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BACKGROUND Analyses of some r and omised trials show that calcium-channel blockers reduce the risk of stroke more than expected on the basis of mean blood pressure alone and that beta blockers are less effective than expected . We aim ed to investigate whether the effects of these drugs on variability in blood pressure might explain these disparities in effect on stroke risk . METHODS The Anglo-Sc and inavian Cardiac Outcomes Trial Blood Pressure Lowering Arm ( ASCOT-BPLA ) compared amlodipine-based regimens with atenolol-based regimens in 19 257 patients with hypertension and other vascular risk factors and the Medical Research Council ( MRC ) trial compared atenolol-based and diuretic-based regimens versus placebo in 4396 hypertensive patients aged 65 - 74 years . We expressed visit-to-visit variability of blood pressure during follow-up in the two trials as st and ard deviation ( SD ) and as transformations uncorrelated with mean blood pressure . For ASCOT-BPLA , we also studied within-visit variability and variability on 24 h ambulatory blood-pressure monitoring ( ABPM ) . RESULTS In ASCOT-BPLA , group systolic blood pressure ( SBP ) SD was lower in the amlodipine group than in the atenolol group at all follow-up visits ( p<0.0001 ) , mainly because of lower within-individual visit-to-visit variability . Within-visit and ABPM variability in SBP were also lower in the amlodipine group than in the atenolol group ( all p<0.0001 ) . Analysis of changes from baseline showed that variability decreased over time in the amlodipine group and increased in the atenolol group . The lower risk of stroke in the amlodipine group ( hazard ratio 0.78 , 95 % CI 0.67 - 0.90 ) was partly attenuated by adjusting for mean SBP during follow-up ( 0.84 , 0.72 - 0.98 ) , but was abolished by also adjusting for within-individual SD of clinic SBP ( 0.99 , 0.85 - 1.16 ) . Findings were similar for coronary events . In the ABPM sub study , reduced variability in daytime SBP in the amlodipine group ( p<0.0001 ) partly accounted for the reduced risk of vascular events , but reduced visit-to-visit variability in clinic SBP had a greater effect . In the MRC trial , group SD SBP and all measures of within-individual visit-to-visit variability in SBP were increased in the atenolol group compared with both the placebo group and the diuretic group during initial follow-up ( all p<0.0001 ) . Subsequent temporal trends in variability in blood pressure during follow-up in the atenolol group correlated with trends in stroke risk . INTERPRETATION The opposite effects of calcium-channel blockers and beta blockers on variability of blood pressure account for the disparity in observed effects on risk of stroke and expected effects based on mean blood pressure . To prevent stroke most effectively , blood-pressure-lowering drugs should reduce mean blood pressure without increasing variability ; ideally they should reduce both Objective : The aims of this sub analysis of the COLM trial [ NCT00454662 ] were to compare visit-to-visit variability ( VVV ) of blood pressure ( BP ) between age groups and between two treatment combinations , that is , the angiotensin II receptor blocker , olmesartan combined with a calcium channel blocker ( CCB ) , or a diuretic and to investigate the effect of VVV of BP on cardiovascular events in elderly hypertensive patients . Methods : Hypertensive patients ages 65–84 years with a history of and /or risk factors for cardiovascular disease were r and omized to receive treatment with olmesartan along with either a CCB or a diuretic  for at least 3 years . This sub analysis comprised 4876 patients who had their office BP measured at least three occasions ( median nine occasions ) during the follow-up period .  VVV of BP was defined by several metrics including the within-individual st and ard deviation of every visit during the follow-up period . Results : VVV of SBP was larger in the very elderly group ( 75–84 years ) than in the elderly group ( 65–74 years ) . VVV of SBP was smaller in the olmesartan along with CCB group than in the olmesartan along with diuretic group , especially in very elderly patients and also isolated systolic hypertensive patients . The incidence rate of primary endpoint increased along with an increment in the SD of SBP in all of the age and treatment groups . Conclusion : VVV of SBP may mediate the preferable effect of combination of angiotensin II receptor blocker along with CCB on cardiovascular events in the very elderly and also isolated systolic hypertensive patients Objective : To determine the association between discrete antihypertensive drug classes and incident dementia controlling for blood pressure variability ( BPV ) in the preceding 4 years . Methods : A total of 6,537 participants ( mean age 79 years , 62 % women ) in a prospect i ve population -based cohort were followed up for incident dementia . A 4-year time lag period was created to classify drug exposure and measure blood pressure . BPV ( percent coefficient of variation [ CV ] ) was regressed against 9 antihypertensive drug classes ( BPVreg ) . Cox regression models were employed to determine hazard ratios ( HRs ) for incident dementia thereafter according to drug class , adjusted for mean blood pressure , covariates , and BPV or BPVreg . Results : Over a median 8.4 years follow-up ( interquartile range 6.7–9.0 ) , lower dementia risk was associated with nondihydropyridine calcium channel blocker ( HR 0.56 ; 95 % confidence interval [ CI ] 0.31–1.00 , p = 0.05 ) and loop diuretics ( HR 0.45 ; 95 % CI 0.22–0.93 , p = 0.03 ) after adjusting for CV-BPV . Similar findings were obtained in analyses restricted to antihypertensive drug users for nondihydropyridine calcium channel blocker ( HR 0.52 ; 95 % CI 0.28–0.95 , p = 0.03 ) and loop diuretics ( HR 0.40 ; 95 % CI 0.19–0.83 , p = 0.01 ) . All systolic BPV × antihypertensive drug interaction terms were not different from p < 0.05 . Conclusions : Nondihydropyridine calcium channel blocker and loop diuretics were associated with a reduced dementia risk independent of CV-BPV in the preceding 4 years . Systolic BPV was not the primary mechanism through which antihypertensive drug classes lower dementia risk 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 Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes .  Dihydropyridine calcium channel blockers , however , may lower blood pressure but not albuminuria in these patients . Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics . We conducted a double blind r and omized controlled trial on 332 hypertensive , albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year . The trial employed a non-inferiority design . Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort . The percentage of patients progressing to overt proteinuria was similar for both groups . When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria . We conclude that initial treatment using benzaepril with a diuretic result ed in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker . In contrast , blood pressure reduction , particularly the diastolic component , favored the combination with amilodipine . The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure 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 BACKGROUND It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk . The objective of the study was to compare the efficacy of these treatments in elderly , high-risk Japanese hypertensive patients . METHODS The OlmeSartan and Calcium Antagonists R and omized ( OSCAR ) study was a multicenter , prospect i ve , r and omized , open-label , blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease . Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were r and omly assigned to receive 40 mg/d olmesartan ( high-dose angiotensin II receptor blocker ) or a calcium channel blocker + 20 mg/d olmesartan ( angiotensin II receptor blocker + calcium channel blocker ) . The primary end point was a composite of cardiovascular events and noncardiovascular death . RESULTS During a 3-year follow-up , blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group . Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group . More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group ( 58 vs 48 events , hazard ratio [ HR ] , 1.31 , 95 % confidence interval , 0.89 - 1.92 ; P=.17 ) . In patients with cardiovascular disease at baseline , more primary events occurred in the high-dose angiotensin II receptor blocker group ( HR , 1.63 , P=.03 ) ; in contrast , fewer events were observed in the subgroup without cardiovascular disease ( HR , 0.52 , P=.14 ) . This treatment-by-subgroup interaction was significant ( P=.02 ) . CONCLUSION The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease . The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent 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 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 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 Calcium-channel blockers can alter apoptosis , a mechanism for destruction of cancer cells . We examined whether the long-term use of calcium-channel blockers is associated with an increased risk of cancer . METHODS Between 1988 and 1992 we carried out a prospect i ve cohort study of 5052 people aged 71 years or more and who lived in three regions of Massachusetts , Iowa , and Connecticut USA . Those taking calcium-channel blockers ( n = 451 ) were compared with all other participants ( n = 4601 ) . The incidence of cancer was assessed by survey of hospital discharge diagnoses and causes of death . These outcomes were vali date d by the cancer registry in the one region where it was available . Demographic variables , disability , cigarette smoking , alcohol consumption , blood pressure , body-mass index , use of other drugs , hospital admissions for other causes , and comorbidity were all assessed as possible confounding factors . FINDINGS The hazard ratio for cancer associated with calcium-channel blockers ( 1549 person-years , 47 events ) compared with those not taking calcium-channel blockers ( 17225 person-years , 373 events ) was 1.72 ( 95 % CI 1.27 - 2.34 , p = 0.0005 ) , after adjustment for confounding factors . A significant dose-response gradient was found . Hazard ratios associated with verapamil , diltiazem , and nifedipine  did not differ significantly from each other . The results remained unchanged in community-specific analyses . The association between calcium-channel blockers and cancer was found with most of the common cancers . INTERPRETATION Calcium-channel blockers were associated with a general increased risk of cancer in the study population s , which suggested a common mechanism . These observational findings should be confirmed by other studies In patients with insufficient blood pressure ( BP ) control , despite using a combination regimen containing an angiotensin receptor blocker and a calcium channel blocker ( CCB ) , whether a greater dose of CCB or adding a diuretic is more effective at lowering BP remains unclear . We conducted a multicenter r and omized clinical trial to compare the efficacy of switching from the daily administration of a single-pill fixed-dose combination of irbesartan ( 100 mg ) and amlodipine ( 5 mg ) to irbesartan ( 100 mg ) with an increased dose of amlodipine ( 10 mg ) ( HD group , n=62 ) or irbesartan ( 100 mg ) and amlodipine ( 5 mg ) with 1 mg of indapamide ( D group , n=63 ) in patients with poorly controlled hypertension .  BP measured at home was monitored by a physician using a telemonitoring system . Between the HD and D groups , no significant differences were observed in morning home BP changes ( mean reduction of systolic/diastolic BP , 1.7/0.9 mmHg ; 95 % confidence intervals , −2.4 to 5.7/−1.4 to 3.2 ; P=0.19/0.37 ) , achievement rate of target BP ( 45.2 % vs. 42.9 % , P=0.80 ) , BP variability independent of the mean ( P⩾0.74 ) , other variability indices ( P⩾0.55 ) and time to stabilization , which was calculated using a fitted analysis ( 13.1 days vs. 11.4 days , P=0.99 ) . Although a significant increase in serum uric acid was observed in the D group ( P<0.0001 ) , neither clinical ly relevant abnormal laboratory test results nor critical BP changes were observed throughout the trial period . Both antihypertensive drug combination strategies were effective treatment options . Further investigation is required to determine the appropriate use of both therapies based on the various pathologies associated with hypertension 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 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 Most treatment recommendations for hypertension are based on criteria that consider efficacy , safety and cost . Given the need for long-term use of antihypertensive agents , treatment compliance should also be taken into consideration in the selection process . OBJECTIVE The purpose of the present study was to estimate persistence and adherence to  antihypertensive agents in a real-life setting . METHODS Persistence and adherence to treatment were estimated using data from the Regie de l'assurance maladie du Quebec . RESULTS Data from a r and om sample of 4561 subjects with a diagnosis of hypertension covered by the Regie de l'assurance maladie du Quebec drug plan and using one of the antihypertensive agents reimbursed by the drug plan for the first time between January 2000 and December 2001 were analyzed . The persistence rate observed after a two-year period with diuretics was significantly lower ( 52.8 % ) than with any other classes of antihypertensive agent ( P<0.01 ) . Persistence rates for beta-blockers , calcium channel blockers , angiotensin-II receptor blockers and angiotensin-I converting enzyme inhibitors were 69.3 % , 64.3 % , 60.9 % and 58.9 % , respectively . After two years , the proportion of patients who were 80 % adherent to their treatment was 64.9 % for angiotensin-I converting enzyme inhibitors , 65.0 % for angiotensin-II receptor blockers , 64.2 % for calcium channel blockers , 60.3 % for beta-blockers and 50.9 % for diuretics . The proportion of patients who were 80 % adherent to their treatment was significantly lower for diuretics than with any other antihypertensive agents ( P<0.01 ) . CONCLUSION Persistence and adherence to treatment are essential to treatment success . Results of the present study indicate that , in a real-life setting , patients are significantly less compliant to diuretics than to any other antihypertensive agents Objectives Current guidelines recommend the use of multiple medications for hypertension . The present study was aim ed at determining which combination was optimal to prevent cardiovascular events . Methods We conducted a prospect i ve , r and omized , open-label , blinded-endpoint trial . Hypertensive out patients aged between 40 and 85 years who did not achieve target blood pressure ( BP<140/90 mmHg ) with calcium channel blocker ( CCB ) benidipine 4 mg/day were r and omly assigned to receive angiotensin receptor blocker ( ARB ) , & bgr;-blocker , or thiazide diuretic in addition to benidipine . Results Among a total of 3501 patients ( 1167 , benidipine-ARB ; 1166 , benidipine-&bgr;-blocker ; and 1168 , benidipine-thiazide ) , 3293 patients ( 1110 , 1089 , and 1094 , respectively ) who received each combination treatment were included in the analysis . Median follow-up was 3.61 years . At the end of the treatment , 64.1 , 66.9 , and 66.0 % of patients in the benidipine-ARB , benidipine-&bgr;-blocker , and benidipine-thiazide groups achieved target BP , respectively . The cardiovascular composite endpoint occurred in 41 ( 3.7 % ) , 48 ( 4.4 % ) , and 32 ( 2.9 % ) patients , respectively : the hazard ratio was 1.26 in the benidipine-ARB ( P = 0.3505 ) and 1.54 in the benidipine-&bgr;-blocker ( P = 0.0567 ) groups compared with the benidipine-thiazide group . The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes ( P = 0.0109 ) and benidipine and ARB significantly reduced new-onset diabetes ( P = 0.0240 ) compared with benidipine and & bgr;-blocker . All trial treatments were safe and well tolerated . Conclusion CCB combined with ARB , & bgr;-blocker , or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP 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 OBJECTIVES To ascertain the baseline characteristics of the high-risk hypertensive patients entering the International Nifedipine GITS Study : Intervention as a Goal in Hypertension Treatment ( INSIGHT ) . To determine the success of single and combination therapy in achieving target blood pressures in such a population . DESIGN INSIGHT is a double-blind , prospect i ve outcome trial comparing the efficacy of the calcium channel blocker , nifedipine GITS , and the thiazide , co-amilozide , in preventing myocardial infa rct ion and stroke . We recruited 2996 men and 3454 women , aged 55 - 80 years , with blood pressure during placebo run-in > 150/95 mmHg or isolated systolic blood pressure > 160 mmHg from nine countries . Treatment allocation to nifedipine GITS 30 mg daily or co-amilozide ( hydrochlorothiazide 25 mg/amiloride 5 mg ) once daily was performed by minimization rather than r and omization to balance additional risk factors . This was followed by four optional increases in treatment : dose-doubling of the primary drug , addition of atenolol 25/50 mg or enalapril 5/10 mg , and then any other hypotensive drug excluding calcium blockers or diuretics . Target blood pressure was 140/90 mmHg or a fall > or = 20/10 mmHg . RESULTS Blood pressure at r and omization was 172+/-15 / 99+/-9 mmHg . Thirteen per cent of the patients were previously untreated . The proportions of each additional risk factors were : smoking > 10/day , 29 % ; cholesterol > 6.43 mmol/l , 52 % ; family history of premature myocardial infa rct ion or stroke , 21 % ; diabetes mellitus 20 % ; left ventricular hypertrophy , 10 % ; previous myocardial infa rct ion , other presentations of coronary heart disease , and peripheral vascular disease , each 6 % ; proteinuria , 3 % . Fifty-five per cent of patients had one additional risk factor , whereas 33 % , 9 % and 3 % had two , three or more additional risk factors , respectively . The blood pressure ( and falls in blood pressure ) at the end of titration and at 1 year after minimization was 139+/-12 / 82+/-7 mmHg ( 33+/-15 / 17+/-9 ) in the 5226 patients still on r and omized treatment The numbers requiring the four treatment increments were , respectively , 1591 , 780 , 597 and 294 , meaning that almost 70 % of patients on r and omized treatment in INSIGHT are receiving only the primary drug . At one year , 69 % of patients had a blood pressure < or = 140/90 mmHg . CONCLUSION INSIGHT is one of the first double-blind comparisons of active antihypertensive treatments , requiring high-risk patients to achieve sufficient power . Despite this requirement , it is possible to achieve good blood pressure control in most patients without the addition of multiple additional treatments that may dilute any differences between the primary agents Objective : The aim of the present study was to compare the cardiovascular effects of olmesartan , an angiotensin II receptor blocker , combined with a calcium channel blocker ( CCB ) or a diuretic , in a prospect i ve , r and omized , open-label , blinded endpoint trial . Methods : Japanese hypertensive patients aged at least 65 to less than 85 years with SBP at least 140 mmHg and /or DBP at least 90 mmHg with antihypertensive treatment , or SBP at least 160 mmHg and /or DBP at least 100 mmHg without antihypertensive treatment were r and omized to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic . If SBP and /or DBP remained at least 140 and /or at least 90 mmHg , the other antihypertensive drug was added . The primary endpoint was a composite of fatal and nonfatal cardiovascular events . The median follow-up time was 3.3 years . Results : Blood pressure decreased similarly in both groups . The primary endpoint occurred in 116/2568 patients ( 4.5 % ) in the olmesartan plus CCB group and in 135/2573 patients ( 5.3 % ) in the olmesartan plus diuretic group [ hazard ratio 0.83 , 95 % confidence interval ( CI ) 0.65–1.07 , P = 0.16 ] . Rates of all-cause death and cardiovascular deaths were similar . Among patients aged at least 75 years , the incidence of stroke tended to be lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group ( hazard ratio 0.63 , 95 % CI 0.38–1.02 , P = 0.059 , interaction P = 0.019 ) . Fewer patients in the olmesartan plus CCB group ( 8.2 % , 211/2568 ) than in the olmesartan plus diuretic group ( 9.8 % , 253/2573 ; P = 0.046 ) experienced serious adverse events . Conclusion : Despite no significant difference in cardiovascular events , the different safety profiles suggest that the combination of olmesartan and CCB may be preferable to that of olmesartan and diuretic OBJECTIVE Blood pressure variation is one of the factors that affects the risk of stroke recurrence and prognosis . This study investigates the effects of calcium channel blockers and beta-blockers on blood pressure variability in severe ischemic stroke patients . PATIENTS AND METHODS The clinical data of 24 patients with ischemic stroke in our intensive care unit were analyzed , and received amlodipine or metoprolol for more than 14 days with 24-hour ambulatory blood pressure monitoring .  All patients aged 61 - 90 years , with GCS score ≤ 8 or associated with other organ dysfunction . RESULTS Among these 24 ischemic stroke patients , 12 received amlodipine and 12 received metoprolol . The observation period was divided into two phases : 1 - 6 days and 7 - 14 days . The decrease in blood pressure was faster in the metoprolol group than in the amlodipine group , while the average st and ard deviation was significantly greater and the smoothness index was less . CONCLUSIONS Metoprolol has faster onset  than amlodipine  and less blood pressure variability than metoprolol BACKGROUND Previous studies have reported an increased risk of cancer with calcium-channel blockers in man . Other work in animals suggests that inhibitors of angiotensin-I-converting enzyme ( ACE ) protect against cancer . We aim ed to assess the risk of cancer in hypertensive patients receiving ACE inhibitors or other antihypertensive drugs .  METHODS Our retrospective cohort study was based on the records of 5207 patients who attended the Glasgow Blood Pressure Clinic between Jan 1 , 1980 , and Dec 31 , 1995 . The patients ' records are linked with the Registrar General Scotl and and the West of Scotl and Cancer Registry . FINDINGS Compared with the West of Scotl and controls , the relative risks of incident and fatal cancer among the 1559 patients receiving ACE inhibitors were 0.72 ( 95 % CI 0.55 - 0.92 ) and 0.65 ( 0.44 - 0.93 ) . Among the 3648 patients receiving antihypertensive drugs other than ACE inhibitors ( calcium-channel blockers 1416 , diuretics 2099 , beta-blockers 2681 ) , the corresponding relative risks were 110 ( 0.97 - 1.22 ) and 1.03 ( 0.87 - 1.20 ) . The relative risk of cancer was lowest in women on ACE inhibitors : 0.63 ( 0.41 - 0.93 ) for incident cancer ; 0.48 ( 0.23 - 0.88 ) for fatal cancer ; and 0.37 ( 0.12 - 0.87 ) for female-specific cancers . The reduced relative risk of cancer in patients on ACE inhibitors was greatest with follow-up of longer than 3 years . Calcium-channel blockers , diuretics , and beta-blockers had no apparent effect on risk of cancer . INTERPRETATION Long-term use of ACE inhibitors may protect against cancer . The status of this finding is more that of hypothesis generation than of hypothesis testing ; r and omised controlled trials are needed A multicenter , r and omized , controlled , double-blind U.S. trial is comparing the combined effects of diet treatment and 1 of 5 active drug regimens with diet treatment alone , for the long-term management of middle-aged adults with " mild " hypertension . Factors stimulating this trial are data documenting the high prevalence of mild hypertension in the adult population ; mild hypertension 's responsibility for a high proportion of morbidity and mortality attributable to hypertension overall ; data from long-term hypertension intervention trials showing reduced morbidity and mortality of people with mild hypertension with use of either diuretics or beta blockers as step-1 therapy , and other trials that failed to demonstrate beneficial impact on morbidity and mortality , possibly due to residual questions concerning aspects of benefit to risk ratios with these medications ; recent data from trials showing long-term control of mild hypertension and other risk factors by nutritional means ; lack of data from long-term trials on benefit to risk ratios with newer drugs such as selective alpha 1 inhibitors , angiotensin converting enzyme inhibitors and calcium channel blockers ; paucity of data from trials on long-term combined effects of diet and drug therapy , and of diet alone , for people with mild hypertension . During the next few years , phase 1 of the trial will study 6 groups of drugs . The step-1 drugs are angiotensin converting enzyme inhibitor ( enalapril ) , alpha 1 inhibitor ( doxazosin ) , beta blocker ( acebutolol ) , calcium channel blocker ( amlodipine ) , diuretic ( chlorthalidone ) and placebo . All participants are to receive vigorous sustained nutritional counseling to reduce obesity , moderate sodium intake and avoid heavy use of alcohol . Key endpoints for phase 1 of the study are the need for additional medication to control mild hypertension , side effects ( i.e. , clinical and biochemical ) and consequent need to discontinue drug and quality of life . Phase-1 data are to be used to complete the phase-2 design , with the ultimate aim to assess effects on morbidity and mortality 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 The objective of the study is to compare fatal and nonfatal cardiovascular endpoints in hypertensive patients r and omised to the calcium-channel blocker , nifedipine GITS or a thiazide diuretic , co-amilozide . A total of 6592 patients from nine countries ( UK , France , Israel , Spain , Italy , The Netherl and s , Sweden , Denmark and Norway ) will be recruited , aged 55 - 80 and with a blood pressure ( BP ) > or = 150/95 or > or = 160 mm Hg ( systolic ) . All patients will have at least one other major cardiovascular risk factor . Patients will be minimised by country and risk factors and r and omised to double-blind treatment with either nifedipine GITS or diuretic . After a single dose titration , additional treatment will be atenolol or enalapril ( where beta-blockade is contra-indicated ) . After achieving a target BP of 140/90 mm Hg patients will be followed for a total of 3 years . Primary endpoints are myocardial infa rct ion , stroke , subarachnoid haemorrhage , heart failure and sudden cardiac death . The study has a power of 80 % at 5 % significance to detect a difference between 8 % event rate over 3 years in diuretic-treated patients and 6 % in those receiving nifedipine BACKGROUND Nocturnal blood pressure ( BP ) is an independent risk factor of cardiovascular events . The NOCTURNE study , a multicenter , r and omized controlled trial ( RCT ) using our recently developed information and communication technology ( ICT ) nocturnal home BP monitoring ( HBPM ) device , was performed to compare the nocturnal HBP-lowering effects of differential ARB-based combination therapies in 411 Japanese patients with nocturnal hypertension ( HT ) . Methods and Results : Patients with nocturnal BP ≥120/70 mmHg at baseline even under ARB therapy ( 100 mg irbesartan daily ) were enrolled . The ARB/CCB combination therapy ( irbesartan 100 mg+amlodipine 5 mg ) achieved a significantly greater reduction in nocturnal home systolic BP ( primary endpoint ) than the ARB/diuretic combination ( daily irbesartan 100 mg+trichlormethiazide 1 mg ) ( -14.4 vs. -10.5 mmHg , P<0.0001 ) , independently of urinary sodium excretion and /or nocturnal BP dipping status . However , the change in nocturnal home systolic BP was comparable among the post-hoc subgroups with higher salt sensitivity ( diabetes , chronic kidney disease , and elderly patients ) . CONCLUSIONS This is the first RCT demonstrating the feasibility of clinical assessment of nocturnal BP by ICT-nocturnal HBPM . The ARB/CCB combination was shown to be superior to ARB/diuretic in patients with uncontrolled nocturnal HT independently of sodium intake , despite the similar impact of the 2 combinations in patients with higher salt sensitivity BACKGROUND Recent reports suggest that calcium-channel blockers may be harmful in patients with diabetes and hypertension . We previously reported that antihypertensive treatment with the calcium-channel blocker nitrendipine reduced the risk of cardiovascular events . In this post hoc analysis , we compared the outcome of treatment with nitrendipine in diabetic and nondiabetic patients . METHODS After stratification according to center , sex , and presence or absence of previous cardiovascular complications , 4695 patients ( age , > or = 60 years ) with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure below 95 mm Hg were r and omly assigned to receive active treatment or placebo . Active treatment consisted of nitrendipine ( 10 to 40 mg per day ) with the possible addition or substitution of enalapril ( 5 to 20 mg per day ) or hydrochlorothiazide ( 12.5 to 25 mg per day ) or both , titrated to reduce the systolic blood pressure by at least 20 mm Hg and to less than 150 mm Hg . In the control group , matching placebo tablets were administered similarly . RESULTS At r and omization , 492 patients ( 10.5 percent ) had diabetes . After a median follow-up of two years , the systolic and diastolic blood pressures in the placebo and active-treatment groups differed by 8.6 and 3.9 mm Hg , respectively , among the diabetic patients . Among the 4203 patients without diabetes , systolic and diastolic pressures differed by 10.3 and 4.5 mm Hg , respectively , in the two groups . After adjustment for possible confounders , active treatment was found to have reduced overall mortality by 55 percent ( from 45.1 deaths per 1000 patients to 26.4 deaths per 1000 patients ) , mortality from cardiovascular disease by 76 percent , all cardiovascular events combined by 69 percent , fatal and nonfatal strokes by 73 percent , and all cardiac events combined by 63 percent in the group of patients with diabetes . Among the nondiabetic patients , active treatment decreased all cardiovascular events combined by 26 percent and fatal and nonfatal strokes by 38 percent . In the group of patients receiving active treatment , reductions in overall mortality , mortality from cardiovascular disease , and all cardiovascular events were significantly larger among the diabetic patients than among the nondiabetic patients ( P=0.04 , P=0.02 , and P=0.01 , respectively ) . CONCLUSIONS Nitrendipine-based antihypertensive therapy is particularly beneficial in older patients with diabetes and isolated systolic hypertension . Thus , our findings do not support the hypothesis that the use of long-acting calcium-channel blockers may be harmful in diabetic patients 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 BACKGROUND Calcium antagonists are a first-line treatment for hypertension . The effectiveness of diltiazem , a non-dihydropyridine calcium antagonist , in reducing cardiovascular morbidity or mortality is unclear . We compared the effects of diltiazem with that of diuretics , beta-blockers , or both on cardiovascular morbidity and mortality  in hypertensive patients . METHODS In a prospect i ve , r and omised , open , blinded endpoint study , we enrolled 10,881 patients , aged 50 - 74 years , at health centres in Norway and Sweden , who had diastolic blood pressure of 100 mm Hg or more . We r and omly assigned patients diltiazem , or diuretics , beta-blockers , or both . The combined primary endpoint was fatal and non-fatal stroke , myocardial infa rct ion , and other cardiovascular death . Analysis was done by intention to treat . FINDINGS Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups ( reduction 20.3/18.7 vs 23.3/18.7 mm Hg ; difference in systolic reduction p<0.001 ) . A primary endpoint occurred in 403 patients in the diltiazem group and in 400 in the diuretic and beta-blocker group ( 16.6 vs 16.2 events per 1000 patient-years ; relative risk 1.00 [ 95 % CI 0.87 - 1.15 ] , p=0.97 ) . Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group ( 6.4 vs 7.9 events per 1000 patient-years ; 0.80 [ 0.65 - 0.99 ] , p=0.04 ) and fatal and non-fatal myocardial infa rct ion in 183 and 157 patients ( 7.4 vs 6.3 events per 1000 patient-years ; 1.16 [ 0.94 - 1.44 ] , p=0.17 ) . INTERPRETATION Diltiazem was as effective as treatment based on diuretics , beta-blockers , or both in preventing the combined primary endpoint of all stroke , myocardial infa rct ion , and other cardiovascular death 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 CONTEXT Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality , but the optimal first-step therapy is unknown . OBJECTIVE To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease ( CHD ) or other cardiovascular disease ( CVD ) events vs treatment with a diuretic . DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , active-controlled clinical trial conducted from February 1994 through March 2002 . SETTING AND PARTICIPANTS A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers . INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n = 15 255 ) ; amlodipine , 2.5 to 10 mg/d ( n = 9048 ) ; or lisinopril , 10 to 40 mg/d ( n = 9054 ) for planned follow-up of approximately 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome was combined fatal CHD or nonfatal myocardial infa rct ion , analyzed by intent-to-treat . Secondary outcomes were all-cause mortality , stroke , combined CHD ( primary outcome , coronary revascularization , or angina with hospitalization ) , and combined CVD ( combined CHD , stroke , treated angina without hospitalization , heart failure [ HF ] , and peripheral arterial disease ) . RESULTS Mean follow-up was 4.9 years . The primary outcome occurred in 2956 participants , with no difference between treatments . Compared with chlorthalidone ( 6-year rate , 11.5 % ) , the relative risks ( RRs ) were 0.98 ( 95 % CI , 0.90 - 1.07 ) for amlodipine ( 6-year rate , 11.3 % ) and 0.99 ( 95 % CI , 0.91 - 1.08 ) for lisinopril ( 6-year rate , 11.4 % ) . Likewise , all-cause mortality did not differ between groups . Five-year systolic blood pressures were significantly higher in the amlodipine ( 0.8 mm Hg , P = .03 ) and lisinopril ( 2 mm Hg , P<.001 ) groups compared with chlorthalidone , and 5-year diastolic blood pressure was significantly lower with amlodipine ( 0.8 mm Hg , P<.001 ) . For amlodipine vs chlorthalidone , secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine ( 10.2 % vs 7.7 % ; RR , 1.38 ; 95 % CI , 1.25 - 1.52 ) . For lisinopril vs chlorthalidone , lisinopril had higher 6-year rates of combined CVD ( 33.3 % vs 30.9 % ; RR , 1.10 ; 95 % CI , 1.05 - 1.16 ) ; stroke ( 6.3 % vs 5.6 % ; RR , 1.15 ; 95 % CI , 1.02 - 1.30 ) ; and HF ( 8.7 % vs 7.7 % ; RR , 1.19 ; 95 % CI , 1.07 - 1.31 ) . CONCLUSION Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive . They should be preferred for first-step antihypertensive therapy Background In a recent case – control study , long-term use of calcium channel blocking drugs was associated with a greater-than-twofold increased breast cancer risk . If prospect ively collected data confirm that calcium channel blocker use increases breast cancer risk , this would have major implication s for hypertension treatment . The objective of this study was to determine whether women using calcium channel blockers for 10 years or more were at increased risk of developing breast cancer compared with women not using calcium channel blockers . Methods The Sister Study is a prospect i ve volunteer cohort study of women from the USA and Puerto Rico design ed to evaluate environmental and genetic risk factors for breast cancer . Beginning in 2003 , women between the ages of 35 and 74 were recruited . They were eligible to participate if they had a sister with breast cancer but had not been diagnosed with breast cancer themselves . In total , 50,884 women enrolled in the cohort between 2003 and 2009 ; 50,757 women with relevant baseline data and available follow-up data are included in this study . The exposure of interest is current use of calcium channel blocking drugs and the reported duration of use at entry into the cohort . Secondary exposures of interest were the duration and frequency of use for all other subclasses of antihypertensive drugs . Our main outcome is a self-reported diagnosis of breast cancer during the study follow-up period . With patient permission , self-reported diagnoses were confirmed using medical records . Results Results showed 15,817 participants were currently using an antihypertensive drug , and 3316 women were currently using a calcium channel blocker  at study baseline ; 1965 women reported a breast cancer diagnosis during study follow-up . Using Cox proportional hazards modeling , we found no increased risk of breast cancer among women who had been using calcium channel blockers for 10 years or more compared with never users of calcium channel blockers ( HR 0.88 , 95 % CI 0.58–1.33 ) . Conclusions We saw no evidence of increased risk of breast cancer from 10 years or more of current calcium channel blocker use . Our results do not support avoiding calcium channel blocking drugs in order to reduce breast cancer risk Nonsteroidal antiinflammatory drugs ( NSAIDs ) are known to attenuate the antihypertensive effects of a variety of antihypertensive agents including diuretics , beta-blockers , and vasodilators . Because of their unique mechanisms of actions , calcium channel blockers may not be subject to this interaction . This multicenter , double-blind , r and omized , placebo-controlled study was design ed to assess the effect of NSAID therapy on blood pressure control in stable hypertensive patients treated with a calcium channel blocker . One hundred patients with stable blood pressure control on 30 mg nicardipine three times a day were treated with 375 mg naproxen twice a day or placebo for 4 weeks . The mean diastolic blood pressures and estimated mean arterial pressures in both groups changed < 1 mm Hg during the 4 weeks of study drug treatment . None of the changes was significantly different from baseline and the two treatment groups were not significantly different from each other . Body weight in the placebo-treated patients did not change significantly whereas body weight in the naproxen-treated patients increased significantly , from 90.3 + /- 3.2 kg to 91.0 + /- 3.2 kg ( mean = 0.7 , P = .0003 ) . At 4 weeks there was a mean loss of 0.1 kg in the placebo group and a mean gain of 0.4 kg in the naproxen group compared to baseline weights , neither of which was statistically significant ( P = .60 and P = .071 , respectively ) . These results indicate that despite a significant increase in body weight , the antihypertensive action of the calcium channel blocker nicardipine is not significantly affected by cotreatment with naproxen beta-Blockers are known to slow the progression of diabetic nephropathy by lowering arterial pressure . Moreover , in individuals with diabetic nephropathy , antihypertensive agents that provide sustained reductions in proteinuria slow the rate of decline in renal function compared with agents without this antiproteinuric effect . To examine whether differential effects on proteinuria affect the progression of diabetic nephropathy , we conducted a r and omized study that compared the effects of a heart rate-lowering calcium channel blocker , sustained-release verapamil , with those of a beta-blocker , atenolol , on the progression of diabetic renal disease . The primary end point of the study was a change in creatinine clearance slope .  Thirty-four African Americans with the following inclusion criteria were r and omized to one of the two groups : serum creatinine greater than 1.4 mg/dL , proteinuria greater than 1500 mg/d , longer than a 5-year history of both non-insulin-dependent diabetes mellitus and hypertension , and exclusion of other renal diseases . Goal blood pressure was less than 140/90 mm Hg . All subjects received loop diuretics as second line agents to help achieve the blood pressure goal . Twenty-four-hour urinary protein and sodium excretions as well as creatinine clearance were measured at 6-month intervals . Blood pressure was measured every 3 months . After a mean follow-up of 54+/-6 months , the calcium channel blocker group demonstrated both a slower rate of decline in creatinine clearance ( -1.7+/-0.9 versus -3.7+/-1.4 mL/min per year per 1.73 m2 , P<.01 ) and a greater reduction in proteinuria compared with the atenolol group . Additionally , a greater proportion of the atenolol group had a 50 % or more increase in serum creatinine compared with the verapamil group ( 32+/-9 % versus 16+/-7 % , P<.05 ) . These between-group differences could not be explained by differences in blood pressure control . These data support the concept that antihypertensive agents that persistently maintain reductions in both arterial pressure and proteinuria slow the progression of diabetic renal disease in African Americans to a greater extent than those agents without these effects 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 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 AIM The influence of oxidative stress ( OS ) and inflammation on up-regulation of blood pressure ( BP ) has been well established . Peripheral polymorphonuclear leukocytes ( PMNLs ) are primed in essential hypertension ( EH ) patients , releasing uncontrolled superoxide anion contributing to OS in these patients . PMNL priming correlates with PMNL intracellular calcium [Ca2+]i . Previous studies have shown that treatment by calcium channel blockers lowers BP , OS and inflammation . In the same time , there are some trials showing down regulation influence of ' ' anti-oxidative ' ' drugs as Vitamin E and C to inflammation and OS . The data of clinical significance of anti-oxidative drugs to BP is controversial . The aim of this paper was to evaluate the benefit of combined treatment by calcium channel blockers ( Lercanidipine ) and antioxidative drugs ( Vitamins C and E ) on BP and on parameters of inflammation and OS . METHODS Sixteen new diagnosed patients with mild to moderate BP were sample d to 2 groups after r and omization by age , sex , and mean arterial pressure ( MAP ) , cholesterol and glucose level . The first group was treated by Lercanidip-ine only , the second group by combination of Lercanidipine and antioxidative drugs both for 6 months . PMNL priming was assessed by the rate of superoxide release from separated , phorbol ester-stimulated PMNLs and by PMNL-CD11b level . Inflammation was reflected by plasma C-reactive protein ( CRP ) and albumin levels , white blood cells ( WBC ) and PMNL counts and by PMNL apoptosis . RESULTS In both groups , BP decreased after 6 months of treatment , and in a more pronounced manner following the combined treatment . In both groups PMNL priming parameters remained unchanged after 6 months of treatment , with transient differences between the two groups during the experimental period . In both groups inflammation parameters remained unchanged after 6 months of treatment , without difference between the two groups , except a pronounced decrease in the percentage of apoptotic PMNLs in the combined treatment group . CONCLUSION Our trial shows a clinical benefit combining calcium channel blockers treatment with antioxidants in BP treatment , although it did not reveal significant influence of complementation of antioxidants to calcium channel blockers on OS and inflammation parameters . Additional clinical and laboratory investigations are needed to clear this issue . Conflicting data are reported on the influence of vitamins E and C on OS and inflammation together with controversy regarding anti-oxidative drugs and their effect on BP BACKGROUND It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications . Because this issue remains controversial , we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were r and omly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study . METHODS The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve , r and omized , blinded trial comparing the effects of moderate control of blood pressure ( target diastolic pressure , 80 to 89 mm Hg ) with those of intensive control of blood pressure ( diastolic pressure , 75 mm Hg ) on the incidence and progression of complications of diabetes . The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes . In the current study , we analyzed data on a secondary end point ( the incidence of myocardial infa rct ion ) in the subgroup of patients in the ABCD Trial who had hypertension . RESULTS Analysis of the 470 patients in the trial who had hypertension ( base-line diastolic blood pressure , > or = 90 mm Hg ) showed similar control of blood pressure , blood glucose and lipid concentrations , and smoking behavior in the nisoldipine group ( 237 patients ) and the enalapril group ( 233 patients ) throughout five years of follow-up . Using a multiple logistic-regression model with adjustment for cardiac risk factors , we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infa rct ions ( a total of 24 ) than enalapril ( total , 4 ) ( risk ratio , 9.5 ; 95 percent confidence interval , 2.7 to 33.8 ) . CONCLUSIONS In this population of patients with diabetes and hypertension , we found a significantly higher incidence of fatal and nonfatal myocardial infa rct ion among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril . Since our findings are based on a secondary end point , they will require confirmation 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 Hypertension is the most common condition seen in primary care and leads to myocardial infa rct ion , stroke , renal failure , and death if not detected early and treated appropriately . Patients want to be assured that blood pressure ( BP ) treatment will reduce their disease burden , while clinicians want guidance on hypertension management using the best scientific evidence . This report takes a rigorous , evidence -based approach to recommend treatment thresholds , goals , and medications in the management of hypertension in adults . Evidence was drawn from r and omized controlled trials , which represent the gold st and ard for determining efficacy and effectiveness . Evidence quality and recommendations were grade d based on their effect on important outcomes . There is strong evidence to support treating hypertensive persons aged 60 years or older to a  BP goal  of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg ; however , there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal , or in those younger than 30 years for a diastolic goal , so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion . The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease ( CKD ) as for the general hypertensive population younger than 60 years . There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor , angiotensin receptor blocker , calcium channel blocker , or thiazide-type diuretic in the nonblack hypertensive population , including those with diabetes . In the black hypertensive population , including those with diabetes , a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy . There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes . Although this guideline provides evidence -based recommendations for the management of high BP and should meet the clinical needs of most patients , these recommendations are not a substitute for clinical judgment , and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient 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 Objective To test the primary hypothesis that a newer antihypertensive treatment regimen ( calcium channel blocker ± an angiotensin converting enzyme inhibitor ) is more effective than an older regimen ( β-blocker ± a diuretic ) in the primary prevention of coronary heart disease ( CHD ) . To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterol ⩽ 6.5 mmol/l . Design Prospect i ve , r and omized , open , blinded endpoint trial with a double-blinded 2 × 2 factorial component . Setting Patients were recruited mainly from general practice s. Patients Men and women aged 40–79 were eligible if their blood pressure was ⩾160 mmHg systolic or ⩾ 100 mmHg diastolic ( untreated ) or ⩾140 mmHg systolic or ⩾ 90 mmHg diastolic ( treated ) at r and omization . Interventions Patients received either amlodipine ( 5/10 mg ) ± perindopril ( 4/8 mg ) or atenolol ( 50/100 mg ) ± bendroflumethiazide ( 1.25/2.5 mg ) + K+ with further therapy as required to reach a blood pressure of ⩽140 mmHg systolic and 90 mmHg diastolic . Patients with a total cholesterol of ⩽ 6.5 mmol/l were further r and omized to receive either atorvastatin 10 mg or placebo daily . Main outcome measure Non-fatal myocardial infa rct ion ( MI ) and fatal coronary heart disease ( CHD ) . Results 19 342 men and women were initially r and omized , of these 10 297 were also r and omized into the lipid-lowering limb . All patients had three or more additional cardiovascular risk factors . Conclusions The study has 80 % power ( at the 5 % level ) to detect a relative difference of 20 % in CHD endpoints between the calcium channel blocker-based regimen and the β-blocker-based regimen . The lipid-lowering limb of the study has 90 % power at the 1 % level to detect a relative difference of 30 % in CHD endpoints between groups Introduction : The optimal combination treatment for hypertension has not been established . We investigated the effect of a calcium channel blocker or a diuretic added to angiotensin II receptor blockers ( ARBs ) on the augmentation index ( AI ) , as a marker of arterial stiffness and wave reflection , in hypertensive patients . Methods : Thirty-seven patients treated with ARBs  were r and omly allocated to either of the 2 groups receiving an ARB plus azelnidipine ( AZ group ) or trichlormethiazide ( TCM group ) . Changes in brachial blood pressure ( BP ) , AI , high-sensitive C-reactive protein ( hsCRP ) , and serum asymmetric dimethylarginine , as an endogenous nitric oxide synthase inhibitor , were determined . Results : Systolic and diastolic blood pressure after 6 months were significantly reduced in both the groups similarly ; however , after adjustment for baseline covariates , the extent of the reduction in AI ( % ) in the AZ group was significantly greater than in the TCM group ( between-group difference was 3.2 ; 95%CI : 0.2–6.3 ; P = 0.03 ) . The reduction of high-sensitive C-reactive protein ( mg/L ) and serum asymmetric dimethylarginine ( & mgr;mol/L ) was significantly greater in the AZ group than in the TCM group ( between-group difference was 0.18 and 0.05 ; 95%CI : −0.01 to 0.36 and −0.01 to 0.11 ; P = 0.04 and 0.02 , respectively ) . Further , when patients were analyzed according to age younger than 60 years or older than 60 years , the reduction in AI in the AZ group aged older than 60 years was significantly greater than in the TCM group . Conclusion : The results suggest that azelnidipine has a more beneficial effect on vascular properties in combination therapy with ARB than trichlormethiazide OBJECTIVES The primary objective of the International Verapamil SR/Tr and olapril Study ( INVEST ) is to compare the risk for adverse outcomes ( all-cause mortality , nonfatal myocardial infa rct ion [ MI ] or nonfatal stroke ) in hypertensive patients with coronary artery disease ( CAD ) treated with either a calcium antagonist-based or a noncalcium antagonist-based strategy .  BACKGROUND Treatment recommendations for hypertension include initial therapy with a diuretic or beta-adrenergic blocking agent , for which reductions in morbidity and mortality are documented from r and omized trials but are less than expected from epidemiologic data . For this reason , recent attention has focused on calcium antagonists or angiotensin-converting enzyme inhibitors . While these agents reduce blood pressure , outcome data from large r and omized trials are lacking , but some case-control data , dominated by short-acting dihydropyridines , suggest an increased risk of cardiovascular events . These studies had method ologic limitations and did not differentiate among calcium antagonist types and formulations . Several studies differentiating among calcium antagonist types and an overview of published r and omized trials show no increased risk with verapamil and suggestion for benefit in CAD patients . METHODS A total of 27,000 CAD patients with hypertension will be r and omized at 1,500 primary care sites to receive either a calcium antagonist-based ( verapamil ) or beta-blocker/diuretic-based ( atenolol/hydrochlorothiazide ) antihypertensive care strategy . The study uses a novel , electronic " paper-less " system for direct on-screen data entry , r and omization and drug distribution from a mail pharmacy linked to the coordination center via the Internet . RESULTS Contract negotiations with the United States and international sites are ongoing . Patients being enrolled are predominantly elderly ( 72 % aged 60 years or older ) men ( 54 % ) , with either an abnormal coronary angiogram or prior MI ( 71 % ) . In addition to hypertension , CAD and elderly age , most patients ( 89 % ) have one or more associated conditions ( diabetes , dyslipidemia , smoking , cerebral or peripheral vascular disease , etc . ) contributing to increased risk for adverse outcome . While 26 % have diabetes , most of these are noninsulin dependent . Using the protocol strategies , target blood pressures ( according to JNC VI ) have been reached in 58 % at the fourth visit , and as expected most ( 89 % ) are requiring multiple antihypertensive drugs . CONCLUSION The design and baseline characteristics of the initial patients recruited for a prospect i ve , r and omized , international , multicenter study comparing two therapeutic strategies to control hypertension in CAD patients are described Essential hypertension is a major Public Health issue . Although the number of treated hypertensive patients has increased , only 25 % of treated patients have their blood pressure levels under control . The benefit of treating hypertension has been proven , but cardiovascular morbidity and mortality rates remain high . The ideal antihypertensive drug should not only normalize blood pressure levels , but also reduce the associated cardiovascular morbidity and mortality rates . The role of angiotensin II in systemic hypertension and its complications has been recently redefined . The potent trophic effects of angiotensin II on blood vessels and on cardiac cells have been well demonstrated , especially the role of angiotensin II in left ventricular hypertrophy , vascular hypertrophy , endothelial dysfunction , and congestive heart failure . Of all ongoing mortality and morbidity trials in systemic hypertension , VALUE ( Valsartan Antihypertensive Long-term Use Evaluation ) is the only one comparing an angiotensin II antagonist ( valsartan ) with a third-generation calcium channel blocker ( amlodipine ) . The main hypothesis of the VALUE trial is that , for an equivalent decrease in blood pressure , valsartan will be more effective than amlodipine in decreasing cardiac mortality and morbidity . VALUE is a prospect i ve , multinational , multicentre , double-blind , r and omized , active-controlled , 2-arm parallel group comparison with a response-dependent dose titration scheme . VALUE involves 14,400 patients in over 30 countries , who will be followed for 4 years or until 1450 patients experience a primary endpoint . The population to be included in VALUE consists of hypertensive men and women , aged 50 years or older , and at a relatively high risk of sustaining a cardiovascular event . The high risk profile is defined taking into account age , gender , and a list of cardiovascular risk factors and disease factors . Risk factors are cigarette smoking , hypercholesterolaemia , diabetes mellitus , uncomplicated left ventricular hypertrophy , proteinuria , and high serum creatinine . Disease factors include documented history of myocardial infa rct ion , peripheral vascular disease , stroke or transient ischaemic attack , or the presence of left ventricular hypertrophy with strain on the ECG . A unique feature of VALUE is the assessment of the predictive power of this cardiovascular risk factor scale in a large population of treated hypertensive patients . The trial started on 10 September 1997 BACKGROUND Hypertension is a common comorbidity in patients with type 2 diabetes mellitus and a major risk factor for microvascular and macrovascular disease . Although the blood pressure-lowering effects of sodium-glucose cotransporter 2 ( SGLT2 ) inhibitors are already established , guidance is needed on how to use these drugs in patients already receiving antihypertensive therapy . We aim ed to compare blood pressure and glycaemic effects of the SGLT2 inhibitor dapagliflozin with placebo in patients with inadequately controlled type 2 diabetes mellitus and hypertension . METHODS In this double-blind , placebo-controlled , phase 3 study we enrolled patients from 311 centres in 16 countries across five continents . Patients had uncontrolled type 2 diabetes ( HbA1c 7·0%-10·5 % ; 53 - 91 mmol/mol ) and hypertension ( systolic 140 - 165 mm Hg and diastolic 85 - 105 mm Hg at both enrolment and r and omisation , and a mean 24 h blood pressure of ≥130/80 mm Hg by ambulatory monitoring within 1 week of r and omisation ) and were receiving oral antihyperglycaemic drugs , insulin , or both  , plus a renin-angiotensin system blocker and an additional antihypertensive drug . Using an interactive voice-response system , we r and omly assigned ( 1:1 ) patients to dapagliflozin 10 mg once a day or to placebo , with r and omisation stratified by additional antihypertensive drug use and insulin use at baseline , in a block size of two . The co- primary endpoints were changes in seated systolic blood pressure and HbA1c measured in the full analysis set , which included all patients who received at least one dose of study drug and had both a baseline and at least one post-baseline measurement of efficacy . This trial is registered with Clinical Trials.gov , number NCT01195662 . FINDINGS Between Oct 29 , 2010 , and Oct 4 , 2012 , we r and omly assigned 225 patients to dapagliflozin and 224 to placebo . Seated systolic blood pressure was significantly reduced in the group assigned to dapagliflozin ( adjusted mean change from baseline -11·90 mm Hg [ 95 % CI -13·97 to -9·82 ] ) compared with those assigned to placebo ( -7·62 mm Hg [ -9·72 to -5·51 ] ; placebo-adjusted difference for dapagliflozin -4·28 mm Hg [ -6·54 to -2·02 ] ; p=0·0002 ) . Reductions in HbA1c concentrations were also significantly greater in patients assigned to dapagliflozin ( adjusted mean change from baseline -0·63 % [ 95 % CI -0·76 to -0·50 ] ) than in those assigned to placebo ( -0·02 % [ -0·15 to 0·12 ] ; placebo-adjusted difference -0·61 % [ -0·76 to -0·46 , ] ; p<0·0001 ) . In a post-hoc analysis , we found difference in blood pressure versus placebo was greater in patients receiving a β blocker ( -5·76 mm Hg [ 95 % CI -10·28 to -1·23 ] ) or a calcium-channel blocker ( -5·13 mm Hg , [ -9·47 to -0·79 ] ) as their additional antihypertensive drug than in those receiving a thiazide diuretic ( -2·38 mm Hg [ -6·16 to 1·40 ] ) . Adverse events were similar in the dapagliflozin and placebo groups ( 98 [ 44 % ] patients vs 93 [ 42 % ] , respectively , had at least one adverse event ) , with few adverse events related to renal function ( 1 % vs < 1 % ) or volume depletion ( < 1 % vs 0 % ) . INTERPRETATION Dapagliflozin 10 mg significantly improved blood pressure and HbA1c and was tolerated similarly to placebo . Its blood pressure-lowering properties were particularly favourable in patients already receiving a β blocker or calcium-channel blocker . Dapagliflozin could benefit patients with type 2 diabetes who need a diuretic-like effect to optimise control of blood pressure , adding meaningful efficacy to antihypertensive drug regimens . FUNDING Bristol-Myers Squibb , AstraZeneca In the double-blind Systolic Hypertension in Europe ( Syst-Eur ) Trial , active treatment was initiated with nitrendipine ( 10 to 40 mg/d ) with the possible addition of enalapril ( 5 to 20 mg/d ) and /or hydrochlorothiazide ( 12.5 to 25 mg/d ) titrated or combined to reduce sitting systolic blood pressure by at least 20 mm Hg to < 150 mm Hg . In the control group , matching placebos were used similarly . In view of persistent concerns about the use of calcium channel blockers as first-line antihypertensive drugs , this report explored to what extent nitrendipine , administered alone , prevented cardiovascular complications .  Age at r and omization averaged 70.2 years and systolic/diastolic blood pressure 173.8/85.5 mm Hg . Of 2398 actively treated patients , 1327 took only nitrendipine ( average dose , 23.4 mg/d ) , and 1042 progressed to other treatments including nitrendipine ( n=757 ; 35.7 mg/d ) , enalapril ( n=783 ; 13.4 mg/d ) , and /or hydrochlorothiazide ( n=294 ; 21.0 mg/d ) . Compared with the whole placebo group ( n=2297 ) , patients receiving monotherapy with nitrendipine had 25 % ( P=0.05 ) fewer cardiovascular end points , and those progressing to other active treatments showed decreases ( P</=0 . 01 ) in total mortality ( 40 % ) , stroke ( 59 % ) , and all cardiovascular end points ( 39 % ) . Among the control patients , 863 used only the first-line placebo . Compared with this subgroup , patients receiving monotherapy with nitrendipine showed a nearly 50 % ( P</=0.004 ) reduction of all types of end points , including total and cardiovascular mortality . The full relative benefit from nitrendipine was seen as early as 6 months after r and omization . To ascertain that the benefit conferred by the dihydropyridine was not due to selection bias , the 1327 patients remaining on monotherapy with nitrendipine  were matched by gender , age , previous cardiovascular complications , and systolic blood pressure at entry with an equal number of placebo patients . In this analysis , nitrendipine reduced ( P</=0.05 ) cardiovascular mortality by 41 % , all cardiovascular end points by 33 % , and fatal and nonfatal cardiac end points by 33 % . Despite the limitations inherent in post hoc analyses , the present findings suggest that the calcium channel blocker nitrendipine , given as a single antihypertensive medication , prevents cardiovascular complications in older patients with isolated systolic hypertension 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 BACKGROUND Nonsteroidal anti-inflammatory drugs ( NSAIDs ) cause substantial morbidity and mortality from upper gastrointestinal tract disease . Ketorolac tromethamine has been singled out as an NSAID with a distinct gastrotoxicity profile . Calcium channel blockers , a class of antihypertensive drugs , have also been found to increase the risk of gastrointestinal tract bleeding . METHODS We identified 1505 patients hospitalized because of upper gastrointestinal tract bleeding and /or perforation , and we r and omly sample d 20,000 controls in the source population . RESULTS The adjusted relative risk ( RR ) for upper gastrointestinal tract bleeding and /or perforation in NSAID users compared with nonusers was 4.4 ( 95 % confidence interval [ CI ] , 3.7 - 5.3 ) . The risk increased with higher daily doses . Ketorolac presented the highest risk ( RR , 24.7 ; 95 % CI , 9.6 - 63.5 ) and piroxicam ranked second ( RR , 9.5 ; 95 % CI , 6.5 - 13.8 ) . Ketorolac was 5 times more gastrotoxic than all other NSAIDs ( RR , 5.5 ; 95 % CI , 2.1 - 14.4 ) . The excess risk with  ketorolac  was observed with both oral and intramuscular administration and was already present during the first week of therapy . Among the various antihypertensive drug classes , beta-blockers were associated with the lowest relative risk ( RR , 1.0 ; 95 % CI , 0.7 - 1.4 ) , and current use of calcium channel blockers with the highest ( RR , 1.7 ; 95 % CI , 1.3 - 2.1 ) . The association with calcium channel blockers declined when adjusting for various markers of comorbidity ( RR , 1.4 ; 95 % CI , 1.1 - 1.8 ) . Past use of calcium channel blockers was also associated with an increased risk ( RR , 1.5 ; 95 % CI , 1.3 - 1.8 ) . CONCLUSIONS The excess risk of major upper gastrointestinal tract complications associated with outpatient use of ketorolac suggests an unfavorable risk-benefit assessment compared with other NSAIDs . More data are required to reduce the uncertainty about the apparent small increased risk of upper gastrointestinal tract bleeding in patients using calcium channel blockers BACKGROUND The optimal combination drug therapy for hypertension is not established , although current U.S. guidelines recommend inclusion of a diuretic . We hypothesized that treatment with the combination of an angiotensin-converting-enzyme ( ACE ) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic . METHODS In a r and omized , double-blind trial , we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide . The primary end point was the composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for angina , resuscitation after sudden cardiac arrest , and coronary revascularization . RESULTS The baseline characteristics of the two groups were similar . The trial was terminated early after a mean follow-up of 36 months , when the boundary of the prespecified stopping rule was exceeded . Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group . There were 552 primary - outcome events in the benazepril-amlodipine group ( 9.6 % ) and 679 in the benazepril-hydrochlorothiazide group ( 11.8 % ) , representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2 % and a relative risk reduction of 19.6 % ( hazard ratio , 0.80 , 95 % confidence interval [ CI ] , 0.72 to 0.90 ; P<0.001 ) . For the secondary end point of death from cardiovascular causes , nonfatal myocardial infa rct ion , and nonfatal stroke , the hazard ratio was 0.79 ( 95 % CI , 0.67 to 0.92 ; P=0.002 ) . Rates of adverse events were consistent with those observed from clinical experience with the study drugs . CONCLUSIONS The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events . ( Clinical Trials.gov number , NCT00170950 . BACKGROUND Hypertension and hyperuricaemia are common side-effects of cyclosporin A ( CsA ) treatment in renal transplant recipients . While it is well established that the calcium channel blocker amlodipine can control CsA-induced hypertension effectively in this patient population , recent evidence suggests amlodipine might also reduce hyperuricaemia . The present study was design ed to compare the effects of the calcium channel blocker amlodipine ( 5 - 10 mg/day ) and the beta-adrenoceptor antagonist tertatolol ( 5 - 10 mg/day ) on CsA-induced hyperuricaemia in post-renal transplant recipients with hypertension . METHODS Forty-eight hypertensive renal transplant recipients on a stable dose of CsA were r and omized in a double-blind , parallel-group manner to receive either amlodipine ( n = 24 ) or tertatolol ( n = 24 ) for 60 days . The primary outcome measure was the change from baseline in serum uric acid concentration . Secondary analyses of efficacy were based on changes in renal function and blood pressure . RESULTS Amlodipine significantly decreased serum uric acid levels from 483 + /- 99 to 431 + /- 110 microM/l ( P < 0.001 ) , while tertatolol significantly increased uric acid from 450 + /- 98 to 476 + /-84 microM/l ( P = 0.006 ) . Amlodipine also significantly increased glomerular filtration rate ( P = 0.0048 ) and the clearance rate of uric acid ( P = 0.023 ) and it reduced the fractional proximal tubular reabsorption of sodium ( P < 0.001 ) , compared with tertatolol . Renal plasma flow and filtered fraction were unaffected by both treatments , as was trough CsA blood concentration .  Amlodipine lowered systolic blood pressure to a significantly greater extent than did tertatolol ( P = 0.007 ) . The time-dependent profile of diastolic blood pressure did not differ significantly between treatment groups . Both drugs were well tolerated . CONCLUSIONS Amlodipine could be more appropriate than tertatolol for CsA-induced hypertension and hyperuricaemia in renal transplant recipients BACKGROUND Recent reports suggest that antihypertensive ( AH ) medications may reduce the risk of dementing illnesses . OBJECTIVES To examine the relationship of AH medication use with incidence of Alzheimer disease ( AD )  among the elderly population ( aged 65 years and older ) of Cache County , Utah , and to examine whether the relationship varies with different classes of AH medications . METHODS After an initial ( wave 1 ) multistage assessment ( 1995 through 1997 ) to identify prevalent cases of dementia , we used similar methods 3 years later ( wave 2 ) to identify 104 incident cases of AD among the 3308 survivors . At the baseline assessment , we obtained a detailed drug inventory from the study participants . We carried out discrete time survival analyses to examine the association between the use of AH medications ( including angiotensin converting enzyme inhibitors , beta-blockers , calcium channel blockers , and diuretics ) at baseline with subsequent risk of AD . RESULTS Use of any  AH medication  at baseline was associated with lower incidence of AD ( adjusted hazard ratio , 0.64 ; 95 % confidence interval , 0.41 - 0.98 ) . Examination of medication subclasses showed that use of diuretics ( adjusted hazard ratio , 0.57 ; 95 % confidence interval , 0.33 - 0.94 ) , and specifically potassium-sparing diuretics ( adjusted hazard ratio , 0.26 ; 95 % confidence interval , 0.08 - 0.64 ) , was associated with the greatest reduction in risk of AD . Corresponding analysis with a fully examined sub sample controlling for blood pressure measurements did not substantially change our findings . CONCLUSIONS These data suggest that AH medications , and specifically potassium-sparing diuretics , are associated with reduced incidence of AD . Because the latter association is a new finding , it requires confirmation in further study The Combination Therapy of Hypertension to Prevent Cardiovascular Events ( COPE ) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker ( ARB ) , a β-blocker , or a thiazide diuretic ( thiazide ) were similarly effective in preventing cardiovascular events and achieving the target blood pressure ( BP ; < 140/90 mm Hg ) . We further evaluated the efficacy and safety of these combination therapies in older ( ⩾65 years ) and younger ( < 65 years ) hypertensive patients . In this sub- analysis of the COPE trial 3293 patients ( 1533⩾65 years old and 1760 < 65 years old ) were r and omly assigned to receive benidipine-based therapy with an ARB , a β-blocker or a thiazide . In each group , the average BP did not differ among the three treatment groups . The incidence of the primary cardiovascular composite end point in the older group was higher than in the younger group ( 12.7 vs. 8.3 per 1000 person-years , P=0.023 ) . The primary composite cardiovascular end point , achievement ( % ) of target BP , and cardiovascular hard composite end points were similar among the three treatment groups . However , the hazard ratios and 95 % confidence intervals in older patients were 2.74 ( 1.08–6.96 ; β-blocker vs. thiazide , P=0.022 ) for fatal and non-fatal stroke , and 2.47 ( 1.03–5.91 ; β-blocker vs. ARB , P=0.043 ) for new-onset diabetes . Thus , benidipine combined with an ARB , a β-blocker , or a thiazide was similarly effective in preventing cardiovascular events and achieving the target BP in both older and younger hypertensive patients . Further studies will be necessary to evaluate the usefulness of benidipine combined with a β-blocker in terms of the incidence of stroke and new-onset diabetes in older patients 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 BACKGROUND Primary pulmonary hypertension is a progressive , fatal disease of unknown cause . Vasodilator drugs have been used as a treatment , but their efficacy is uncertain . METHODS We treated 64 patients with primary pulmonary hypertension with high doses of calcium-channel blockers . Patients who responded to treatment ( defined as those whose pulmonary-artery pressure and pulmonary vascular resistance immediately fell by more than 20 percent after challenge ) were treated for up to five years . Their survival was compared with that of the patients who did not respond and with patients enrolled in the National Institutes of Health ( NIH ) Registry on Primary Pulmonary Hypertension . Warfarin was given to 55 percent of the patients as concurrent therapy , on the basis of a lung scan showing nonuniformity of pulmonary blood flow ( 47 percent of patients who responded and 57 percent of those who did not respond ) . RESULTS Seventeen patients ( 26 percent ) responded to treatment , as indicated by a 39 percent fall in pulmonary-artery pressure and a 53 percent fall in the pulmonary-vascular-resistance index ( P less than 0.001 ) . Nifedipine ( mean [ + /- SD ] daily dose , 172 + /- 41 mg ) was given to 13 patients , and diltiazem ( mean daily dose , 720 + /- 208 mg ) was given to 4 patients . After five years , 94 percent of the patients who responded ( 16 of 17 ) were alive , as compared with 55 percent of the patients who did not respond ( 26 of 47 , P = 0.003 ) . The survival of the patients who responded was also significantly better than that of the NIH registry cohort ( P = 0.002 ) and patients from the NIH registry who were treated at the University of Illinois ( P = 0.001 ) . The use of warfarin was associated with improved survival ( P = 0.025 ) , particularly in the patients who did not respond . CONCLUSIONS This study suggests that high doses of calcium-channel blockers in patients with primary pulmonary hypertension who respond with reductions in pulmonary-artery pressure and pulmonary vascular resistance may improve survival over a five-year period Objective : To perform a subgroup analysis on those patients in STOP‐Hypertension‐2 who had isolated systolic hypertension . Design and methods : The STOP‐Hypertension‐2 study evaluated cardiovascular mortality and morbidity in elderly hypertensives comparing treatment with conventional drugs ( diuretics , beta‐blockers ) with that of newer ones [ angiotensin‐converting enzyme ( ACE ) inhibitors , calcium antagonists ] . In all , 6614 elderly patients with hypertension ( mean age 76.0 years , range 70–84 years at baseline ) were included in STOP‐Hypertension‐2 . In the present subgroup analysis of STOP‐Hypertension‐2 , isolated systolic hypertension was defined as systolic blood pressure at least 160 mmHg and diastolic blood pressure below 95 mmHg , in accordance with the Syst‐Eur and Syst‐China study criteria . In total , 2280 patients in STOP‐Hypertension‐2 met these criteria . In the study , patients were r and omized to one of three treatment groups : “ conventional ” antihypertensive therapy with beta‐blockers or diuretics ( atenolol 50 mg , metoprolol 100 mg , pindolol 5 mg , or fixed‐ratio hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily ) ; ACE inhibitors ( enalapril 10 mg or lisinopril 10 mg daily ) ; or calcium antagonists ( felodipine 2.5 mg or isradipine 2.5 mg daily ) . Analysis was by intention to treat . Results : The blood pressure lowering effect in patients with systolic hypertension was similar with all three therapeutic regimens : 35/13 mmHg in the conventional group ( n = 717 ) , 34/12 mmHg in the ACE inhibitor group ( n = 724 ) , and 35/13 mmHg in the calcium antagonist group ( n = 708 ) . Prevention of cardiovascular mortality , the primary endpoint of the study , did not differ between the three treatment groups . All stroke events , i.e. fatal and non‐fatal stroke together , were significantly reduced by 25 % in the newer‐drugs group compared with the conventional group ( 95 % CI 0.58–0.97 ; p = 0.027 ) . This difference was attributable to reduction of non‐fatal stroke while fatal stroke events did not differ between groups . New cases of atrial fibrillation were significantly increased by 43 % ( 95 % CI 1.02–1.99 ; p = 0.037 ) on “ newer ” drugs compared with “ conventional ” therapy , mainly attributable to the calcium antagonists . There were no significant differences between the three treatment groups with respect to the risks of myocardial infa rct ion , sudden death or congestive heart failure . Conclusions : The analysis demonstrated that “ newer ” therapy ( ACE inhibitors/calcium antagonists ) was significantly better ( 25 % ) than “ conventional ” ( diuretics/beta‐blockers ) in preventing all stroke in elderly patients with isolated systolic hypertension Background The benefits of treating hypertension in elderly diabetic patients , in terms of achieving reductions in cardiovascular morbidity and mortality , have been documented in several recent prospect i ve trials . There has , however , been some controversy regarding the effect of different antihypertensive drugs on the frequency of myocardial infa rct ion in this group of patients . Design STOP Hypertension-2 was a prospect i ve , r and omized , open trial with blinded endpoint evaluation . Methods We studied 6614 elderly patients aged 70–84 years ; 719 of them had diabetes mellitus at the start of the study ( mean age 75.8 years ) . Patients were r and omly assigned to one of three treatment strategies : conventional antihypertensive drugs ( diuretics or β-blockers ) , calcium antagonists , or angiotensin converting enzyme ( ACE ) inhibitors . Results Reduction in blood pressure was similar in the three treatment groups of diabetics . The prevention of cardiovascular mortality was also similar ; the frequency of this primary endpoint did not differ significantly between the three groups . There were , however , significantly fewer ( P = 0.025 ) myocardial infa rct ions during ACE inhibitor treatment ( n = 17 ) than during calcium antagonist treatment ( n = 32 ; relative risk 0.51 , 95 % confidence interval 0.28–0.92 ) ; but a ( non-significant ) tendency to more strokes during ACE inhibitor treatment ( n = 34 compared with n = 29 ; relative risk 1.16 , 95 % confidence interval 0.71–1.91 ) . Conclusion Treatment of hypertensive diabetic patients with conventional antihypertensive drugs ( diuretics , β-blockers , or both ) seemed to be as effective as treatment with newer drugs such as calcium antagonists or ACE inhibitors CONTEXT Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk , but the benefit compared with other drug classes is controversial . OBJECTIVE To determine whether initial therapy with controlled-onset extended-release ( COER ) verapamil is equivalent to a physician 's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized clinical trial conducted at 661 centers in 15 countries . A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31 , 2000 . After a mean of 3 years of follow-up , the sponsor closed the study before unblinding the results . INTERVENTION Initially , 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide . Other drugs ( eg , diuretic , beta-blocker , or an angiotensin-converting enzyme inhibitor ) could be added in specified sequence if needed . MAIN OUTCOME MEASURES First occurrence of stroke , myocardial infa rct ion , or cardiovascular disease-related death . RESULTS Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group . There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group ( hazard ratio [ HR ] , 1.02 ; 95 % confidence interval [ CI ] , 0.88 - 1.18 ; P = .77 ) . For fatal or nonfatal stroke , the HR was 1.15 ( 95 % CI , 0.90 - 1.48 ) ; for fatal or nonfatal myocardial infa rct ion , 0.82 ( 95 % CI , 0.65 - 1.03 ) ; and for cardiovascular disease-related death , 1.09 ( 95 % CI , 0.87 - 1.37 ) . The HR was 1.05 ( 95 % CI , 0.95 - 1.16 ) for any prespecified cardiovascular disease-related event and 1.08 ( 95 % CI , 0.93 - 1.26 ) for all-cause mortality . Nonstroke hemorrhage was more common with participants in the COER-verapamil group ( n = 118 ) compared with the atenolol or hydrochlorothiazide group ( n = 79 ) ( HR , 1.54 [ 95 % CI , 1.16 - 2.04 ] ; P = .003 ) . More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil ( 99/277 ) and atenolol or hydrochlorothiazide ( 88/274 ) groups ; HR , 1.15 ( 95 % CI , 0.86 - 1.53 ) . CONCLUSIONS The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker . When considered in the context of other trials of calcium antagonists , these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment OBJECTIVE --To establish whether treatment with diuretic or beta blocker in hypertensive older adults reduces risk of stroke , coronary heart disease , and death . DESIGN --R and omised , placebo controlled , single blind trial . SETTING --226 general practice s in the MRC general practice research framework . SUBJECTS--4396 patients aged 65 - 74 r and omised to receive diuretic , beta blocker , or placebo . Patients had mean systolic pressures of 160 - 209 mm Hg and mean diastolic pressures less than 115 mm Hg during an eight week run in and were not taking antihypertensive treatment . INTERVENTION-- Patients were r and omised to atenolol 50 mg daily ; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg daily ; or placebo . The regimens were adjusted to achieve specified target pressures . Mean follow up was 5.8 years . MAIN OUTCOME MEASURES --Strokes , coronary events , and deaths from all causes . RESULTS --Both treatments reduced blood pressure below the level in the placebo group . Compared with the placebo group , actively treated subjects ( diuretic and beta blocker groups combined ) had a 25 % ( 95 % confidence interval 3 % to 42 % ) reduction in stroke ( p = 0.04 ) , 19 % ( -2 % to 36 % ) reduction in coronary events ( p = 0.08 ) , and 17 % ( 2 % to 29 % ) reduction in all cardiovascular events ( p = 0.03 ) . After adjusting for baseline characteristics the diuretic group had significantly reduced risks of stroke ( 31 % ( 3 % to 51 % ) p = 0.04 ) , coronary events ( 44 % ( 21 % to 60 % ) , p = 0.0009 ) , and all cardiovascular events ( 35 % ( 17 % to 49 % ) , p = 0.0005 ) compared with the placebo group . The beta blocker group showed no significant reductions in these end points . The reduction in strokes was mainly in non-smokers taking the diuretic . CONCLUSION --Hydrochlorothiazide and amiloride reduce the risk of stroke , coronary events , and all cardiovascular events in older hypertensive adults Background . Studies have provided conflicting results as to the protective role of calcium channel blockers ( CCB ) in  cyclosporine-treated patients with regard to blood pressure control and preservation of renal graft function .  Lacidipine is a dihydropyridine CCB that possesses antioxidative , anti-atherosclerotic , and anti-adhesion properties and was shown to prevent cyclosporine-induced nephrotoxicity in a rat model . Methods . We conducted a multicenter prospect i ve , r and omized , placebo-controlled study in 131 de novo recipients of a cadaveric renal allograft on cyclosporine therapy .  The aim of this 2-year study was to assess the effects of lacidipine on graft function ( plasma iohexol clearance ) , renal plasma flow , anastomotic arterial blood flow , deterioration of renal function , blood pressure , acute rejection , and hospitalization rate . Results . A total of 118 recipients were available for intention-to-treat analysis on efficacy ( lacidipine : n=59 ; placebo : n=59 ) . Graft function assessed by serum creatinine concentration and glomerular filtration rate measured as plasma iohexol clearance , was persistently better in lacidipine-treated patients from 1 year onwards ( respectively , P<0.01 and P<0.05 ) . Renal plasma flow and anastomotic blood flow were not significantly higher in lacidipine-treated patients . Three patients on lacidipine therapy and four on placebo experienced treatment failure defined as an increase in serum creatinine from baseline of more than 60 % ( log-rank test : P=0.57 ) . Study groups did not differ in acute rejection rate , trough blood cyclosporine concentrations , blood pressure , number of antihypertensive drugs , hospitalization rate , and adverse event rate . Conclusions . The use of calcium channel blockers in cyclosporine-treated renal recipients results in a significantly better allograft function at 2 years and this effect is independent of blood pressure lowering To determine the antihypertensive benefit of adding low dose sprinolactone to multi-drug regimens that included a diuretic , a calcium channel blocker and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in patients with moderately severe chronic kidney disease ( CKD ) [ glomerular filtration rate ( GFR ) 25 - 50 mL/min ] and resistant hyper-tension , we studied 41 patients r and omly divided into two groups : group 1 : patients who received  placebo as spironolactone  and group 2 : patients who received spironolactone 25 - 50 mg/day . The patients were evaluated during follow-up at the 6th and 12th weeks . The mean decrease in systolic and diastolic blood pressure after 6 weeks of spironolactone was 33 ± 8 and 13 ± 2 mmHg , respectively , and it was maintained after 12 weeks of spironolactone wherein the values were 36 ± 10 and 12 ± 2 mmHg , respectively , while there was no change in the blood pressure in the control group . Hyperkalemia ( serum potassium > 5.5 meq/L ) occurred in one subject in the spironolactone group . We conclude that low-dose spironolactone may provide a significant additive blood pressure reduction in CKD patients ( stage 2 and 3 ) with resistant hypertension Background In the outcome trials that provided information on renal function in older hypertensive patients , diuretics and β-blockers were mostly used as first-line drugs . The long-term renal effects of calcium-channel blockers remain unclear . Objective To compare the changes in renal function in 2258 treated and 2148 untreated patients with isolated systolic hypertension , of whom 455 had diabetes mellitus and 390 had proteinuria . Methods We performed a post-hoc analysis of the double-blind placebo-controlled Systolic Hypertension in Europe ( Syst-Eur ) Trial . Active treatment was initiated with nitrendipine ( 10–40 mg/day ) with the possible addition of enalapril ( 5–20 mg/day ) , hydrochlorothiazide ( 12.5–25 mg/day ) , or both , titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg , to less than 150 mmHg . The main outcome measures were serum creatinine concentration and creatinine clearance calculated by the formula of Cockroft and Gault . Results Serum creatinine concentration at the time when participants were r and omly allocated to study groups was less than 176.8 μmol/l ( 2.0 mg/dl ) , averaging 88 μmol/l . At the time of the last serum creatinine measurement , the blood pressure difference ( P < 0.001 ) between the two groups was 11.6/4.1 mmHg . In the intention-to-treat analysis ( 11 427 patient – years ) , serum creatinine and the calculated creatinine clearance were not influenced by active treatment . However , in the patients assigned r and omly to receive active treatment , the incidence of mild renal dysfunction ( serum creatinine at least 176.8 mmol/l ) decreased by 64 % ( P = 0.04 ) and that of proteinuria by 33 % ( P = 0.03 ) . Active treatment reduced the risk of proteinuria more in diabetic than in non-diabetic patients : by 71 % , compared with 20 % ( P = 0 . 04 ) . In non-proteinuric patients , active treatment did not influence serum creatinine , whereas in patients with proteinuria at entry to the study , serum creatinine decreased on active treatment ( P < 0 . 001 ) . Furthermore , in on-r and omized treatment comparison stratified for risk at baseline , serum creatinine concentration did not change ( P = 0.98 ) in patients continuing to receive monotherapy with nitrendipine , whereas it increased by 6.73 mmol/l ( P < 0.001 ) in patients who received hydrochlorothiazide alone or in combination with other study medication ( P < 0.001 for difference in trends ) . Conclusions In older patients with isolated systolic hypertension , antihypertensive treatment starting with the dihydropyridine calcium-channel blocker , nitrendipine , did not decrease blood pressure at the expense of renal function and prevented the development of proteinuria , especially in diabetic patients BACKGROUND Placebo-controlled trials have found that angiotensin-converting enzyme inhibitors ( ACEIs ) decrease proteinuria and slow the progression of nondiabetic nephropathies . However , head-to-head comparisons of ACEIs and calcium channel blockers ( CCBs ) have shown conflicting results . Indeed , a recent meta analysis concluded that there is still uncertainty about the greater renoprotection seen with ACEIs or angiotensin II receptor blockers in nondiabetic patients with renal disease , particularly when using true glomerular filtration rate ( GFR ) as the primary outcome . OBJECTIVE The objective of this 3-year , r and omized , multicenter , double-blind , placebo-controlled study was to compare true GFR decline ( measured by yearly 51Cr-EDTA blood clearance ) in nondiabetic , nonnephrotic adult hypertensive patients with estimated creatinine clearance of 20 to 60 mL/min.1.73 m(2 ) , when r and omized to a CCB ( amlodipine , 5 - 10 mg/d ) or an ACEI ( enalapril , 5 - 20 mg/d ) . METHODS Patients ( aged 18 - 80 years ) entered a 4-week placebo run-in washout period and previous antihypertensive drugs were tapered off over 2 weeks . Add-on treatments were atenolol ( 50 - 100 mg/d ) , loop diuretics ( furosemide , 20 - 500 mg/d or torsemide , 5 - 200 mg/d ) , alpha-blockers ( prazosin , 2.5 - 5 mg/d or doxazosin , 1 - 16 mg/d ) , and central ly acting drugs ( rilmenidine , 1 - 2 mg/d or methyldopa , 250 - 500 mg/d ) . The primary end point was true GFR measured by yearly (51)Cr-EDTA blood clearance . Secondary end points included a clinical composite of renal events and tolerability collected by a full clinical and laboratory evaluation at each study visit . Post hoc analyses for the change in GFR , proteinuria , and time to clinical events were also planned on baseline proteinuria subgroups ( < 1 and > or=1 g/d ) before unblinding the data base . RESULTS Three hundred eighteen patients entered the run-in period and 263 patients ( 156 men/107 women ; mean age , 58 years ) were r and omized to receive either amlodipine ( 5 mg/d , n=132 ) or enalapril ( 5 mg/d , n=131 ) . Blood pressure declined from 165/102 mm Hg to 138/84 mm Hg and 138/85 mm Hg with amlodipine and enalapril , respectively ( no between-group significance ) . Only 20.8 % of the patients r and omized to ACEI treatment received diuretics at the last observation . No statistically significant difference was found between amlodipine and enalapril in GFR decline ( -4.92 and -3.98 mL/min.1.73 m(2 ) , respectively , at last observation ) and composite secondary end point after a median follow-up of 2.9 years , including in the subgroup of patients with proteinuria > 1 g/d at baseline . Protein excretion rate decreased significantly from baseline in patients taking enalapril plus diuretics ( median -270 mg/d ; P<0.001 ) but not in patients taking amlodipine plus diuretics ( -25 mg/d at last observation ) . CONCLUSION In this cohort of nondiabetic , nonnephrotic hypertensive patients , no statistically significant difference in true GFR decline was found over 3 years between amlodipine-treated patients and enalapril-treated patients with main add-on treatment with ss-blockers , including in the subgroup of patients with proteinuria > 1 g/d BACKGROUND Concern has been raised about the potential for adverse cognitive effects associated with the use of calcium-channel blockers ( CCBs ) in older people . This study was undertaken to examine prospect ively the association between the use of these and other antihypertensive drugs and cognitive function . METHODS The authors examined data from the Canadian Study of Health and Aging ( CSHA ) , a population -based , prospect i ve 5-year investigation of the epidemiology of dementia and other health problems in Canadians 65 years of age and older . The risk of cognitive decline , as indicated by a decline in performance on the Modified Mini-Mental State ( 3MS ) examination over the 5-year period , was assessed in relation to the use of antihypertensive and diuretic drugs by 205 subjects with a history of hypertension and no evidence of dementia at baseline . RESULTS The proportion of subjects whose cognitive performance declined over the study period was significantly higher in the group using CCBs than in the group using other antihypertensive agents ( 75 % v. 59 % ) . The adjusted odds ratio ( OR ) for a significant decline in cognitive performance ( defined as a decrease in 3MS score of 10 points or more ) was 2.28 ( 95 % confidence interval [ CI ] 1.12 - 4.66 ) for subjects using CCBs . The adjusted ORs ( and 95 % CIs ) for cognitive decline in subjects using selected antihypertensive agents or diuretics relative to those exposed to beta-blockers were as follows : angiotensin-converting-enzyme inhibitor , OR 1.36 ( 95 % CI 0.41 - 4.55 ) ; diuretic or other antihypertensive drug , OR 1.45 ( 95 % CI 0.51 - 4.14 ) ; dihydropyridine CCB ( nifedipine ) , OR 1.94 ( 95 % CI 0.52 - 7.27 ) and non-dihydropyridine CCB ( diltiazem or verapamil ) , OR 3.72 ( 95 % CI 1.22 - 11.36 ) . INTERPRETATION Older people taking CCBs were significantly more likely than those using other agents to experience cognitive decline . These findings are consistent with the results of previous cross-sectional research and emphasize the need for further trials to examine the associations between CCB use , blood pressure and cognitive impairment in elderly patients CONTEXT The NPPA gene codes for the precursor of atrial natriuretic polypeptide , suggesting that NPPA may modulate the efficacy of some antihypertensive drugs . OBJECTIVE To test whether participants with minor NPPA alleles in the T2238C or G664A variants had different rates of cardiovascular disease or blood pressure (  BP ) changes than common allele homozygotes when treated with a diuretic vs other antihypertensive medications . DESIGN , SETTING , AND PATIENTS Post hoc analysis of 38,462 participants with hypertension from ALLHAT , a multicenter r and omized clinical trial conducted in the United States and Canada . Genotyping was performed from February 2004 to January 2005 . INTERVENTION Participants were r and omly assigned to receive a diuretic ( chlorthalidone ; n = 13,860 ) , a calcium antagonist ( amlodipine ; n = 8174 ) , an angiotensin-converting enzyme inhibitor ( lisinopril ; n = 8233 ) , or an alpha-blocker ( doxazosin ; n = 8195 ) . MAIN OUTCOME MEASURE The primary outcome measure was coronary heart disease ( CHD ) , defined as fatal CHD or nonfatal myocardial infa rct ion ( mean follow-up , 4.9 years ) . Secondary outcomes were stroke , all-cause mortality , combined cardiovascular disease outcomes , and 6-month systolic and diastolic BP changes . Genotype x treatment interactions were tested where genotypes were modeled additively and dominantly . RESULTS Depending on genotype , the event rates per 1000 person-years were 15.3 to 19.7 for CHO , 9.6 to 15.4 for stroke , and 27.4 to 30.7 for all-cause mortality . For the NPPA T2238C variant , lower event rates were found for the C allele carriers than for the TT homozygous individuals when comparing chlorthalidone and amlodipine ( CHD : CC = 0.86 ; TC = 0.90 ; TT = 1.09 ; P = .03 [ dominant model ] ; stroke : CC = 1.18 ; TC = 0.82 ; TT = 1.26 ; P = .01 [ additive and dominant models ] ; all-cause mortality : CC = 0.87 ; TC = 0.98 ; TT = 1.12 ; P = .05 [ dominant model ] ) . Combined end points yielded similar results . Consistent with these clinical findings , 6-month changes in systolic BP for those with the CC genotype showed larger reductions with chlorthalidone ( -6.5 mm Hg ) than with amlodipine ( -3.8 mm Hg ) , lisinopril ( -2.4 mm Hg ) , or doxazosin ( -3.8 mm Hg ) . Among those with the TT genotype , systolic BP differences between drugs were less ( range , -5.4 to -7.5 mm Hg ; P value , < .001 to .003 for interaction ) ; diastolic BP showed similar results . We found no pharmacogenetic associations with the NPPA G664A variant . CONCLUSIONS The NPPA T2238C variant was associated with modification of antihypertensive medication effects on cardiovascular disease and BP . Minor C allele carriers experienced more favorable cardiovascular disease outcomes when r and omized to receive a diuretic , whereas TT allele carriers had more favorable outcomes when r and omized to receive a calcium channel blocker
Effects of antihypertensive drugs on SBP variability are dose-dependent and persist when used in combinations .
Use of a high dose of a calcium channel blocker alone or in combination with other agents is therefore likely to be particularly effective in prevention of stroke
BACKGROUND AND PURPOSE Recent studies have shown that visit-to-visit blood pressure variability is a powerful risk factor for stroke , is reduced by calcium channel blockers and diuretics , and increased by β-blockers .
However , it is unknown whether these effects are dose-dependent and persist in combination with other drugs .