : 20.8 to 23.0/9.0 to 10.1 mm Hg ; P<0.001 ) ; the BP reduction was largely unaffected by age , sex , smoking , and diabetic status . Spironolactone was generally well tolerated ; 6 % of participants discontinued the drug because of adverse effects . The most frequent adverse events were gynecomastia or breast discomfort and biochemical abnormalities ( principally hyperkaliemia ) , which were recorded as adverse events in 6 % and 2 % of participants , respectively . In conclusion , spironolactone  effectively lowers blood pressure in patients with hypertension uncontrolled by a mean of ≈3 other drugs . Although nonr and omized and not placebo controlled , these data support the use of spironolactone in uncontrolled hypertension 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 Objective To determine the long-term efficacy and safety of a fixed , very-low-dose tablet combining one-half the st and ard dose of perindopril with one-quarter the st and ard dose of indapamide as first-line treatment in elderly patients . Design Double-blind , r and omized , placebo-controlled study in an outpatient setting . Patients and interventions Following a single-blind , placebo run-in period of 4 weeks , patients [ 65–85 years , with mild-to-moderate essential hypertension or isolated systolic hypertension ( ISH ) ] were r and omized to receive one tablet of perindopril 2 mg/indapamide 0.625 mg ( Per/ Ind ) ( n = 193 ) or placebo ( n = 190 ) , daily for 12 weeks . After this first 12-week period , all patients on Per/Ind ( n = 138 ) and patients responding to placebo ( n = 61 ) were maintained on their previous regimen for a further 48 weeks . Patients in the placebo group whose blood pressure was not normalized , were switched to Per/Ind ( n = 60 ) . Main outcome measure The primary endpoint was the proportion of patients with blood pressure that normalized between weeks 0 and 60 . Results After 1 year of treatment ( intention-to-treat ) supine systolic and diastolic blood pressure decreased by 23.0 ± 15.3 mmHg and 13.3 ± 9.4 mmHg with Per/Ind ( n = 253 : 193 from r and omized Per/Ind group and 60 from the placebo group switched at week 12 ) . The mean decreases in systolic blood pressure were similar in essential hypertension and ISH ( systolic blood pressure 23.2 versus 22.7 mmHg , respectively ) . Per/Ind treatment ( n = 253 ) achieved an initial normalization of blood pressure in 96.2 % [ 95 % confidence interval ( CI ) 93.6–98.9 % ; Kaplan-Meier estimate ] of Per/Ind-treated patients ; 79.8 % ( 95 % CI 74.1–85.5 % ) of these maintained a normalized blood pressure throughout the 1-year follow-up . The incidence of adverse events was similarly low in the placebo and active therapy groups . Efficacy and safety results for the over 75 years subgroup were similar to those for the younger elderly subjects Conclusions The fixed , very low-dose combination of perindopril 2 mg/indapamide 0.625 mg results in sustained blood pressure control when used as first line treatment of elderly hypertensive patients over 1-year , and is well-tolerated 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 Abstract Background : Current hypertension guidelines differ in their recommendations for first-line antihypertensive therapy . Objective : To evaluate the cost effectiveness of ACE inhibitor therapy as antihypertensive first-line therapy as compared with conventional antihypertensive therapy with β-adrenoceptor antagonists or diuretics . Study design : Cost-effectiveness analysis based on data from r and omised trials and observational studies comparing the effectiveness of ACE inhibitor and conventional antihypertensive therapy , we constructed a Markov model to compare four strategies in the management of uncomplicated hypertension : ( i ) prescribing ACE inhibitor therapy to all patients ; ( ii ) prescribing conventional therapy to all patients ; ( iii ) individualised antihypertensive therapy based on the presence or absence of left ventricular hypertrophy on electrocardiography ( ECG ) ; or ( iv ) individualised antihypertensive therapy based on the presence or absence of left ventricular hypertrophy on echocardiography . Methods : Cost data were derived from the medical literature and focus groups , and utility values were derived from patients on antihypertensive monotherapy . All costs were calculated in 1999 Canadian dollars , but are reported in US dollars according to the 1999 purchasing power parity rate for medical and healthcare . The effectiveness of ACE inhibitor therapy in the presence of left ventricular hypertrophy was derived from observational studies . The time horizon was over a lifetime . Perspective : Third-party payer . Patients / participants : A cohort of men aged 40 years without cardiovascular comorbidity requiring antihypertensive drug therapy . Main outcome measures and results : In the baseline analysis , all four strategies result ed in expected discounted QALYs that differed from each other only at the third decimal point ( i.e. less than 0.003 ) . Given the uncertainties in the variable estimates and the small size of the differences , these differences are extremely small and unlikely to represent real differences . Even accepting the small gains as real , the result ing cost-effectiveness ratios are unattractively high : $ US200 000 per QALY gained for the echocardiography strategy ( compared with ECG ) , and $ US700 000 for the ‘ ACE inhibitor for all ’ strategy ( compared with ECG ) . The incremental cost effectiveness of prescribing ACE inhibitor therapy to everybody was never less than $ US100 000/QALY in the sensitivity analysis . Conclusions : Prescribing ACE inhibitors as antihypertensive first-line therapy in patients without cardiovascular morbidity can not be recommended at the present time unless the aquisition costs of ACE inhibitors become substantially more attractive Background — Diuretics are recommended as first-line agents for the treatment of hypertension . This r and omized , double-blind , multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension . Methods and Results — After a 2- to 4-week placebo run-in , 1124 patients ( mean sitting diastolic blood pressure [ BP ] 95 to 109 mm Hg ) were r and omized to aliskiren 150 mg ( n=459 ) , hydrochlorothiazide 12.5 mg ( n=444 ) , or placebo ( n=221 ) once daily . Forced titration ( to aliskiren 300 mg or hydrochlorothiazide 25 mg ) occurred at week 3 ; at week 6 , patients receiving placebo were reassigned ( 1:1 ratio ) to aliskiren 300 mg or hydrochlorothiazide 25 mg . From week 12 , amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled . Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method . BP reductions ( mean sitting systolic BP/mean sitting diastolic BP ) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 ( −20.3/−14.2 versus −18.6/−13.0 mm Hg ; P<0.05 ) and were also greater at week 52 ( −22.1/−16.0 versus −21.2/−15.0 mm Hg ; P<0.05 for mean sitting diastolic BP ) . At the end of the monotherapy period ( week 12 ) , aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP ( −17.4/−12.2 versus −14.7/−10.3 mm H ; P<0.001 ) . Adverse event rates were similar with aliskiren- ( 65.2 % ) and hydrochlorothiazide-based therapy ( 61.5 % ) . Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy ( 17.9 % versus 0.9 % ; P<0.0001 ) . Conclusions — Aliskiren treatment , both as monotherapy and with optional addition of amlodipine , provided significantly greater BP reductions than the respective hydrochlorothiazide regimens . Aliskiren-based therapy was well tolerated . Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension 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 In hypertensive patients with chronic renal disease ,  angiotensin receptor blockers ( ARBs ) are among the first-line drugs , and calcium channel blockers ( CCBs ) are recommended as a second line . We examined the effects of two therapeutic strategies using ARBs and benidipine , a CCB , on blood pressure ( BP ) , urinary albumin excretion ( UAE ) , and cost-effectiveness in hypertensive patients with albuminuria . Patients whose BP was 140/90 mmHg or higher despite treatment with low- or medium-dose ARBs were assigned r and omly to two groups . In Group A ( n=14 ) , the ARB dose was maximized and then benidipine was added until BP targets were reached ( < 130/85 mmHg ) . In Group B ( n=18 ) , benidipine was administered first and then the ARB dose was increased until BP targets were reached . The BP targets were achieved by ARB alone in 36 % of Group A patients and by the addition of benidipine in 83 % of Group B patients . Finally , BP decreased in each group , reaching the targets in 93 % of Group A patients and 94 % of Group B patients after a 4-month therapeutic period . UAE was decreased in both groups after a 4-month therapeutic period compared to the allocation period ( −33±6 % in Group A , −31±6 % in Group B ; p<0.001 , respectively ) . The monthly drug cost was higher ( 11,426±880 vs. 8,955±410 yen , p=0.012 ) and the cost-effectiveness of antihypertensive treatment was lower ( p=0.003 ) in Group A than in Group B. We conclude that the addition of benidipine to low- or medium-dose ARB is , in light of the renal protection and the cost-effectiveness of this approach , a useful therapeutic strategy for controlling BP in hypertensive patients with albuminuria Objective To compare the efficacy and safety of the angiotensin II antagonist olmesartan medoxomil ( O ) and the ACE inhibitor ramipril ( R ) in elderly patients with essential arterial hypertension . Methods After a 2-week placebo wash-out 1102 treated or untreated elderly hypertensive patients aged 65–89 years ( office sitting diastolic blood pressure , DBP , 90–109 mmHg and /or office sitting systolic blood pressure , SBP , 140–179 mmHg ) were r and omized double-blind to 12-week treatment with O 10 mg or R 2.5 mg once-daily . After the first 2 and 6 weeks doses could be doubled in non-normalized [ blood pressure ( BP ) < 140/90 mmHg for nondiabetic and < 130/80 mmHg for diabetic ) individuals , up to 40 mg for O and 10 mg for R. Office BPs were assessed at r and omization , after 2 , 6 and 12 weeks of treatment , whereas 24-h ambulatory BP was recorded at r and omization and after 12 weeks . Results In the intention-to-treat population ( 542 patients O and 539 R ) after 12 weeks of treatment baseline-adjusted office SBP and DBP reductions were greater ( P < 0.01 ) with O [ 17.8 ( 95 % confidence interval : 16.8/18.9 ) and 9.2 ( 8.6/9.8 ) mmHg ] than with R [ 15.7 ( 14.7/16.8 ) and 7.7 ( 7.1/8.3 ) mmHg ] . BP normalization rate was also greater under O ( 52.6 vs. 46.0 % R , P < 0.05 ) . In the subgroup of patients with valid ambulatory BP recording ( 318 O and 312 R ) the reduction in 24-h average BP was larger ( P < 0.05 ) with O [ SBP : 11.0 ( 12.2/9.9 ) and DBP : 6.5 ( 7.2/5.8 ) mmHg ] than with R [ 9.0 ( 10.2/7.9 ) and 5.4 ( 6.1/4.7 ) mmHg ] . The larger blood pressure reduction obtained with O was particularly evident in the last 6 h from the dosing interval ; a better homogeneity of the 24-h BP control with O was confirmed by higher smoothness indices . The proportion of patients with drug-related adverse events was comparable in the two groups ( 3.6 O vs. 3.6 % R ) , as well as the number of patients discontinuing study drug because of a side effect ( 14 O vs. 19 R ) . Conclusion In elderly patients with essential arterial hypertension O provides an effective , prolonged and well tolerated BP control , representing a useful option among first-line drug treatments of hypertension in this age group A prospect i ve r and omised trial compared the immediate haemodynamic effects of intravenous diuretic ( frusemide ) , venodilator ( isosorbide dinitrate ) . arteriolar dilator ( hydralazine ) , and positive inotropie stimulation ( prenalterol ) as first-line therapy for acute left ventricular ( LV ) failure following myocardial infa rct ion . Forty-eight patients with transmural myocardial infa rct ion and a pulmonary artery occluded pressure ( PAOP ) of > 20 mm Hg were studied within 18 h of admission to a coronary care unit . Both frusemide ( -4 mm Hg : p < 0.01 ) and isosorbide dinitrate ( -6 mm Hg : p < 0.01 ) reduced LV filling pressure without change in cardiac index and heart rate . Although both hydralazine and prenalterol  increased cardiac index ( p < 0.01 ) , the reduction in LV filling pressure ( -2 mm Hg : p < 0.05 ) was less than with frusemide and isosorbide dinitrate . and was associated with an increased heart rate ( + 8 and + 13 beats min−1 : p < 0.01 ) . These data suggest that in acute heart failure following myocardial infa rct ion the four treatment modalities could be ranked in descending order of potential benefit as follows : ( a ) venodilatation ( isosorbide dinitrate )  — decrease of LV pressure/work : ( b ) diuretic therapy (frusemide)—  decrease of LV pressure/work offset by a transient pressor effect : ( c ) arteriolar dilatation ( hydralazine ) —decrease of LV pressure/work and of PAOP . but offset by tachycardia : and ( d ) positive inotropic therapy ( β1-agonist prenalterol )  — tachycardia and augmented LV afterload . Combination of the former and latter agents , because of their differing modes of action , should offer haemodynamic advantages over monotherapy and deserves further evaluation A r and omized prospect i ve controlled study , the National Interventional Cooperative Study in Elderly Hypertensives ( NICS-EH ) , previously demonstrated that the preventive effect of the long-acting calcium channel blocker nicardipine on the cardiovascular endpoint was similar to that of the diuretic , trichlormethiazide . The present report is a sub- analysis in which we compare the tolerability and safety of the calcium channel blocker with that of a diuretic in the long-term treatment of elderly hypertensives . A total of 429 elderly patients with hypertension were assigned to the nicardipine group or the diuretic group by the double-dummy method and were followed up for 5 years . Two hundred four patients in the nicardipine group and 210 patients in the diuretic group were analyzed . The incidences of fatal and nonfatal cardiovascular ( CV ) events in the two groups were comparable , and there was no significant difference in the cumulative event-free rate . However , the total incidence of adverse reactions , including non-CV events and unfavorable BP changes , was 31 cases ( 15.2 % ) in the nicardipine group , which was significantly lower than the 47 cases ( 22.4 % ) in the diuretic group ( log-rank : p=0.026 , G. Wilcoxon : p=0.01 ) . The total number of medical endpoints , including CV events , the withdrawal of the patient from the study , was 52 ( 25.5 % ) in the nicardipine group , which was significantly lower than the 65 ( 31.0 % ) in the diuretic group ( log-rank : p=0.078 , G. Wilcoxon : p=0.044 ) . It was concluded that sustained-release nicardipine is better tolerated , as it exhibits a lower incidence of medical-related withdrawals such as adverse drug reactions , non-cardiovascular events and unfavorable BP responses during the treatment Remikiren ( Ro 42 - 5892 ) is a new orally active renin inhibitor with high potency and specificity in vitro . In the present study , the drug was given in a short-term study in patients with essential hypertension , either as monotherapy or with added hydrochlorothiazide . Following a wash-out period of at least 3 weeks and then 8 days of single-blind placebo , 29 patients with essential hypertension were given remikiren 600 mg orally for 8 days . After 4 days of remikiren , hydrochlorothiazide 12.5 mg or 25 mg or placebo was added in double-blind fashion for the last 4 days . There were no significant changes in blood pressure in patients given remikiren alone . In patients given additional hydrochlorothiazide for 4 days , a marked reduction in blood pressure was observed . Remikiren effectively inhibited the plasma renin activity 24 h post-dose , whereas angiotensin II was reduced only during the first hours after drug administration . It is concluded that remikiren is orally effective . Its antihypertensive effect during short-term administration was not significant , but when given with a diuretic , a marked potentiation occurred . Further studies are needed to establish the long-term effects of remikiren alone and in combination therapy Our objective was to evaluate gefitinib ( IRESSA ) , an epidermal growth factor receptor tyrosine kinase inhibitor , versus docetaxel as second-line monotherapy for advanced non-small-cell lung cancer ( NSCLC ) . SIGN ( Second-line Indication of Gefitinib in NSCLC ; code 1839IL/0503 ) was a multicenter , r and omized , parallel-group , open-label , phase II trial that investigated oral gefitinib ( 250 mg/day ) or i.v . docetaxel ( 75 mg/m2 every 3 weeks ) in patients with advanced NSCLC who had previously received one chemotherapy regimen . The primary objective was assessment of symptom improvement ( using the FACT-L Lung Cancer Subscale ) . Secondary objectives included quality of life ( FACT-L total score ) , response rate ( using RECIST ) , overall survival and safety . This trial recruited 141 patients ( 68 to gefitinib and 73 to docetaxel ) who received treatment for a median duration of 3.0 ( gefitinib ) and 2.8 ( docetaxel ) months . Similar efficacy was observed with gefitinib and docetaxel , 36.8 and 26.0 % symptom improvement rates , 33.8 and 26.0 % quality -of-life improvement rates , 13.2 and 13.7 % objective response rates , and 7.5 and 7.1 months median overall survival , respectively . Fewer drug-related adverse events were observed with gefitinib compared with docetaxel ( all grade s : 51.5 versus 78.9 % ; Common Toxicity Criteria grade 3/4 : 8.8 versus 25.4 % ) . There were no withdrawals or deaths due to drug-related adverse events with gefitinib , while three patients withdrew and three died due to adverse events in the docetaxel group that were possibly drug related . We conclude efficacy with gefitinib was similar to docetaxel , but with a more favorable tolerability profile , in the second-line treatment of advanced NSCLC . These results support further investigation of gefitinib in this disease setting 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 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , sponsored by the National Heart , Lung , and Blood Institute ( NHLBI ) , is the largest outcome trial of antihypertensive treatment ever carried out and the only large blood pressure ( BP ) trial to be carried out in a US population in the past decade.1 The rationale for ALLHAT , which was design ed in the early 1990s , was the urgent need to determine which of the several classes of antihypertensive drugs that had been developed and released for clinical use was most effective in preventing coronary heart disease ( CHD ) , defined as fatal CHD and nonfatal myocardial infa rct ion.2 The only r and omized trials that had previously compared representatives of the antihypertensive drug classes , the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents3 and the Treatment of Mild Hypertension Study (TOMHS),4 showed BP reductions with all classes but were not powered to evaluate CHD outcomes . Further , prior outcome trials had shown that the reduction in CHD event rates with antihypertensive treatment was less than expected based on epidemiologic data .5 Adverse effects of study drugs , particularly diuretics , including hypokalemia , hypomagnesemia , hyperuricemia , hyperlipidemia , insulin resistance , and ventricular ectopic activity , had been adduced to account for the disappointing outcomes of earlier trials by off setting the beneficial effects of BP reduction.6,7 To further complicate the picture , benefits beyond BP reduction had been attributed to some antihypertensive drug classes , ie , improved survival and reduced morbidity in persons with heart failure or left ventricular dysfunction treated with angiotensin-converting enzyme ( ACE ) inhibitors8–10 and improved insulin sensitivity and lipid profiles with α-blocker treatment.11 In contrast , another antihypertensive drug class , the dihydropyridine calcium channel blockers ( CCBs ) , had been associated with unfavorable outcomes in patients with acute myocardial infa rct ion or unstable angina.12 There were no data 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 1 . The anti-hypertensive actions of timolol and hydrochlorothiazide were analysed in a double-blind 2 x 2 factorial trial in twenty patients with essential hypertension . Each patient went through four phases of 8 weeks in r and omized order , receiving timolol alone , hydrochlorothiazide alone , timolol plus hydrochlorothiazide , and placebo . 2 . Supine mean arterial pressure fell from 119 mmHg in the placebo phase , to 110 mmHg during the thiazide phase , 106 mmHg during the timolol phase , and to 101 mmHg during the combined timolol plus hydrochlorothiazide phase . 3 . Factorial analysis revealed that the hypotensive actions of the beta-receptor-blocking drug and the diuretic were additive , without any synergism or antagonism . 4 . Plasma renin activity measured in ng 3 h-1 ml-1 rose from 5 - 02 in the placebo phase to 9 - 54 in the diuretic phase , but fell to 1 - 79 in the beta-receptor blockade . It was unchanged in the combined therapy phase , despite the greater drop in blood pressure . These results suggest that the fall in plasma renin activity during beta-receptor blockade is of little importance in the hypotensive action of beta-receptor-blocking drugs 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 Little is known about the patterns of treatment and adequacy of blood pressure control in older women . The Women ’s Health Initiative , a 40-center national study of risk factors and prevention of heart disease , breast and colorectal cancer , and osteoporosis in postmenopausal women , provides a unique opportunity to examine these issues in the largest , multiethnic , best-characterized such cohort . Baseline data from the initial 98 705 women , aged 50 to 79 years , enrolled were analyzed to relate prevalence , treatment , and control of hypertension to demographic , clinical , and risk-factor covariates , and logistic regression analyses were performed to estimate odds ratios after adjusting for multiple potential confounders . Overall , 37.8 % of the women had hypertension , which is defined as systolic blood pressure ≥140 mm Hg and /or diastolic blood pressure ≥90 mm Hg or being on medication for high blood pressure ; 64.3 % were treated with drugs , and blood pressure was controlled in only 36.1 % of the hypertensive women , with lower rates of control in the oldest group . After adjustment for multiple covariates , current hormone users had higher prevalence than did nonusers ( odds ratio 1.25 ) . Hypertensive women had more comorbid conditions than did nonhypertensive women , and women with comorbidities were more likely to be treated pharmacologically . Diuretics were used by 44.3 % of hypertensives either as monotherapy or in combination with other drug classes . As monotherapy ,  calcium channel blockers were used in 16 % , angiotensin-converting enzyme inhibitors in 14 % , & bgr;-blockers in 9 % , and diuretics in 14 % of the hypertensive women . Diuretics as monotherapy were associated with better blood pressure control than any of the other drug classes as monotherapy . In conclusion , hypertension in older women is not being treated aggressively enough because a large proportion , especially those most at risk for stroke and heart disease by virtue of age , does not have sufficient blood pressure control Central aortic systolic blood pressure ( BP ) is an important determinant of cardiac workload and cardiac hypertrophy . The relationship of central aortic systolic BP and brachial BP varies depending on the stiffness of blood vessels . It is not certain whether the different drug classes affect the brachial and aortic systolic BP in a similar manner . In a double-blind crossover study , we measured the effects of the four major drug classes compared with placebo on central aortic pressure . Central aortic pressure and various indices were determined using the Sphygmo Cor apparatus . The study was undertaken in patients aged 65 to 85 years with systolic BP > 150 mm Hg at study entry . Results are reported for 32 patients who had satisfactory applanation tonometry in all five periods .  Calcium channel blockers and diuretics caused a greater fall in brachial artery systolic BP than angiotensin-converting enzyme ( ACE ) inhibitors or beta-blocking drugs . On placebo , central aorta augmentation pressure and index were 23 mm Hg and 33.3 % ; on ACE inhibitors the values were 18 mm Hg and 30 % ; on beta-blockers , 26 mm Hg and 38.5 % ; on calcium channel blockers , 16 mm Hg and 28 % ; and on diuretics , 17 mm Hg and 28.8 % . The augmentation pressure on beta-blocking drugs was greater than on the other three drug classes ( P < .05 ) , and augmentation pressures on ACE inhibitors , calcium channel blockers , and diuretics were less than on placebo ( P < .05 ) . The lowest central aortic pressures were achieved with calcium blocking drugs and diuretics . Therapy based on brachial artery recordings may thus overestimate the effect of beta-blocking drugs on central aortic systolic BP and underestimate the effectiveness of ACE inhibitors and calcium blocking drugs . The clinical importance of this discrepancy needs to be evaluated OBJECTIVE To assess the effect of low-dose , diuretic-based antihypertensive treatment on major cardiovascular disease ( CVD ) event rates in older , non-insulin-treated diabetic patients with isolated systolic hypertension ( ISH ) , compared with nondiabetic patients . DESIGN Double-blind , r and omized , placebo-controlled trial : the Systolic Hypertension in the Elderly Program ( SHEP ) . SETTING Multiple clinical and support centers in the United States . PARTICIPANTS A total of 4736 men and women aged 60 years and older at baseline with ISH ( systolic blood pressure [ BP ] , > or = 160 mm Hg ; diastolic BP , < 90 mm Hg ) at baseline , 583 non-insulin-dependent diabetic patients and 4149 nondiabetic patients ( 4 additional patients not so classifiable were r and omized but not included in these analyses ) . Diabetes mellitus defined as physician diagnosis , taking oral hypoglycemic drugs , fasting glucose level of 7.8 mmol/L or more ( > or = 140 mg/dL ) , or any combination of these characteristics . INTERVENTION The active treatment group received a low dose of chlorthalidone ( 12.5 - 25.0 mg/d ) with a step-up to atenolol ( 25.0 - 50.0 mg/d ) or reserpine ( 0.05 - 0.10 mg/d ) if needed . The placebo group received placebo and any active antihypertensive drugs prescribed by patient 's private physician for persistently high BP . MAIN OUTCOME MEASURES The 5-year rates of major CVD events , nonfatal plus fatal stroke , nonfatal myocardial infa rct ion ( MI ) and fatal coronary heart disease ( CHD ) , major CHD events , and all-cause mortality . RESULTS The SHEP antihypertensive drug regimen lowered BP of both diabetic and nondiabetic patients , with few adverse effects . For both diabetic and nondiabetic patients , all outcome rates were lower for participants r and omized to the active treatment group than for those r and omized to the placebo group . Thus , 5-year major CVD rate was lower by 34 % for active treatment compared with placebo , both for diabetic patients ( 95 % confidence interval [ CI ] , 6%-54 % ) and nondiabetic patients ( 95 % CI , 21%-45 % ) . Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic vs nondiabetic patients ( 101/1000 vs 51/1000 r and omized participants at the 5-year follow-up ) , reflecting the higher risk of diabetic patients . CONCLUSION Low-dose diuretic-based ( chlorthalidone ) treatment is effective in preventing major CVD events , cerebral and cardiac , in both non-insulin-treated diabetic and nondiabetic older patients with ISH Notwithst and ing the availability of antihypertensive drugs and practice guidelines , blood pressure control remains suboptimal . The complexity of current treatment guidelines may contribute to this problem . To determine whether a simplified treatment algorithm is more effective than guideline -based management , we studied 45 family practice s in southwestern Ontario , Canada , using a cluster r and omization trial comparing the simplified treatment algorithm with the Canadian Hypertension Education Program guidelines . The simplified treatment algorithm consisted of the following : ( 1 ) initial therapy with a low-dose angiotensin-converting enzyme inhibitor/diuretic or angiotensin receptor blocker/diuretic combination ; ( 2 ) up-titration of combination therapy to the highest dose ; ( 3 ) addition of a calcium channel blocker and up-titration ; and ( 4 ) addition of a non — first-line antihypertensive agent . The proportion of patients treated to target blood pressure ( systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg for patients without diabetes mellitus or systolic blood pressure < 130 mm Hg and diastolic blood pressure < 80 mm Hg for diabetic patients ) at 6 months was analyzed at the practice level . The proportion of patients achieving target was significantly higher in the intervention group ( 64.7 % versus 52.7 % ; absolute difference : 12.0 % ; 95 % CI : 1.5 % to 22.4 % ; P=0.026 ) . Multivariate analysis of patient-level data showed that assignment to the intervention arm increased the chance of reaching the target by 20 % ( P=0.028 ) , when adjusted for other covariates . In conclusion , the Simplified Treatment Intervention to Control Hypertension Study indicates that a simplified antihypertensive algorithm using initial low-dose fixed-dose combination therapy is superior to guideline -based practice for the management of hypertension OBJECTIVE To assess the association between  first myocardial infa rct ion and the use of antihypertensive agents .  DESIGN AND SETTING We conducted a population -based case-control study among enrollees of the Group Health Cooperative of Puget Sound ( GHC ) . PATIENTS AND METHODS Cases were hypertensive patients who sustained a first fatal or nonfatal myocardial infa rct ion from 1986 through 1993 among women and from 1989 through 1993 among men . Controls were a stratified r and om sample of hypertensive GHC enrollees , frequency matched to the cases on age , sex , and calendar year . All 623 cases and 2032 controls had pharmacologically treated hypertension . Data collection included a review of the ambulatory medical record a brief telephone interview of consenting survivors . Antihypertensive therapy was assessed using the GHC 's computerized pharmacy data base . RESULTS The first analysis included only the 335 cases and 1395 controls initially free of cardiovascular disease . Compared with users of diuretics alone , the adjusted risk ratio of myocardial infa rct ion was increased by about 60 % among users of calcium channel blockers with or without diuretic ( risk ratio = 1.62 % ; 95 % confidence interval [ Cl ] , 1.11 to 2.34 ; P = .01 ) . The second analysis was restricted to 384 cases and 1108 controls who were taking either a calcium channel blocker or a beta-blocker .  Among these subjects , the use of calcium channel blockers compared with beta-blockers was associated with about a 60 % increase in the adjusted risk of myocardial infa rct ion ( risk ratio = 1.57 ; 95 % Cl , 1.21 to 2.04 ; P < .001 ) . While high doses of beta-blockers were associated with a decreased risk of myocardial infa rct ion ( trend P = .04 ) , high doses of calcium channel blockers were associated with an increased risk ( trend P < .01 ) . CONCLUSIONS In this study of hypertensive patients , the use of short-acting calcium channel blockers , especially in high doses , was associated with an increased risk of myocardial infa rct ion . Ongoing large-scale clinical trials will assess the effect of various antihypertensive therapies , including calcium channel blockers , on several important cardiovascular end points . Until these results are available , the findings of this study support the current guidelines from the Joint National Committee on the Detection , Evaluation and Treatment of High Blood Pressure that recommend diuretics and beta-blockers as first-line agents unless contraindicated , unacceptable , or not tolerated BACKGROUND Nonsteroidal anti-inflammatory drugs may attenuate the antihypertensive effects of diuretics , beta-blockers , angiotensin-converting enzyme inhibitors , central alpha-agonists , and other vasodilators . Their effects on the antihypertensive efficacy of calcium channel blockers are inadequately studied in small numbers of patients but appear to be minimal . METHODS A three-phase , r and omized , double-blind , placebo-controlled  multicenter study included 162 patients aged 18 to 75 years with essential hypertension . After diastolic blood pressure was controlled to 90 mm Hg or less with once-daily verapamil hydrochloride , patients received ibuprofen , naproxen , or placebo matching capsules for 3 weeks , and blood pressure , heart rate , weight , and adverse effects were evaluated . A general linear model with 95 % confidence intervals was used to compare each nonsteroidal anti-inflammatory drug treatment group with the placebo group . RESULTS No significant differences in sitting , st and ing , or supine blood pressure were noted with naproxen or ibuprofen compared with placebo . The percentages of patients in each treatment group with increases of 10 mm Hg or more in either systolic or diastolic blood pressure were similar . Statistically significant increases in weight were seen with both nonsteroidal anti-inflammatory drug therapies . Changes in pulse rate were not significant . The incidence of adverse effects was similar across all three treatment groups . CONCLUSIONS The addition of naproxen or ibuprofen to the treatment of hypertensive patients in whom blood pressure is controlled by once-daily verapamil does not cause an increase in blood pressure .  Verapamil may therefore offer considerable advantages in maintaining control of blood pressure in patients who regularly receive nonsteroidal anti-inflammatory drug therapy The effectiveness of a new potent diuretic , xipamide , was evaluated in the treatment of patients with mild to moderate essential hypertension . The effects of daily doses of 40 mg xipamide were compared with those of 100 mg chlorthalidone with respect to systolic and diastolic blood pressure , using a double-blind crossover design . Patients received each drug for 6 weeks , the order of treatments being at r and om and the periods being separated by a ' washout ' period of 7 days . The results showed that xipamide was as effective as chlorthalidone in controlling blood pressure , both in the upright and supine positions , and when administered after chlorthalidone produced a further reduction . No such further reduction occurred when chlorthalidone was given after xipamide . Serum electrolyte changes induced by the two diuretics were comparable . Both drugs were well tolerated and caused few side-effects 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 OBJECTIVES Sequential therapy appears to achieve a higher  Helicobacter pylori eradication rate than triple therapy . We assessed the efficacy and tolerability of modified sequential therapy containing levofloxacin and high-dose esomeprazole in second-line therapy . METHODS Patients who failed first-line triple therapy with clarithromycin , amoxicillin and a proton pump inhibitor were eligible in this multicentre trial . Eligible patients were treated with esomeprazole 40 mg and amoxicillin 1 g for the first 5 days , followed by esomeprazole 40 mg , levofloxacin 250 mg and metronidazole 500 mg for another 5 days ( all given twice daily ) . Eradication was confirmed with a (13)C-urea breath test 6 weeks after therapy . Drug susceptibility , presence/absence of gyrA mutation and CYP2C19 genotype were also determined . RESULTS A total of 142 patients were enrolled . The eradication rate was 95.1 % [ 135/142 , 95 % confidence interval ( CI ) 91.5%-98.6 % ] in the intention-to-treat analysis and 96.4 % ( 133/138 , 95 % CI 93.3%-99.5 % ) in the per protocol analysis . Four patients ( 2.8 % ) failed to take at least 80 % of the drugs due to adverse effects . The eradication rates were 50 % ( 4/8 ) and 97.7 % ( 43/44 ) in patients with and without metronidazole resistance , respectively ( P = 0.001 ) . The eradication rates were 84.6 % ( 11/13 ) and 95.1 % ( 58/61 ) in patients with and without gyrA mutation , respectively ( P = 0.210 ) . The eradication rates were not affected by the CYP2C19 polymorphism ( P = 0.421 ) . CONCLUSIONS This modified sequential therapy achieved an excellent eradication rate ( > 95 % ) in second-line treatment and the eradication rate appeared to be affected by metronidazole resistance To determine the nature of the result ant effect on blood pressure when angiotensin converting enzyme ( ACE ) inhibitors are combined with other hypotensive agents in the treatment of uncomplicated essential hypertension , two r and omized , double-blind , crossover trials were conducted . In each trial there were four treatment phases , each 4 weeks in duration , comprising a 2 X 2 factorial experiment . Twenty-one patients completed the first study in which the effects of enalapril ( 10 mg twice daily ) were compared with hydrochlorothiazide ( 25 mg twice daily ) , with the two drugs in combination and with placebo . All blood pressure parameters were reduced in the three active treatment phases compared with placebo ( P less than 0.001 ) . Enalapril and hydrochlorothiazide were equally effective and in combination their hypotensive effects were fully additive . Sixteen patients completed the second study which compared the effects of enalapril ( 20 mg daily ) , atenolol ( 50 mg daily ) , the two drugs in combination and placebo . All blood pressure parameters were again reduced in all phases compared with placebo ( P less than 0.001 ) . Enalapril and atenolol were also equally effective , but in combination their hypotensive effects were less than fully additive , with attenuation of the potential additive response by 30 - 50 % . These results indicate that a diuretic-ACE inhibitor combination can be expected to have a greater hypotensive effect than a beta-blocker-ACE inhibitor combination . Both hydrochlorothiazide and atenolol increased plasma atrial natriuretic peptide ( ANP ) concentrations ( P less than 0.01 ) , suggesting that ANP could contribute to the hypotensive effects of these two drug classes OBJECTIVE To compare the effectiveness of the combination of hydrochlorothiazide ( HCT ) plus sustained-release nifedipine with the combination of HCT plus reserpine in lowering  high blood pressure ( BP )  unresponsive to HCT monotherapy . DESIGN An open , r and omised crossover drug trial . SETTING Out patients ' clinic in Parirenyatwa Hospital , Harare , a tertiary referral centre . SUBJECTS 32 Black patients of both sexes with newly diagnosed or previously treated hypertension aged between 21 and 65 years who had a BP > 140/95 after receiving HCT 25 mg daily for four weeks were studied . INTERVENTION Patients were kept on HCT 25 mg daily and were r and omised to receive either reserpine 0.25 mg daily or nifedipine ( Adalat Retard ) 20 mg bd for four weeks . This was followed by a two week washout period during which patients received HCT 25 mg daily only . After the washout period patients were crossed over to the alternative treatment for four weeks . Patients were kept on HCT 25 mg daily throughout the trial . MAIN OUTCOME MEASURES The main outcome measure was the fall in BP which was taken as the difference between the BP at baseline and the BP at the end of each treatment period . Both systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) measurements were taken . RESULTS Both second line drugs were effective in lowering SBP and DBP and there was no significant difference between them . Nifedipine reduced SBP by 18.9 mmHg ( 95 % CI 12.1 to 25.7 ) and DBP by 9.6 mmHg ( 95 % CI 7.2 to 12.0 ) . Reserpine reduced SBP by 15.9 mmHg ( 95 % CI 8.4 to 23.4 ) and DBP by 11.1 mmHg ( 95 % CI 7.5 to 14.6 ) . However , only two patients attained the target DBP of < or = 90 mmHg after each active treatment period . CONCLUSION AND RECOMMENDATIONS Since both agents were equally effective in reducing both SBP and DBP and reserpine is much cheaper than nifedipine , it is recommended that for a developing country like Zimbabwe , the combination of HCT and reserpine at the above doses should be used as the first step to treat mild to moderate hypertension without evidence of end organ damage . However , further trials should compare BP lowering effects as well as end organ protection offered by the trial drugs 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 The purpose of this study was to compare several diltiazem-based antihypertensive drug combinations and assess the usefulness of home blood pressure monitoring in the evaluation of the efficacy of combination pharmacotherapy . Sixteen general practitioners recruited hypertensive subjects uncontrolled on diltiazem monotherapy , who were r and omized to receive eight weeks of add-on therapy with a diuretic ( chlorthalidone ) , a dihydropyridine calcium antagonist ( felodipine ) , an ACE inhibitor ( lisinopril ) , or an angiotensin blocker ( valsartan ) .  Sitting office and home blood pressure was measured using electronic devices A&D 767 . A total of 211 patients were r and omized , and 185 completed the study . Of 52 subjects r and omized to felodipine  , 15 were withdrawn due to ankle edema . The additional antihypertensive effect of the second drug was smaller in 18 subjects with a white coat effect ( p < 0.01 ) . All combinations produced a significant decline in office ( 21.2 ± 14.8 / 7.7 ± 9.7 mmHg ) and home ( 17.1 ± 11.9 / 6.0 ± 7.0 ) blood pressure ( systolic / diastolic , p < 0.001 ) . There were no differences in the efficacy of the four combinations assessed using office or home blood pressure monitoring . These data suggest that diuretics , dihydropyridines , ACE inhibitors , and angiotensin receptor blockers provide significant additional antihypertensive effects in hypertensive patients uncontrolled on diltiazem monotherapy . The diltiazem-dihydropyridine combination is often intolerable because of ankle edema . Home blood pressure monitoring is useful in the assessment of the efficacy of combination pharmacotherapy and also allows for the detection of subjects who do not require treatment intensification Abstract Objective : To develop a working model with which prescribing behaviour among general practitioners might be influenced . Design : Intervention based on feedback on prescribing rates and problem-oriented educational outreach visits , using educational material and local opinion leaders . R and omised study with three parallel intervention groups of general practitioners , which also served as controls for each other . The pharmacotherapeutic fields chosen were hypertension , peptic ulcer/dyspepsia and depression . Prescription data were retrieved from the electronic patient records for periods of 1 year before and after the intervention . Setting : Six health care centres and three continuing medical education groups in Stockholm . Subjects : Forty general practitioners . Main outcome measures : Drug prescribing rates and patterns before and after the intervention . Results : In the hypertension field , desired trends in fractional prescribing ( favouring diuretics and beta blocking agents ) were recorded , with a significant ( P<0.05 ) effect on prescriptions for agents acting on the renin – angiotensin system , despite a pre-existing prescribing behaviour already much in line with the goals . In the peptic ulcer/dyspepsia field , desired trends were recorded for both types of therapies addressed . The fractional prescribing rates for proton-pump inhibitors decreased from 61.0 % to 52.6 % in the intervention arm and increased from 68.1 % to 76.0 % in the control arm ( not significant due to low power ) . The depression group focused on better general attention to the disease and only minor changes were registered . Conclusion : Feedback of individual prescribing rates , combined with problem-oriented educational outreach visits , is a promising model for the improvement of prescribing behaviour . Data from the electronic patient record were feasible for feedback on prescribing rates OBJECTIVES To determine rates and causes of switching from first- to second-line antiretroviral treatment ( ART ) regimens in a large treatment-naive cohort ( a South African community-based ART service ) where a targeted adherence intervention was used to manage initial virological breakthrough . METHODS ART-naive adults ( n=929 ) commencing first-line non-nucleoside-based ART [ according to WHO ( 2002 ) guidelines ] between September 2002 and August 2005 were studied prospect ively . Viral load ( VL ) and CD4 + T-cell counts were monitored every 4 months . All drug switches were recorded . Counsellor-driven adherence interventions were targeted to patients with a VL > 1000 copies/ml at any visit ( virological breakthrough ) and the VL measurement was repeated within 8 weeks . Two consecutive VL measurements > 1000 copies/ml was considered virological failure , triggering change to a second-line regimen . RESULTS During 760 person-years of observation [ median ( IQR ) 189 ( 85 - 441 ) days ] , 823 ( 89 % ) patients were retained on ART , 2 % transferred elsewhere , 7 % died and 3 % were lost to follow-up . A total of 893 ( 96 % ) patients remained on first-line therapy and 16 ( 1.7 % ) switched to second-line due to hypersensitivity reactions ( n=9 ) or lactic acidosis ( n=7 ) . A Kaplan-Meier estimate for switching to second-line due to toxicity was 3.0 % at 32 months . Virological breakthrough occurred in 67 ( 7.2 % ) patients , but , following use of a targeted adherence intervention , virological failure was confirmed in just 20 ( 2.2 % ) . Kaplan-Meier estimates at 32 months were 20 % for virological breakthrough but only 5.6 % for confirmed virological failure . CONCLUSION Regimen switches were due to virological failure or toxicity . Although follow-up time was limited , over 95 % of individuals remained on first-line ART using a combination of viral monitoring and a targeted adherence intervention 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 BACKGROUND A favourable benefit/risk ratio for treatment of rheumatoid arthritis ( RA ) with second-line drugs has been established only in short-term studies . The present investigation addresses the question of whether RA patients with a good response to long-term treatment with second-line drugs benefit from continuation of such treatment . METHODS A 52-week r and omised double-blind placebo-controlled  multicentre study was conducted to assess the effect of stopping second-line therapy in 285 RA patients with a good long-term therapeutic response . The patients either continued the second-line drug ( n = 142 ) or received a placebo ( n = 143 ) . The endpoint was a flare , defined as recurrence of synovitis . FINDINGS At entry into the study median duration of second-line drug therapy was 5 years ( range 2 - 33 ) . At 52 weeks the cumulative incidence of a flare was 38 % for the placebo group and 22 % for the continued therapy group ( p = 0.002 ) . The risk of a flare was 2.0 times higher for patients receiving placebo than for those continuing the second-line drug ( 95 % CI 1.27 to 3.17 ) . The same trend was found for each second-line drug separately , with the exception of  d-penicillamine . Side-effects that necessitated dose reduction or discontinuation occurred in 2 patients in each group . INTERPRETATION Second-line drugs continue to be effective in RA patients who have responded well to initial treatment 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 As the number of active drugs for colorectal cancer increases , we continually revisit the question of how best to integrate them . We investigated whether sequential chemotherapy consisting of only bolus plus infusional 5-fluorouracil/folinic acid could be comparable , concerning overall survival , to sequential chemotherapy consisting of bolus 5-fluorouracil/folinic acid plus " new-generation " drugs like CPT-11 or oxaliplatin .  Patients with histologically verified locally advanced disease and /or metastatic colorectal adenocarcinoma , without possibility for surgical resection , were eligible for the study . The treatments were : Cohort A -- Mayo Clinic Regimen ( MCR ) in first line , " de Gramont " regimen in second line ; Cohort B -- MCR in first line , CPT-11 ( 350mg/m2 ) in second line ; Cohort C -- MCR in first line , oxaliplatin ( 85mg/m2 ) plus " de Gramont " regimen in second line . A total of 89 patients received first plus second line chemotherapy and all of them were analyzed for survival . Number of patients /cohort : A-32 B-27 ; C-30 . The median survival time of the patients was 15 , 11 , and 17 months for the patients in cohorts A , B , and C , respectively . Survival of the patients in cohort C was significantly better than survival of the patients in cohort B ( log-rank test , p=0.04 ) . There was not a significant difference in overall survival between the cohorts A vs. C ( log-rank test , p=0.52 ) and B vs. C ( log-rank test , p=0.27 ) . It is conceivable that infusional HD 5-FU could serve as a basis for first and second-line protocol s in which other drugs are added to this regimen . Infusional 5-FU plus oxaliplatin in sequential pattern of application after bolus 5-FU has the best overall survival in comparison to other cohorts . CPT-11 applied as a single drug , was not effective enough in comparison to other treatment options Background Obstructive sleep apnea ( OSA ) and hypertension are well-known cardiovascular risk factors . Their control could reduce the burden of heart disease across population s. Several drugs are used to control hypertension , but the only consistently effective treatment of OSA is continuous positive airway pressure . The identification of a drug capable of improving OSA and hypertension simultaneously would provide a novel approach in the treatment of both diseases . Methods / Design This is a r and omized double-blind clinical trial , comparing the use of chlorthalidone with amiloride versus amlodipine as a first drug option in patients older than 40 years of age with stage I hypertension ( 140 to 159/90 to 99 mmHg ) and moderate OSA ( 15 to 30 apneas/hour of sleep ) . The primary outcomes are the variation of the number of apneas per hour and blood pressure measured by ambulatory blood pressure monitoring . The secondary outcomes are adverse events , somnolence scale ( Epworth ) , ventilatory parameters and C reactive protein levels . The follow-up will last 8 weeks . There will be 29 participants per group . The project has been approved by the ethics committee of our institution . Discussion The role of fluid retention in OSA has been known for several decades . The use of diuretics are well established in treating hypertension but have never been appropriately tested for sleep apnea . As well as testing the efficacy of these drugs , this study will help to underst and the mechanisms that link hypertension and sleep apnea and their treatment . Trial registration Clinical Trials.gov : 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 INTRODUCTION Hypertension is one of the major public health challenges worldwide . Angiotensin receptor blockers ( ARBs ) and Calcium channel blockers ( CCBs ) are among the first line antihypertensive drugs . However , optimal treatment strategies in mild to moderate hypertensives who failed to achieve  blood pressure ( BP ) control  with low-dose mono-therapy are not well established . This study was done to compare efficacy and safety of high dose mono-therapy of Amlodipine , Telmisartan and their low dose combination in mild to moderate hypertensives who failed to achieve BP control with low dose mono-therapy of either drug . MATERIAL S AND METHODS A total of 96 patients , fulfilling inclusion and exclusion criteria were enrolled in the study after obtaining informed consent . Patients were r and omized into three treatment groups i.e. Telmisartan 80 mg , Amlodipine 10 mg and low dose combination of Telmisartan 40 mg + Amlodipine 5 mg once daily for two months . The systolic BP , Diastolic BP , and ADRs were recorded at 0 , 2 , 4 , 8 weeks . RESULTS In the present study , significant reduction of mean systolic blood pressure ( SBP ) and mean diastolic blood pressure ( DBP ) was seen in all the three treatment groups . Low dose combination of Amlodipine 5 mg and Telmisartan 40 mg showed statistically significant reduction in SBP as compared to Telmisartan 80 mg mono-therapy and in DBP as compared to Amlodipine 10 mg mono-therapy . Maximum adverse drug reactions ( ADRs ) were reported in Amlodipine mono-therapy group , like ankle oedema , constipation , headache and fatigue . DISCUSSION AND CONCLUSION In term of BP control , low-dose combination therapy appears a better therapeutic approach than high-dose mono-therapy Abstract Objective : To compare the effectiveness and tolerability of hydrochlorothiazide , atenolol , nitrendipine , and enalapril in patients with mild to moderate hypertension . Design : R and omised multicentre trial over 48 weeks with double blind comparison of treatments . Setting : 48 centres in four countries . Patients : 868 patients with essential hypertension ( diastolic blood pressure 95 - 120 mm Hg ) Interventions : Initial treatment ( step 1 ) consisted of 12.5 mg hydrochlorothiazide ( n=215 ) , 25 mg atenolol ( n=215 ) , 10 mg nitrendipine ( n=218 ) , or 5 mg enalapril ( n=220 ) once daily . If diastolic blood pressure was not reduced to < 90 mm Hg within four weeks , doses were increased to 25 mg , 50 mg , 20 mg , 10 mg , respectively , once daily ( step 2 ) and after two more weeks to twice daily ( step 3 ) . The eight week titration phase was followed by an additional 40 weeks for patients who had reached the target diastolic pressure . Main outcome measure : Blood pressure by means of an automatic device with repeated measurements . Results : After eight weeks the response rate for  atenolol  ( 63.7 % ) was significantly higher than for enalapril ( 50.0 % ) , hydrochlorothiazide ( 44.7 % ) , or nitrendipine ( 44.5 % ) . After one year atenolol was still more effective ( 48.0 % ) than hydrochlorothiazide ( 35.4 % ) and nitrendipine ( 32.9 % ) , but not significantly better than enalapril ( 42.7 % ) . The treatment related dropout rate was higher ( P<0.001 ) in the nitrendipine group ( n=28 ) . Conclusions : There is no evidence of superiority for antihypertensive effectiveness or tolerability of the “ new ” classes of antihypertensives ( calcium channel blockers and angiotensin converting enzyme inhibitors ) . As these drugs are now widely used as treatment of first choice , our results further emphasise the need for studies confirming that they also reduce morbidity and mortality , as has been shown for diuretics and ß blockers . Key messages Calcium channel blockers and angiotensin converting enzyme inhibitors as initial monotherapy in the treatment of hypertension Reduction in mortality has been shown only with established ß blockers and diuretics Comparison of treatment with hydrochlorothiazide , atenolol , nitrendipine , and enalapril showed no superiority of the new drug classes Atenolol was the most effective drug , while nitrendipine showed the highest drop out rat  Elderly patients  respond better to hydrochlorothiazide and nitrendipine , and women better to enalapril , although in both subgroups the highest rate of response was with Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17 % . R and omized controlled trials of recent US Food and Drug Administration-approved immune checkpoint inhibitors-pembrolizumab ( PEM ) , nivolumab ( NIVO ) , and ipilumumab (IPI)-demonstrate improved patient outcomes , but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear . To inform policy makers about the value of these treatments , we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma . Material s and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs ( 2016 US$ ) and quality -adjusted life years ( QALYs ) for treatment sequences with first-line NIVO , IPI , NIVO + IPI , PEM every 2 weeks , and PEM every 3 weeks . Health states were defined for initial treatment , first and second progression , and death . Rates for drug discontinuation , frequency of adverse events , disease progression , and death obtained from r and omized phase III trials were used to determine the likelihood of transition between states . Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty . Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO , or IPI followed by NIVO . Compared with the first-line dacarbazine treatment strategy , NIVO followed by IPI produced an incremental cost effectiveness ratio of $ 90,871/QALY , and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $ 198,867/QALY . Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma , first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective , immune-based treatment strategies for metastatic melanoma Objective The aim of this open multicentric study was to investigate the efficacy and safety of the addition of an angiotensin converting enzyme ( ACE ) inhibitor ( benazepril , 10 mg/day ) or a diuretic ( hydrochlorothiazide , 12.5 mg/day ) for 4 weeks in patients with mild to moderate essential hypertension having been treated for 4 weeks by an angiotensin II antagonist ( valsartan , 80 mg/day ) but still having a diastolic blood pressure ( BP ) > 90 mmHg on this medication given alone . Methods A total of 327 patients were included in the trial and 153 patients ( 46 % ) had their diastolic BP ⩽ 90 mmHg after 4 weeks of valsartan monotherapy . These patients continued the same treatment regimen for the next 4 weeks , but no further blood pressure reduction was observed . The remaining patients were r and omized to either the valsartan – hydrochlorothiazide or the valsartan – benazepril combination . Results The two combinations induced an additional significant BP reduction , which was of similar magnitude for diastolic BP ( −4.5 during valsartan – hydrochlorothiazide treatment and −3.3 mmHg during valsartan – benazepril treatment ) , but of greater magnitude for systolic BP during valsartan – hydrochlorothiazide ( −6.77 mmHg ) than during valsartan – benazepril co-administration ( −3.2 mmHg ) . At the end of the trial , the BP of the responders to the valsartan monotherapy was lower than that of patients having required a combination therapy . Valsartan given alone or in association with hydrochlorothiazide or benazepril was well tolerated . Conclusion These data therefore show that in patients not responding sufficiently to angiotensin II receptor blockade BP can be further and safely lowered by adding a small dose of a diuretic or an ACE inhibitor , with the diuretic-containing combination tending to being more effective in controlling systolic BP Background Blood pressure ( BP ) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension , which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age . Non-drug interventions to prevent hypertension have had low effectiveness . In individuals with previous cardiovascular disease or diabetes , the use of BP-lowering agents reduces the incidence of major cardiovascular events . In the absence of higher baseline risk , the use of BP agents reduces the incidence of hypertension . The PREVER-prevention trial aims to investigate the efficacy , safety and feasibility of a population -based intervention to prevent the incidence of hypertension and the development of target-organ damage . Methods This is a r and omized , double-blind , placebo-controlled clinical trial , with participants aged 30 to 70 years , with pre-hypertension . The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo . The primary outcomes will be the incidence of hypertension , adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG . The secondary outcomes will be fatal or non-fatal cardiovascular events : myocardial infa rct ion , stroke , heart failure , evidence of new sub- clinical atherosclerosis , and sudden death . The study will last 18 months . The sample size was calculated on the basis of an incidence of hypertension of 14 % in the control group , a size effect of 40 % , power of 85 % and P alpha of 5 % , result ing in 625 participants per group . The project was approved by the Ethics committee of each participating institution . Discussion The early use of blood pressure-lowering drugs , particularly diuretics , which act on the main mechanism of blood pressure rising with age , may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension . If this intervention shows to be effective and safe in a population -based perspective , it could be the basis for an innovative public health program to prevent hypertension in Brazil . Trial Registration Clinical Trials NCT00970931 The aim of this study was to assess the effectivity of dietary measures in the treatment of hypertension . Therefore , a single-blind r and omised clinical trial was carried out in elderly persons with recently diagnosed hypertension . Patients were recruited from a general practice ( 6555 persons ) during visits or after written invitation or invitation by phone . New hypertensive patients ( with measurements taken on three different occasions > 159 mm Hg systolic and /or > 94 mm Hg diastolic ) , aged 60–80 years , without target-organ damage , dementia , diabetes mellitus or malignant disease entered a 3-month intervention programme of either intensive dietary counselling , receiving a sodium-reduced ( < 100 mmol/24h ) , potassium-enriched ( > 75 mmol/24h ) , and weight-reducing diet ( BMI < 25 ) , or only 25 mg chlorthalidone a day .  forty-two newly diagnosed hypertensive subjects met the inclusion criteria . two dropped out from the chlorthalidone group , one with side effects and another after a myocardial infa rct ion . although blood pressure ( bp ) in the diet group decreased less than in the drug group , of the patients in the diet group 45 % fell back to a normal systolic and 50 % to a normal diastolic bp ( drug treatment group , systolic 75 % and diastolic 85 % ) . in contrast with the diet group , lipid spectrum and blood glucose concentration in the diuretic group , however , deteriorated slightly . the dietary intervention was effective in elderly patients with a systolic or diastolic bp in the range of 160–180 and 95–100 mm hg , respectively . reduction in weight should be the primary aim . it is argued that sodium reduction can be achieved better by collective measures . in patients with a bp of more than 180 mm hg systolic or 100 mm hg diastolic , dietary advice and drug treatment should be combined BACKGROUND The eradication rate of first-line Helicobacter pylori treatment is only 70 - 85 % and has been decreasing due to the increase in antibiotic resistance . The aim of this study was to evaluate the efficacy of bismuth-containing quadruple therapy as second-line treatment for H. pylori infection based on treatment duration . METHODS We prospect ively enrolled 227 patients that were found to have persistent H. pylori infection after first-line proton-pump inhibitor-clarithromycin-amoxicillin triple therapy .  Patients were r and omized to 1-week ( 112 patients ) and 2-week ( 115 patients ) quadruple therapy with tripotassium dicitrate bismuthate 300 mg q.i.d . , metronidazole 500 mg t.i.d . , and tetracycline 500 mg q.i.d . and esomeprazole 20 mg b.i.d . The eradication rate , drug compliance , and adverse events were compared based on treatment duration . RESULTS The eradication rates were 72/112 ( 64.3 % , 95 % CI : 0.504 - 0.830 ) and 71/92 ( 77.2 % , 0.440 - 0.749 ) with 1-week group , and 95/115 ( 82.6 % , 1.165 - 2.449 ) an 88/94 ( 93.6 % , 1.213 - 5.113 ) with 2-week group by intention-to-treat therapy ( p = .002 ) and per- protocol analysis ( p = .001 ) , respectively . The adverse events increased as the treatment duration s increased from 7 to 14 days ( 20.0 and 42.5 % , respectively , p < .001 ) . However , there was no significant difference in the patient compliance or the rate of major adverse events between the 1- and 2-week groups ( 6.3 and 12.5 % , respectively , p = .133 ) . CONCLUSION Two-week bismuth-containing quadruple therapy was more effective than the 1-week treatment , and should be considered for second-line treatment in Korea 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 Background A challenge for implementation research ers is to develop principles that could generate testable hypotheses that apply across a range of clinical context s , thus leading to generalisability of findings . Such principles may be provided by systematic ally developed theories . The opportunity has arisen to test some of these theoretical principles in the Ontario Printed Educational Material s ( OPEM ) trial by conducting a sub-trial within the existing trial structure . OPEM is a large factorial cluster-r and omised trial evaluating the effects of short directive and long discursive educational messages embedded into informed , an evidence -based newsletter produced in Canada by the Institute for Clinical Evaluative Sciences ( ICES ) and mailed to all primary care physicians in Ontario . The content of educational messages in the sub-trial will be constructed using both st and ard methods and methods inspired by psychological theory . The aim of this study is to test the effectiveness of the  TheoRY-inspired MEssage ( ' TRY-ME '  ) compared with the ' st and ard ' message in changing prescribing behaviour . Methods The OPEM trial participants r and omised to receive the short directive message attached to the outside of informed(an ' outsert ' )  will be sub-r and omised to receive either a st and ard message or a message informed by the theory of planned behaviour ( TPB ) using a two ( long insert or no insert ) by three ( theory-based outsert or st and ard outsert or no outsert ) design . The messages will relate to prescription of thiazide diuretics as first line drug treatment for hypertension ( described in the accompanying protocol , " The Ontario Printed Educational Material s trial " ) . The short messages will be developed independently by two research teams . The primary outcome is prescription of thiazide diuretics , measured by routinely collected data available within ICES . The study is design ed to answer the question , is there any difference in guideline adherence ( i.e. , thiazide prescription rates ) between physicians in the six groups ? A  process evaluation survey instrument based on the TPB will be administered pre- and post-intervention ( described in the accompanying protocol , " Looking inside the black box " ) . The second research question concerns processes that may underlie observed differences in prescribing behaviour . We expect that effects of the messages on prescribing behaviour will be mediated through changes in physicians ' cognitions . Trial registration numberCurrent controlled trial IS RCT BACKGROUND Lafutidine is an H2-receptor antagonist with gastroprotective action through capsaicin-sensitive afferent neurons and relatively inexpensive compare to proton-pump inhibitors ( PPIs ) . A 7-day course of PPIs-amoxicillin-metronidazole is recommended as st and ard second-line Helicobacter pylori therapy and is covered by national health insurance in Japan . The aim of this study was to determine the efficacy and safety of second-line eradication using the H2-receptor antagonist lafutidine as a substitute for a PPI . MATERIAL S AND METHODS Fifty-two patients who failed in first-line eradication using PPI-amoxicillin-clarithromycin were r and omly assigned to a 7-day course of rabeprazole at 10 mg b.i.d . , amoxicillin at 750 mg b.i.d . , and metronidazole at 250 mg b.i.d . ( RPZ-AM ) or a 7-day course of lafutidine at 10 mg t.i.d . , amoxicillin at 750 mg b.i.d . , and metronidazole at 250 mg b.i.d . ( LFT-AM ) as second-line therapy . Eradication was assessed by the ( 13 ) C urea breath test . A drug susceptibility test was performed before the second-line therapy . RESULTS Prior to second-line H. pylori eradication , the rate of resistance to clarithromycin was 86.5 % and the rate of resistance to metronidazole was 3.8 % . The eradication rates for both LFT-AM and RPZ-AM groups were 96 % ( 95%CI = 88.6 - 100 % ) . There were no severe adverse events in either group . CONCLUSIONS Lafutidine plus metronidazole-amoxicillin as second-line therapy provided a high eradication rate and safe treatment similar to a PPI-based regimen . Lafutidine-based eradication therapy is therefore considered to be a promising alternative and is also expected to reduce health care costs in H. pylori eradication In accordance with international recommendations on the need to decrease doses of antihypertensive drugs , a low-dose ( 1.5 mg ) sustained-release form of indapamide was developed so as to optimize the safety/efficacy ratio , while maintaining a once-daily administration . The new formulation ensures that the active ingredient release occurs in a sustained manner over 24 hours , with mean concentrations close to the maximal concentration over a prolonged period , while avoiding peak plasma concentrations . Clinical data were obtained mainly through two European multicenter , r and omized , double-blind trials , totalling 690 patients . Firstly , the antihypertensive efficacy ' of the new indapamide 1.5 mg form was demonstrated by measuring blood pressure 24 hours after the last drug intake , using a mercury sphygmomanometer ; the equivalence of its antihypertensive efficacy with the immediate-release form of indapamide 2.5 mg was then verified . Biochemical safety data showed better acceptability with indapamide 1.5 mg with in particular a reduction of more than 50 % of the number of patients with kalemia < 3.4 mmol/l ; clinical safety data confirmed the good acceptability observed with the 2.5 mg immediate-release form of indapamide since many years , especially regarding glucose and lipid neutrality . In conclusion , the 1.5 mg sustained-release form of indapamide has an improved antihypertensive efficacy/safety ratio which is in accordance with international recommendations for the usage of low doses of antihypertensive drugs and diuretics in the first-line treatment of hypertension Recent studies and authorities have advocated the use of low-dose thiazide diuretics as first-line treatment agents in elderly hypertensives . However , these recommendations were based solely on blood pressure ( BP ) measured in the clinic . The objective of the present 32-week double-blind study was to compare the effects of hydrochlorothiazide ( HCTZ ) and amlodipine ( AML ) in elderly patients with confirmed ambulatory hypertension . After a 4-week placebo washout period , 42 ( 25 men , 17 women ) patients ( mean age , 69 years ) with clinic sitting diastolic BP of 95 to 114 mm Hg and daytime ambulatory diastolic BP of > or = 90 mm Hg were r and omized double-blind to receive AML 5 to 10 mg ( n = 21 ) or HCTZ 12.5 to 25 mg ( n = 21 ) once daily . After 8 weeks of monotherapy , patients in whom clinic diastolic BP remained > or = 90 mm Hg were given combination therapy with the other agent . Amlodipine monotherapy induced significant reductions in clinic , mean 24-h , daytime and sleep systolic/diastolic BPs whereas only clinic BP decreased significantly in patients treated with HCTZ monotherapy . Moreover , 19/21 versus 8/21 patients on AML and HCTZ monotherapies achieved adequate BP control . At the end of the 32-week treatment period , combination therapy in the HCTZ group result ed in statistically significant reductions in clinic as well as in 24-h , daytime and sleep ambulatory BPs that were similar to those observed in the AML monotherapy group . In conclusion , the administration of AML monotherapy induced significant reductions in both clinic and ambulatory BPs in elderly patients whereas only clinic BP was significantly decreased by HCTZ monotherapy . Moreover , the addition of AML to HCTZ in patients inadequately controlled by monotherapy has permitted statistically significant decrements in clinic as well as in ambulatory BP . Consequently , the results of the present study suggest that the use of HCTZ in doses of up to 25 mg daily is inadequate for ambulatory BP control in the elderly despite official recommendations The objectives of this study were to compare indices of 24-hour blood pressure ( BP ) following a physician-pharmacist collaborative intervention and to describe the associated changes in antihypertensive medications . This was a secondary analysis of a prospect i ve , cluster-r and omized clinical trial conducted in 6 family medicine clinics r and omized to co-managed ( n=3 clinics , 176 patients ) or control ( n=3 clinics , 198 patients ) groups .  Mean ambulatory systolic BP ( SBP ) was significantly lower in the co-managed vs the control group : daytime BP 122.8 mm Hg vs 134.4 mm Hg ( P<.001 ) ; nighttime SBP 114.8 mm Hg vs 123.7 mm Hg ( P<.001 ) ; and 24-hour SBP 120.4 mm Hg vs 131.8 mm Hg ( P<.001 ) , respectively . Significantly more drug changes were made in the co-managed than in the control group ( 2.7 vs 1.1 changes per patient , P<.001 ) , and there was greater diuretic use in co-managed patients ( 79.6 % vs 62.6 % , P<.001 ) . Ambulatory BPs were significantly lower for the patients who had a diuretic added during the first month compared with those who never had a diuretic added ( P<.01 ) . Physician-pharmacist co-management significantly improved ambulatory BP compared with the control group . Antihypertensive drug therapy was intensified much more for patients in the co-managed group Background R and omised controlled trials of implementation strategies tell us whether ( or not ) an intervention results in changes in professional behaviour but little about the causal mechanisms that produce any change . Theory-based process evaluations collect data on theoretical constructs alongside r and omised trials to explore possible causal mechanisms and effect modifiers . This is similar to measuring intermediate endpoints in clinical trials to further underst and the biological basis of any observed effects ( for example , measuring lipid profiles alongside trials of lipid lowering drugs where the primary endpoint could be reduction in vascular related deaths).This study protocol describes a theory-based process evaluation alongside the Ontario Printed Educational Message ( OPEM ) trial . We hypothesize that the OPEM interventions are most likely to operate through changes in physicians ' behavioural intentions due to improved attitudes or subjective norms with little or no change in perceived behavioural control . We will test this hypothesis using a well-vali date d social cognition model , the theory of planned behaviour ( TPB ) that incorporates these constructs . Methods / design We will develop theory-based surveys using st and ard methods based upon the TPB for the second and third replications , and survey a sub sample of Ontario family physicians from each arm of the trial two months before and six months after the dissemination of the index edition of informed , the evidence based newsletter used for the interventions . In the third replication , our study will converge with the " TRY-ME " protocol ( a second study conducted alongside the OPEM trial ) , in which the content of educational messages was constructed using both st and ard methods and methods informed by psychological theory . We will modify Dillman 's total design method to maximise response rates . Preliminary analyses will initially assess the internal reliability of the measures and use regression to explore the relationships between predictor and dependent variable ( intention to advise diabetic patients to have annual retinopathy screening and to prescribe thiazide diuretics for first line treatment of uncomplicated hypertension ) . We will then compare groups using methods appropriate for comparing independent sample s to determine whether there have been changes in the predicted constructs ( attitudes , subjective norms , or intentions ) across the study groups as hypothesised , and will assess the convergence between the process evaluation results and the main trial results .Trial registration numberCurrent controlled trial IS RCT AIM : Quadruple therapy is generally recommended as second-line therapy after Helicobacter pylori ( H. pylori ) eradication failure . However , this regimen requires the administration of four drugs with a complex scheme , is associated with a relatively high incidence of adverse effects , and bismuth salts are not available worldwide anymore . Our aim was to evaluate the efficacy and tolerability of a triple second-line levofloxacin-based regimen in patients with H. pylori eradication failure . METHODS : Design : Prospect i ve multicenter study . Patients : in whom a first treatment with proton pump inhibitor-clarithromycin-amoxicillin had failed . Intervention : A second eradication regimen with levofloxacin ( 500 mg b.i.d . ) , amoxicillin ( 1 g b.i.d . ) , and omeprazole ( 20 mg b.i.d . ) was prescribed for 10 days . Outcome : Eradication was confirmed with 13C-urea breath test 4–8 wk after therapy . Compliance with therapy was determined from the interview and the recovery of empty envelopes of medications . Incidence of adverse effects was evaluated by means of a specific question naire . RESULTS : Three hundred consecutive patients were included . Mean age was 48 yr , 47 % were male , 38 % had peptic ulcer , and 62 % functional dyspepsia . Almost all ( 97 % ) patients took all the medications correctly . Per- protocol and intention-to-treat eradication rates were 81 % ( 95 % CI 77–86 % ) and 77 % ( 73–82 % ) . Adverse effects were reported in 22 % of the patients , mainly including nausea ( 8 % ) , metallic taste ( 5 % ) , abdominal pain ( 3 % ) , and myalgias ( 3 % ) ; none of them were severe . CONCLUSION : Ten-day levofloxacin-based rescue therapy constitutes an encouraging second-line strategy , representing an alternative to quadruple therapy in patients with previous proton pump inhibitor-clarithromycin-amoxicillin failure , being simple and safe Objective Hypertension guidelines recommend initial treatment with a β-blocker or diuretic and adding the other drug where blood pressure is not controlled . We hypothesized that systematic rotation through the major classes of antihypertensive drugs would demonstrate substantial differences in the pattern of an individual patient 's response , and suggest a more rational approach to choosing best treatment . Design Thirty-four young hypertensives ( age 28–55 , median 47 ) rotated in a double-blind , Latin-square , crossover fashion through 6 weeks of treatment each with amlodipine , doxazosin , lisinopril , bisoprolol , bendrofluazide and placebo . Blood pressure was measured at each visit . ‘ Best ’ drug , defined by efficacy and tolerability , was repeated at the end . Results Rotation doubled the number of patients reaching target blood pressure ( systolic < 140 mmHg ) on one drug ( P = 0.03 ) . All five drugs were represented among the ‘ best ’ drugs . In six patients , the blood pressure on ‘ best ’ drug was at least 10 mmHg lower than on any other . Response to the ‘ best ’ drug was highly correlated ( r = 0.79 ) with its previous administration . By contrast , there were only weak correlations between responses to pairs of drugs , except for angiotensin-converting enzyme ( ACE ) inhibitor ( A ) with β-blocker ( B ) , and calcium blocker ( C ) with diuretic ( D ) – each r = 0.71 , P < 0.005 ) . In these young patients , the majority of patients ( 23/34 ) responded best to a drug suppressing the renin system ( A and B ) . Conclusions Patients vary reproducibly in their response to initial treatment , and switching among drugs can increase the efficacy of monotherapy . The results support an AB/CD scheme for choosing therapy , in which the first drug is taken from one of these pairs , and uncontrolled patients switch to one of the other pair To evaluate the effects on depressive mood of withdrawal of antihypertensive medication , we conducted a r and omized , multi-center study with clinical centers at the Albert Einstein College of Medicine , Bronx , NY , University of Alabama School of Medicine , Birmingham , and the University of Mississippi School of Medicine in Jackson . Patients were formerly active participants in the Hypertension Detection and Follow-Up Program ( HDFP ) whose blood pressure was controlled with drugs for a period of 5 years . Of 496 patients , 431 had both baseline and " 1-year " mood scores . Patients , stratified by obesity , were r and omized to one of three groups : continue the HDFP medication ; discontinue medication with no dietary intervention , or with sodium restriction and potassium increase ; or , for those overweight , to a weight reduction intervention .  Depression was assessed using the CES-D scale ( Center for Epidemiological Studies --Depressed Mood ) , administered at baseline and again approximately 1 year after r and omization . Of the seven treatment groups , only those who continued their HDFP medication showed significant improvement in mood from baseline . The overweight continue-medication group showed significantly greater improvement compared to the no-drugs , no-diet intervention groups , and to the overweight sodium-restriction group . Patients who had their blood pressure successfully controlled with weight reduction had a significant improvement in mood from 11.0 scale points to 8.0 , P = .006 . Comparisons between those withdrawn from diuretic alone and those withdrawn from both diuretic plus reserpine were inconclusive . Dietary Intervention Study of Hypertension ( DISH ) shows no evidence that continued use of chlorthalidone has a negative impact on quality of life , while our results concerning reserpine were inconclusive . ( ABSTRACT TRUNCATED AT 250 WORDS 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 Summary The Oslo Hypertension Study started in 1972 and lasted for 66 ( range 60–78 ) months . A total of 785 healthy men , aged 40 to 49 years , with mild hypertension were r and omised to a drug-treated group and to an untreated , control group . The drugs used for treatment were hydrochlorothiazide alone in 36 % , hydrochlorothiazide and propranolol in 26 % , hydrochlorothiazide and methyldopa in 20 % , and other drugs in 18%.A total of 95 % in the drug-treated group received hydrochlorothiazide . Pressure complications , such as stroke and aneurysms , only occurred in the control group . Coronary events were more numerous in the drug-treated group , so that the total incidence of cardiovascular complications did not significantly differ between the treated and untreated groups . After 5 and 10 years , total mortality was found to be the same in both groups . However , the 10-year coronary heart disease mortality was significantly higher in the drug-treated group than in the untreated controls ( 14 vs 3 , p < 0.01 ) . Possible reasons for the failing effect of drug treatment of hypertension on coronary heart disease is discussed , and attention is drawn to the adverse effect of diuretics and β-adrenergic blockers , both on lipid and carbohydrate metabolism . This is in contrast to the α-adrenergic blocker , prazosin , which has been shown to improve the blood lipid profile 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 Prompt use of an effective anti-malarial drug is essential for controlling malaria and its adverse effects in pregnancy . The World Health Organization recommends an artemisinin-based combination therapy as the first-line treatment of uncomplicated malaria in the second and third trimesters of pregnancy . The study objective was to determine the degree to which presumed episodes of uncomplicated symptomatic malaria in pregnancy were treated with a recommended anti-malarial regimen in a region of Ug and a. Methods Utilizing a population -based r and om sample , we interviewed women living in Jinja , Ug and a who had been pregnant in the past year . Results Self-reported malaria during the index pregnancy was reported among 67 % ( n = 334 ) of the 500 participants . Among the 637 self-reported episodes of malaria , an anti-malarial drug was used for treatment in 85 % of the episodes . Use of a currently recommended treatment in the first trimester was uncommon ( 5.6 % ) . A contraindicated anti-malarial drug ( sulphadoxine-pyrimethamine and /or artemether-lumefantrine ) was involved in 70 % of first trimester episodes . Recommended anti-malarials were used according to the guidelines in only 30.1 % of all second and third trimester episodes . Conclusions Self-reported malaria was extremely common in this population and adherence to treatment guidelines for the management of malaria in pregnancy was poor . Use of artemether-lumefantrine combined with non-recommended anti-malarials was common practice . Overuse of anti-malarial drugs , especially ones that are no longer recommended , undermines malaria control efforts by fueling the spread of drug resistance and delaying appropriate treatment of non-malarial febrile illnesses . Improved diagnostic capacity is essential to ultimately improving the management of malaria-like symptoms during pregnancy and appropriate use of currently available anti-malarials We compared the effects of relaxation therapy in hypertensive patients taking placebo , a beta-blocker ( atenolol , 100 mg/d ) , or a diuretic ( chlorthalidone , 50 mg/d ) , and we also compared the effects of relaxation therapy with the effects of the latter two drugs alone . Blood pressures were measured not only in the relaxation therapists ' office and at a hypertension clinic , but also in the patient 's environment by means of 24-hour ambulatory blood pressure recordings . The effect of relaxation therapy , while statistically significant , was modest . There was no generalization of effect to ambulatory blood pressure .  Atenolol was significantly more effective than  relaxation  in reducing both systolic and diastolic pressure .  Chlorthalidone was significantly more effective than relaxation in reducing systolic but not diastolic pressure in the hypertension clinic only . The long-term effects of relaxation were independent of concomitant drug use , but within the actual relaxation sessions blood pressure dropped further during chlorthalidone than during placebo or atenolol treatment BACKGROUND The renoprotective effect of ACE inhibition in chronic renal disease is well established but the studies on effects of calcium antagonists on progression of renal disease and on proteinuria have given varying results . METHODS We conducted an open long-term r and omized prospect i ve multi-centre study comparing the combination of ramipril and felodipine ER ( F ) with either drug alone in non-diabetic renal disease . Included were patients with uncontrolled hypertension ( diastolic blood pressure ( DBP ) ) > or = 95 mmHg on treatment with a diuretic and a beta-blocker . Fifty-one patients received the combination of R and F , 54 patients R , and 53 patients F. The treatment goal was a DBP < 90 mmHg and a similar BP reduction in the three groups . Mean doses at the last visit were 5 + 5 , 10 and 9 mg , respectively , after a mean treatment time of nearly 2 years . The progression of renal impairment was studied by serial measurements of serum creatinine , iohexol clearance , and albuminuria . RESULTS The reduction in supine systolic ( S ) BP and DBP expressed as median values were -19.0/-14.5,-14.3/-15.0 and -13.5/-13.3 mmHg in the R+F , R , and F groups , respectively . There was no significant difference between the groups . When correction for the acute drug effect was performed the R+F group had a slower progression rate of the renal disease ( loss of glomerular filtration rate ( GFR ) ml/min/year ) compared with the F group ( P<0.05 ) but not to the R group ( P>0.20 ) . There was a rise in albuminuria after 2 years in the F group ( P<0.05 ) , but no significant change was found in the other groups . CONCLUSIONS In patients with non-diabetic renal disease the combination of an ACE inhibitor and a calcium antagonist in reduced doses used in addition to baseline therapy with beta-blockers and diuretics , tended to cause a better BP reduction as each drug per se . The R+F treatment also caused a slower progression of the renal disease compared with F alone . The combination treatment seems to afford better BP control and appears to be a favourable therapeutic option in patients with renal disease and hypertension In a double-blind trial , 545 out- patients with essential hypertension received 25 mg/day chlorthalidone alone ( 274 patients ) or in fixed combination with 200 mg/day slow-release metoprolol ( 271 patients ) for 8 weeks . Both treatments significantly ( P<0.001 ) decreased systolic and diastolic blood pressure ; 45.6 % of patients receiving chlorthalidone and 82.5 % receiving combined therapy had a diastolic blood pressure of less than 95 mmHg . Patients not controlled by chlorthalidone or chlorthalidone plus metoprolol subsequently received chlorthalidone plus metoprolol ( 137 patients ) or chlorthalidone plus metoprolol plus a third drug ( 34 patients ) , respectively , for 8 weeks . A total of 79.5 % of patients receiving chlorthalidone plus metoprolol and 61.8 % receiving chlorthalidone plus metoprolol plus a third drug had a diastolic blood pressure of less than 95 mmHg . Only 5.9 % of patients experienced mild to modérate side-effects . Plasma potassium leveis significantly ( P<0.01 ) decreased during the first 8 weeks only . It is concluded that a diuretic alone or in fixed combination with a β-blocker is effective in the long-term treatment of arterial hypertension 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 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 Summary : Thirty-two adult Nigerians with mild-to-moderate essential hypertension were included in a doubleblind placebo-controlled trial matching nifedipine 20 mg twice daily with placebo for 6 weeks . Nifedipine caused very significant reductions of both systolic and diastolic blood pressures in all patients . Blood pressure fell from a mean of 181.3 ( SE 3.9)/114.7 ( SE 2.4 ) to 122.8 ( SE 1.9)/79.4 ( SE 1.6 ) . Mean arterial pressure fell from a mean of 136.75 ( SE −2.2 ) to 94.19 ( SE −1.39 ) . Polyuria was a common side effect in six of the 16 patients who received nifedipine . One additional patient developed transient occipital headache .  Nifedipine monotherapy would appear to be an effective first-line drug in the management of essential hypertension in adult blacks BACKGROUND Hypertension can not always be adequately controlled with available drugs . We investigated the blood-pressure-lowering effects of the new vasodilatory , selective endothelin type A antagonist , darusentan , in patients with treatment-resistant hypertension . METHODS This r and omised , double-blind study was undertaken in 117 sites in North and South America , Europe , New Zeal and , and Australia . 379 patients with systolic blood pressure of 140 mm Hg or more ( > /=130 mm Hg if patient had diabetes or chronic kidney disease ) who were receiving at least three blood-pressure-lowering drugs , including a diuretic , at full or maximum tolerated doses were r and omly assigned to 14 weeks ' treatment with placebo ( n=132 ) or darusentan 50 mg ( n=81 ) , 100 mg ( n=81 ) , or 300 mg ( n=85 ) taken once daily . R and omisation was made central ly via an automated telephone system , and patients and all investigators were masked to treatment assignments . The primary endpoints were changes in sitting systolic and diastolic blood pressures . Analysis was by intention to treat . The study is registered with Clinical Trials.gov , number NCT00330369 . FINDINGS All r and omly assigned participants were analysed . The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg ( SD 14/8 ) with placebo , 17/10 mm Hg ( 15/9 ) with darusentan 50 mg , 18/10 mm Hg ( 16/9 ) with darusentan 100 mg , and 18/11 mm Hg ( 18/10 ) with darusentan 300 mg ( p<0.0001 for all effects ) . The main adverse effects were related to fluid accumulation . Oedema or fluid retention occurred in 67 ( 27 % ) patients given darusentan compared with 19 ( 14 % ) given placebo . One patient in the placebo group died ( sudden cardiac death ) , and five patients in the three darusentan dose groups combined had cardiac-related serious adverse events . INTERPRETATION Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs . As with other vasodilatory drugs , fluid management with effective diuretic therapy might be needed . FUNDING Gilead Sciences Thirty-three moderate hypertensives were converted to a 2-drug regimen of metoprolol and diuretic and BPs stabilized at a well-controlled level . They then completed one of three conditions over an 8-week interval : ( I ) 16 sessions of TBF ( h and and foot warming ) ; ( II ) 16 sessions of frontal EMG-BF ; ( III ) regular home monitoring of BP . Attempts were then made to withdraw the patients from the sympatholytic medication . Those successfully withdrawn were followed up for one year . There were no significant advantages for TBF over the other two conditions in the short term or with long-term follow-up . Only 27 % of treated patients ( including Condition III failures who were remedicated and treated with TBF ) were successfully off of the sympatholytic at a one-year follow-up . The generally poor results on clinical outcome were confirmed by clinic BPs , home BPs by patients , and 24-hour ambulatory BPs Sixty-five patients with unclomplicated hypertenive urgencies were treated in the emergency and cardiology departments with 20 mg nifedipine , 20 mg nicardipine , or 25 mg captopril in a r and omized study . The study population consisted of 65 patients ranging in age from forty-one to seventy-one .  Blood pressure and heart rate were assessed for six hours after intake of the antihyper tensive agents . Within sixty minutes nifedipine reduced blood pressure by an average of 74.7 mmHg for the systolic and 35.4 mmHg for the diastolic . Average heart rate increased significantly by 11.6 beats/min at within thirty minutes . Nicardipine and captopril produced equivalent falls in systolic ( -81.6 and -79.4 mmHg ) and diastolic ( -37.3 and -33 mmHg ) blood pressure respectively , but did not increase heart rate significantly . The antihypertensive effect of each drug was maintained until six hours after medication . In conclusion , nifedipine , nicardipine , and captopril show similar efficacy in the treatment of hypertensive urgencies . The authors believe that these drugs can be used as first-line therapy in the treatment of hypertensive urgencies safely and effectively Objective : A case control study has reported a 60 % higher risk of myocardial infa rct ion in hypertensives treated with a calcium channel blocker ( CCB ) . We examined the Department of Health Hypertension Care Computing Project ( DHCCP ) data to see if we could confirm or refute this suggestion . Design : Two case control studies , matched and unmatched , plus two longitudinal studies from 1 year of presentation , one for all subjects given a CCB  for more than 1 year compared with those not given this drug , and the second comparing survival on the different drugs initially given between 3 and 12 months of follow-up . Subjects : A total of 9328 subjects were included in the analyses and 2154 died . Of these , 6406 received one or more of the following index drugs : 26 % a calcium channel blocker ( CCB ) ; 84 % a diuretic ; 29 % alpha methyldopa ; 12 % a beta-blocker ( BB ) ; and 11 % an angiotensin-converting enzyme ( ACE ) inhibitor . The CCBs were nifedipine , diltiazem or verapamil . Results : In the case control studies a group given diuretics ± other treatments ( but not including one of the index drugs ) provided a reference group with a relative risk ( RR ) of 1.0 . In the matched case control study the adjusted RR for a CCB  without a diuretic was 1.32 ( 95 % CI 0.64–2.70 ) for IHD mortality and 1.05 ( 95 % CI 0.60–1.84 ) for cardiovascular mortality . Similar results were observed for methyldopa , BBs and ACE inhibitors . The results in the unmatched case control analysis were also similar . The longitudinal study comparing all those treated for over 1 year with a CCB with all other treatments showed a RR for total mortality of 1.03 ( 95 % CI 0.85–1.25 ) . The longitudinal study of total mortality according to treatment initiated at 3–12 months found results of a similar magnitude for CCBs , methyldopa and BBs . Conclusions : The reference diuretic group had less severe cardiovascular disease than other groups . Treatment with a CCB , BB or methyldopa was associated with an excess mortality in comparison with this reference group . The excess was similar in the different drug groups Goals To assess the efficacy and safety profile of methotrexate ( MTX ) for the treatment of Crohn 's disease ( CD ) in clinical practice . Background MTX is widely used for some chronic immunologic diseases . Although some r and omized controlled trials suggest its efficacy in CD , this drug remains a second-line , underused , immunomodulator . Study Medical records of all patients treated with MTX for CD in our center ( n=44 ) were review ed . Clinical and epidemiologic parameters , including risk factors for hepatotoxicity , were registered . Results MTX was prescribed mainly for steroid-dependency ( n=22 ) and as concomitant treatment to infliximab ( n=18 ) . Mean duration of treatment was 22.9±19 months , with a mean cumulative dose of MTX of 1169±784 mg . Thirty-nine percent of patients developed drug-related side effects , hepatotoxicity being the most frequent [ 13 patients ( 30 % ) ] . However , only 5 patients ( 11 % ) had to discontinue MTX . In steroid-dependent CD patients  , disease remission and complete steroid withdrawal was achieved in 77 % of cases . Seven patients lost their initial response to MTX during follow-up , leading to a cumulative probability of remission of 39 % after 3 years of treatment . Conclusions MTX is well tolerated in most CD patients . Although a great proportion of steroid-dependent CD patients achieve disease remission and steroid withdrawal , there is a trend to a loss of efficacy with time . Larger , long-term studies are necessary to establish the role of MTX in the management of CD The non-sulfhydryl selective angiotensin-converting enzyme inhibitor benazepril ( 20 mg daily ) was compared with hydrochlorothiazide ( 50 mg daily ) in post-infa rct ion ( 6 - 24 months ) patients with symptomatic ( NYHA functional class 2 ) mild heart failure . No concomitant drug therapy was given . The study had a double-blind cross-over design with 3-month treatment periods . Both drugs were well tolerated , and both caused a similar reduction in systolic blood pressure . Heart rate was higher with the diuretic . Benazepril improved the NYHA functional class in 17 out of 29 ( 59 % ) patients , whereas one patient improved with hydrochlorothiazide ( P = 0.0004 ) . With regard to global efficacy score , benazepril was also superior . Thus , angiotensin-converting enzyme inhibitors may be superior to diuretics as first-choice therapy in symptomatic mild heart failure The effect on BP of 100 and 200 mg spironolactone/day has been compared with that of methyl-dopa , 750 mg/day , and with combined treatment with both drugs in 32 patients with essential hypertension . The 28 patients who completed the entire investigation were treated for 30 weeks , divided into 4 treatment periods and 4 placebo periods of equal duration . BP did not fall significantly during the initial placebo period , and at the end of each of the intervening placebo periods it rose to pretreatment levels . A signifcant decrease in mean BP was found during the 4 treatment periods . A fall exceeding 14 % was registered in 32 % of the patients after methyldopa , 750 mg/day , in 50 % of the patients after spironolactone , 200 mg/day , in 89 % after combined treatment with both drugs , and in 29 % after spironolactone , 100 mg/day . Low renin hypertension was found in 9 of the 28 patients . The average decrease in mean BP after sironolactone , 200 mg/day , methyldopa , 750 mg/day , and after combined treatment did not differ significantly between the low and the normal renin group . The rationale for using diuretics such as spironolactone or thiazide as the basic therapy in essential hypertension is discussed . It is concluded that both are useful in the treatment of essential hypertension and might be used alone or in combination To investigate the concept of initiating therapy with low doses of a calcium antagonist and an ACE inhibitor , a fixed combination of isradipine 2.5 mg plus the ACE inhibitor spirapril 3 mg was compared with its components , with the full-dose monotherapies ( isradipine 5 mg or spirapril 6 mg ) , and with placebo . After a 2-week wash out phase in pretreated patients and a subsequent 2-week placebo period , 405 patients with a diastolic blood pressure ( DBP ) between 100 and 114 mmHg were r and omly allocated to 12-week once-daily double-blind treatment in one of the six treatment arms . In patients whose blood pressure was not normalized ( defined as DBP≤90 mmHg ) after 6 weeks of treatment , the dosage of either medication was doubled or , in the placebo group , was switched to the fixed combination . After week 6 , the mean reductions from baseline in sitting systolic/diastolic blood pressure 24 hours after dosing ( trough ) for the fixed combination or the monotherapies isradipine 5 mg , isradipine 2.5 mg , spirapril 6 mg , spirapril 3 mg , and placebo were10.4/8.7 , 10.0/9.4 , 6.5/6.7 , 10.0/8.3 , 7.0/5.8 , and 2.2/4.7 mmHg , respectively . The blood pressure changes obtained with the low-dose fixed combination were essentially identical to those observed with the full-dose monotherapies , thus showing an additive effect of low-dose isradipine and spirapril . In terms of tolerability , the lowest rate of any adverse events was found in the combination group . In this group , typical adverse events of calcium antagonists , such as headache , flushing , ankle edema , or palpitations , were observed only in 5 % , 2 % , 1 % , and 0 % , respectively , dry cough , considered typical for ACE inhibitors , was observed in only 1 % of the combination group . In conclusion , the low-dose components isradipine 2.5 mg and spirapril 3 mg were shown to have an additive effect when combined , exerting a blood pressure – lowering effect comparable with the full doses and a trend to a better tolerability profile in comparison with the st and ard doses . Thus , low-dose combination therapy with these drugs appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension 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 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 Treatment of hypertension with diuretics , beta-blockers , or both leads to improved outcomes . It has been postulated that agents that inhibit the renin-angiotensin system confer benefit beyond the reduction of blood pressure alone . We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting-enzyme ( ACE ) inhibitors with the outcomes in those treated with diuretic agents . METHODS We conducted a prospect i ve , r and omized , open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practice s. Subjects were followed for a median of 4.1 years , and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models . RESULTS At base line , the treatment groups were well matched in terms of age , sex , and blood pressure . By the end of the study , blood pressure had decreased to a similar extent in both groups ( a decrease of 26/12 mm Hg ) . There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group ( 56.1 per 1000 patient-years ) and 736 cardiovascular events or deaths from any cause in the diuretic group ( 59.8 per 1000 patient-years ; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [ 95 percent confidence interval , 0.79 to 1.00 ] ; P=0.05 ) . Among male subjects , the hazard ratio was 0.83 ( 95 percent confidence interval , 0.71 to 0.97 ; P=0.02 ) ; among female subjects , the hazard ratio was 1.00 ( 95 percent confidence interval , 0.83 to 1.21 ; P=0.98 ) ; the P value for the interaction between sex and treatment-group assignment was 0.15 . The rates of nonfatal cardiovascular events and myocardial infa rct ions decreased with ACE-inhibitor treatment , whereas a similar number of strokes occurred in each group ( although there were more fatal strokes in the ACE-inhibitor group ) . CONCLUSIONS Initiation of antihypertensive treatment involving ACE inhibitors in older subjects , particularly men , appears to lead to better outcomes than treatment with diuretic agents , despite similar reductions of blood pressure Objective To assess the current levels of awareness , treatment and control of hypertension in Engl and and to determine the number and type of drugs prescribed . Design A cross-sectional household-based survey of English adults . Subjects A r and om sample from the adult English population of 12 116 adults who participated in the 1994 Health Survey for Engl and . Main outcome measures Prevalences of treatment hypertension , awareness and control . Results Using a definition of hypertension as a systolic blood pressure ≥ 160 mmHg or a diastolic blood pressure ≥ 95 mmHg , or a patient 's being administered antihypertensive treatment , the prevalence of awareness of hypertension was 63 % . Among hypertensives , 50 % were receiving treatment and 30 % had their hypertension controlled ( < 160 mmHg/95 mmHg ) . Awareness , treatment and control rates are considerably lower than the most recently reported rates from the USA . Diuretics and β-blockers remain the most common antihypertensive agents used in Engl and . Conclusion There is considerable scope for improving the treatment and control of hypertension in the English adult population
The effect was similar to that obtained when thiazides are used as a single agent .
Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are added as a first-line drug .
This means that the BP lowering effect of thiazides is additive .
Loop diuretics appear to have a similar blood pressure lowering effect as thiazides at 1 times the recommended starting dose .
Because of the short duration of the trials and lack of reporting of adverse events , this review does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug
BACKGROUND Diuretics are widely prescribed for hypertension not only as a first-line drug but also as a second-line drug .
Therefore , it is essential to determine the effects of diuretics on blood pressure ( BP ) , heart rate and withdrawals due to adverse effects ( WDAEs ) when given as a second-line drug .