title: Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic Hypertension in Europe Trial Investigators. Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention: Principal Results of a Prospective Randomized Controlled Study (MOSES) Shanghai trial of nifedipine in the elderly (STONE). Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. Outcome Results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in Patients With Hypertension and NIDDM Calcium Antagonist Lacidipine Slows Down Progression of Asymptomatic Carotid Atherosclerosis: Principal Results of the European Lacidipine Study on Atherosclerosis (ELSA), a Randomized, Double-Blind, Long-Term Trial Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study Usefulness of Nisoldipine for prevention of restenosis after percutaneous transluminal coronary angioplasty (results of the NICOLE study). NIsoldipine in COronary artery disease in LEuven. Treatment of Isolated Systolic Hypertension: The SHELL Study Results Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy Cardiovascular events in elderly patients with isolated systolic hypertension. A subgroup analysis of treatment strategies in STOP‐Hypertension‐2 Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: the ACTION trial Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) The Verapamil in Hypertension and Atherosclerosis Study (VHAS): Results of long‐term randomized treatment with either verapamil or chlorthalidone on carotid intima‐media thickness Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.
abstract: 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 Background and Purpose — In hypertensive stroke patients , for the same level of blood pressure control , eprosartan will be more effective than nitrendipine in reducing cerebrovascular and cardiovascular morbidity and mortality . Methods — A total of 1405 well-defined , high-risk hypertensives with cerebral event during the last 24 months ( proven by cerebral computed tomography scan or nuclear magnetic resonance ) were r and omized to eprosartan or nitrendipine ( mean follow-up 2.5 years ) . Primary end point was the composite of total mortality and all cardiovascular and cerebrovascular events , including all recurrent events . Results — R and omization was successful without significant differences in the baseline characteristics . Blood pressure was reduced to a comparable extent without any significant differences between the 2 groups during the whole study period ( 150.7/84 mm Hg and 152.0/87.2 mm Hg with eprosartan and nitrendipine therapy to 137.5/80.8 mm Hg and 136.0/80.2 mm Hg , respectively , confirmed by ambulatory blood pressure monitoring ) . Moreover , already after 3 months , normotensive mean values were achieved , and 75.5 % reached values < 140/90 mm Hg with the eprosartan regimen and 77.7 % with the nitrendipine regimen . During follow-up , in total , 461 primary events occurred : 206 eprosartan and 255 nitrendipine ( incidence density ratio [ IDR ] , 0.79 ; 95 % CI , 0.66 to 0.96 ; P=0.014 ) . Cardiovascular events were : 77 eprosartan and 101 nitrendipine ( IDR , 0.75 ; 95 % CI , 0.55 to 1.02 ; P=0.06 ) ; cerebrovascular events : 102 eprosartan and 134 nitrendipine ( IDR , 0.75 ; 95 % CI , 0.58 to 0.97 ; P=0.03 ) . Conclusions — The Morbidity and Mortality After Stroke , Eprosartan Compared With Nitrendipine for Secondary Prevention ( MOSES ) study was the first to compare an angiotensin II type 1 receptor antagonist with a calcium antagonist in secondary stroke prevention . In these high-risk hypertensive stroke patients , an early normotensive and comparable blood pressure was achieved . The combined primary end point was significantly lower in the eprosartan group OBJECTIVE To assess the effectiveness of nifedipine treatment in elderly hypertensives . METHODS A single-blind trial was conducted under the direction of the Shanghai Institute of Hypertension in 1632 subjects aged 60 - 79 years alternatively allocated to either nifedipine or placebo after a 4-week placebo run-in period between 1987 and 1990 with mean follow-up of 30 months . Clinical events and risk modification were analysed in collaboration with the University of Montreal . Seventy-four patients with severe hypertension were reallocated to active nifedipine treatment after placebo run-in . RESULTS Cox 's proportional hazards model accounting for covariates demonstrated a highly significant decrease in the probability of events : ' original treatment assignment ' analysis indicated that 77 events occurred in the placebo and 32 in the nifedipine group . Similar significance s were achieved with ' actual treatment ' or ' changes excluded ' ( excluding reallocated subjects ) analyses . A significant reduction in relative risk was observed for strokes and severe arrhythmia with an overall decrease from 1.0 to 0.41 ( 95 % confidence interval 0.27 - 0.61 ) . CONCLUSION Nifedipine treatment diminished the number of severe clinical outcomes in elderly hypertensives significantly 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 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 ACE inhibitors and calcium antagonists may favorably affect serum lipids and glucose metabolism . The primary aim of the Fosinopril Versus Amlodipine Cardiovascular Events R and omized Trial ( FACET ) was to compare the effects of fosinopril and amlodipine on serum lipids and diabetes control in NIDDM patients with hypertension . Prospect ively defined cardiovascular events were assessed as secondary outcomes . RESEARCH DESIGN AND METHODS Inclusion criteria included a diagnosis of NIDDM and hypertension ( systolic blood pressure of > 140 mmHg or diastolic blood pressure of > 90 mmHg ) . Exclusion criteria included a history of coronary heart disease or stroke , serum creatinine > 1.5 mg/dl , albuminuria > 40 μg/min , and use of lipid-lowering drugs , aspirin , or antihypertensive agents other than beta-blockers or diuretics . A total of 380 hypertensive diabetics were r and omly assigned to open-label fosinopril ( 20 mg/day ) or amlodipine ( 10 mg/day ) and followed for up to 3.5 years . If blood pressure was not controlled , the other study drug was added . RESULTS Both treatments were effective in lowering blood pressure . At the end of followup , between the two groups there was no significant difference in total serum cholesterol , HDL cholesterol , HbA1c , fasting serum glucose , or plasma insulin . The patients receiving fosinopril had a significantly lower risk of the combined outcome of acute myocardial infa rct ion , stroke , or hospitalized angina than those receiving amlodipine ( 14/189 vs. 27/191 ; hazards ratio = 0.49 , 95 % CI = 0.26–0.95 ) . CONCLUSIONS Fosinopril and amlodipine had similar effects on biochemical measures , but the patients r and omized to fosinopril had a significantly lower risk of major vascular events , compared with the patients r and omized to amlodipine Background —Most cardiovascular events associated with hypertension are complications of atherosclerosis . Some antihypertensive agents influence experimental models of atherosclerosis through mechanisms independent of blood pressure lowering . Methods and Results —The European Lacidipine Study on Atherosclerosis ( ELSA ) was a r and omized , double-blind trial in 2334 patients with hypertension that compared the effects of a 4-year treatment based on either lacidipine or atenolol on an index of carotid atherosclerosis , the mean of the maximum intima-media thicknesses ( IMT ) in far walls of common carotids and bifurcations ( CBMmax ) . This index has been shown by epidemiological studies to be predictive of cardiovascular events . A significant ( P < 0.0001 ) effect of lacidipine was found compared with atenolol , with a treatment difference in 4-year CBMmax progression of −0.0227 mm ( intention-to-treat population ) and −0.0281 mm ( completers ) . The yearly IMT progression rate was 0.0145 mm/y in atenolol-treated and 0.0087 mm/y in lacidipine-treated patients ( completers , 40 % reduction;P = 0.0073 ) . Patients with plaque progression were significantly less common , and patients with plaque regression were significantly more common in the lacidipine group . Clinic blood pressure reductions were identical with both treatments , but 24-hour ambulatory systolic/diastolic blood pressure changes were greater with atenolol ( −10/−9 mm Hg ) than with lacidipine ( −7/−5 mm Hg ) . No significant difference between treatments was found in any cardiovascular events , although the relative risk for stroke , major cardiovascular events , and mortality showed a trend favoring lacidipine . Conclusion —The greater efficacy of lacidipine  on carotid IMT progression and number of plaques per patient , despite a smaller ambulatory blood pressure reduction , indicates an antiatherosclerotic action of lacidipine independent of its antihypertensive action BACKGROUND Calcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial . We aim ed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris . METHODS We r and omly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS  ( gastrointestinal therapeutic system ) 60 mg once daily and 3840 to placebo . The primary endpoint was the combination of death , acute myocardial infa rct ion , refractory angina , new overt heart failure , debilitating stroke , and peripheral revascularisation . Mean follow-up was 4.9 years ( SD 1.1 ) . Analysis was by intention to treat . FINDINGS 310 patients allocated nifedipine  died ( 1.64 per 100 patient-years ) compared with 291 people allocated placebo  ( 1.53 per 100 patient-years ; hazard ratio 1.07 [ 95 % CI 0.91 - 1.25 ] , p=0.41 ) . Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo ( 0.97 [ 0.88 - 1.07 ] , p=0.54 ) . With nifedipine , rate of death and any cardiovascular event or procedure was 9.32 per 100 patient-years versus 10.50 per 100 patient-years for placebo ( 0.89 [ 0.83 - 0.95 ] , p=0.0012 ) . The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine , despite an increase in peripheral revascularisation . Nifedipine had no effect on the rate of myocardial infa rct ion . INTERPRETATION Addition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival .  Nifedipine GITS is safe and reduces the need for coronary angiography and interventions BACKGROUND The efficacy of new antihypertensive drugs has been question ed . We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients . METHODS We did a prospect i ve , r and omised trial in 6614 patients aged 70 - 84 years with hypertension ( blood pressure > or = 180 mm Hg systolic , > or = 105 mm Hg diastolic , or both ) . Patients were r and omly assigned conventional antihypertensive drugs ( atenolol 50 mg , metoprolol 100 mg , pindolol 5 mg , or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily ) or newer drugs ( enalapril 10 mg or lisinopril 10 mg , or felodipine 2.5 mg or isradipine 2 - 5 mg daily ) . We assessed fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease . Analysis was by intention to treat . FINDINGS Blood pressure was decreased similarly in all treatment groups . The primary combined endpoint of fatal stroke , fatal myocardial infa rct ion , and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group ( 19.8 events per 1000 patient-years ) and in 438 of 4401 in the newer drugs group ( 19.8 per 1000 ; relative risk 0.99 [ 95 % CI 0.84 - 1.16 ] , p=0.89 ) . The combined endpoint of fatal and non-fatal stroke , fatal and non-fatal myocardial infa rct ion , and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs ( 0.96 [ 0.86 - 1.08 ] , p=0.49 ) . INTERPRETATION Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events . Decrease in blood pressure was of major importance for the prevention of cardiovascular events The NIsoldipine in COronary artery disease in LEuven ( NICOLE ) study investigates ( 1 ) whether nisoldipine , a dihydropyridine calcium antagonist , reduces the progression of minor coronary arterial lesions in the long term , and ( 2 ) whether it reduces the restenosis rate after successful percutaneous transluminal coronary angioplasty ( PTCA ) . The NICOLE study is a single-center , r and omized , double-blind trial in 826 patients , who underwent a successful PTCA .  Nisoldipine 40 mg coat-core or placebo was started the morning after the procedure and continued for 3 years . All coronary arterial segments were measured on preprocedural angiogram and on the second follow-up angiogram at 3 years . On the first follow-up angiogram at 6 months only the dilated segments were measured . Although the study is still ongoing until the primary end point is reached , we report in this study the angiographic restenosis data as well as the clinical events observed at 6-month follow-up . The per- protocol population consisted of 646 patients .  Restenosis , defined as a > or = 50 % loss of the initial gain ( National Heart , Lung , and Blood Institute criterion IV ) occurred in 49 % and 55 % of the 308 nisoldipine-treated and the 338 placebo-treated patients , respectively ( p = NS ) . At follow-up , the rates of death and myocardial infa rct ion were low and similar in both groups , but in the nisoldipine group , less patients required early coronary angiography ( 18 % vs 26 % , p = 0.006 ) and subsequent revascularization procedures ( 32 % vs 41 % , p = 0.057 ) . Thus , nisoldipine did not significantly reduce the angiographic restenosis rate after PTCA , but reduced the number of repeat revascularization procedures , which may be due to its antianginal action Objective : Our aim was to compare the effect of lacidipine and chlorthalidone on cardiovascular outcome as a primary parameter and blood pressure as a secondary in elderly patients with isolated systolic hypertension in a prospect i ve study with an open design . Methods : 1882 males and females out patients ≥60 years were r and omly assigned to the administration of  chlorthalidone 12.5 mg o.d . or lacidipine 4 mg o.d . Patients were recruited if sitting systolic blood pressure was ≥160 mmHg with a diastolic blood pressure equal or lower than 95 mmHg .  Primary endpoint was a composite of cardiovascular and cerebrovascular events . Results : At r and omization mean systolic blood pressure was 178.1 mmHg in the lacidipine and 178.2 mmHg in the chlorthalidone group , the corresponding mean diastolic values being 86.9 and 86.8 mmHg . In both lacidipine and chlorthalidone groups treatment caused a significant ( p < 0.001 ) and marked systolic blood pressure reduction which was maintained throughout the treatment period with a significant ( p < 0.001 ) and steady although less marked reduction in diastolic blood pressure as well . At the end of treatment period ( median 32 months ) , the reduction was 36.8/8.1 mmHg ( systolic/diastolic ) in the chlorthalidone and 38.4/7.9 mmHg in the lacidipine group , the final on treatment blood pressures being 142.0/79.2 and 143.2/79.5 mmHg , respectively . Treatments were similarly effective in males and females and in age groups between 60 and 69 years ( n = 763 ) , 70 and 79 years ( n = 744 ) and ≥80 years ( n = 375 ) . Similar reductions were obtained in a subgroup of patients ( n = 209 ) followed in double-blind fashion for 1 year . The overall incidence of the primary endpoints was 9.3 % with no significant between-group difference . Total mortality was also similar between groups . Conclusions : In elderly patients with isolated systolic hypertension , administration of lacidipine or chlorthalidone markedly reduced systolic blood pressure with no difference in the incidence of cardiovascular events and total mortality Context Previously published results of this r and omized , double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy . Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine .  Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks . Caution s The trial had limited power to detect important differences between groups in mortality or strokes , and most patients received several antihypertensive agents . The Editors Patients with diabetes have an increased risk for cardiovascular complications and death ( 1 ) . Studies that analyzed the effects of inhibition of the reninangiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes ( 2 - 5 ) or were done exclusively in patients with diabetes ( 6 - 8 ) . The meta- analysis of these studies ( 9 ) , the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation ( HOPE ) study ( 2 ) , and the Losartan Intervention for Endpoint Reduction in Hypertension ( LIFE ) trial ( 5 ) demonstrated that angiotensin-converting enzyme ( ACE ) inhibitors ( 2 , 9 ) and angiotensin-receptor blockers ( 5 ) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events . These studies r and omly assigned few patients with renal involvement and overt proteinuria . Overt proteinuria occurred in fewer than 20 % of the 470 patients in the Appropriate Blood Pressure Control in Diabetes ( ABCD ) trial ( 6 ) , and only 11 % of the 1195 patients in the LIFE trial ( 5 ) . The Captopril Prevention Project ( CAPP ) ( 3 ) and the Swedish Trial in Old Patients with Hypertension-2 ( STOP Hypertension-2 ) ( 4 ) did not state the number of patients with diabetes and overt proteinuria . There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial ( FACET ) ( 7 ) , and patients with dipstick-positive albuminuria were excluded from the HOPE trial ( 2 ) . Since proteinuria is an independent risk factor for cardiovascular disease ( 10 , 11 ) , the data obtained in the aforementioned trials can not be extrapolated to patients with type 2 diabetes and overt nephropathy . Trials performed in such patients have reported a blood pressureindependent effect of two different angiotensin-receptor blocker agents to protect against nephropathy ( 12 , 13 ) without a change in all-cause mortality . Apart from studies in heart failure , few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers . We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial ( IDNT ) ( 12 ) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents . Methods Patients The IDNT was a r and omized , double-blind study on the effect of treatment with irbesartan or amlodipine compared with placebo in patients with type 2 diabetic nephropathy . The protocol of this study has been published ( 12 , 14 ) . Entry criteria required that patients be between 30 and 70 years of age and have type 2 diabetes mellitus and overt nephropathy , as evidence d by current treatment for hypertension or by a protein excretion rate of 900 mg/d or greater , serum creatinine level of 89 mol/L ( 1.0 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in women or of 106 mol/L ( 1.2 mg/dL ) to 266 mol/L ( 3.0 mg/dL ) in men , and baseline seated blood pressure greater than 135/85 mm Hg . The institutional review boards of each center approved the protocol . All patients gave written informed consent . Treatment and R and omization Patients were r and omly assigned central ly by computer to receive treatment with irbesartan , 300 mg/d ( Avapro , Bristol-Myers Squibb , Princeton , New Jersey ) ; amlodipine , 10 mg/d ( Norvasc , Pfizer , New York ) ; or matched placebo . To minimize any center effect , r and omization was blocked by center . All patients had blood pressure controlled to the same blood pressure goal of less than 135/85 mm Hg by using antihypertensive agents other than ACE inhibitors , angiotensin II receptor blocking agents , or calcium-channel blockers . For the analysis of cardiovascular end points , patients were followed to initiation of treatment for end-stage renal failure ( dialysis or renal transplantation ) , reaching a serum creatinine level of 530.4 mol/L ( 6.0 mg/dL ) or higher , death , or administrative censoring in December 2000 . Outcomes We prospect ively established cardiovascular outcomes , defined in the Appendix Table . Appendix Table . Classification for Fatal and Nonfatal Cardiovascular Events Ascertainment of Cardiovascular Events Information about hospitalizations and adverse events were screened at Bristol-Myers Squibb , Princeton , New Jersey , by trained , blinded clinical research associates to identify potential cardiovascular events . Investigators used study forms to report and characterize all cardiovascular outcomes . For all potential events , records , including laboratory values , electrocardiograms , and radiographic reports were obtained for clarification . Since myocardial infa rct ions may go unrecognized , a central electrocardiogram reading center was established at Brigham and Women 's Hospital , Boston , Massachusetts , where two cardiologists review ed every electrocardiogram . Electrocardiography was performed at baseline , 6 months , 12 months , and annually thereafter . A total of 5698 electrocardiograms were review ed at the center . When a new Q-wave infa rct ion was found , the cardiologists asked whether a clinical myocardial infa rct ion was reported . Even when myocardial infa rct ions were not clinical ly reported , these Q-wave infa rct ions were adjudicated as myocardial infa rct ions . Adjudication of Cardiovascular Events Investigators at each center reported cardiovascular events , defined in the Appendix Table . The information on all potential events was referred to one member of the Outcomes Confirmation and Classification Committee ( Appendix ) . If the committee member agreed with the judgment of the center investigator , their combined judgment was accepted . If the center investigator and the committee member differed , the case material was review ed by the membership of the committee , whose decision was accepted . Deaths were adjudicated by a Mortality Committee ( Appendix ) . Each death was review ed by two members of the committee and presented to the membership , whose decision was accepted as final . Statistical Analysis For graphical presentation ( Figure ) and overall testing for statistically significant differences among the three treatment groups , time to the first occurrence of either a specific cardiovascular outcome or one of the composite outcomes was analyzed by product-limit survival curves and the log-rank test ( 15 ) . We used proportional hazards modeling to determine hazard ratios . For the cardiovascular death outcome , which could occur only once , we used the st and ard proportional hazards model ( 16 ) , with treatment assignment as the only independent covariate . For other cardiovascular outcomes , which could occur more than once , we used the And ersonGill formulation of the proportional hazards model ( 17 ) , in which patients are considered at risk for the first event from r and omization to the first event , at risk for the second event from the day following the first event to the second event , and so forth , permitting use of all the data . In accordance with the method of Lee and colleagues ( 18 ) , we used a robust variance estimate that accounts for the possibility of correlation of risk for several events within a patient . We believed that occurrence of a first event of a given type increases the likelihood of a subsequent similar event . Therefore , both treatment assignment and a time-dependent covariate indicating whether the event was the first of its type or a subsequent event were included in these analyses . The time-dependent covariate was statistically significant in each case , confirming the above assumption . There was no statistically significant interaction between treatment and the time-dependent covariatethe effects of treatment assignment were similar for first and subsequent events and inclusion of the time-dependent covariate did not change either the estimates of the treatment effect or their statistical significance s. Figure . Time to first cardiovascular composite event as a function of treatment assignment . P Data management and computations were done by using SAS software for Windows , version 8 ( SAS Institute , Inc. , Cary , North Carolina ) , or S-Plus for Windows , version 6.0 ( Insightful Corp. , Seattle , Washington ) . Statistical tests were two sided . A P value of 0.05 or less , unadjusted for the multiple comparisons , was considered statistically significant . Role of the Funding Sources The funding sources were involved in the data collection but not in the analysis or interpretation or the decision to su bmi t the manuscript for publication . Results The baseline characteristics of the three groups are shown in Table 1 . A flow diagram of the study is shown in the Appendix Figure . Table 1 . Baseline Characteristics Appendix Figure . Flow diagram for the Irbesartan Diabetic Nephropathy Trial . Clinical Management During the study , the blood pressure decreased from the baseline values to 140/77 mm Hg in the irbesartan group , 141/77 mm Hg in the amlodipine group , and 144/80 mm Hg in the placebo group . Blood pressure in the two active treatment groups did not differ ; values in both groups were statistically significantly lower than in the placebo group ( P = 0.001 ) . The distribution of non study drugs used to achieve the target blood pressure was similar 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 Objective To examine the effects of nifedipine GITS on clinical outcome in patients with concurrent stable angina and hypertension . Methods Data from the double-blind placebo-controlled ACTION trial was stratified for hypertension ( blood pressure ≥ 140/90 mmHg ) , at baseline . Results A total of 52 % of 7665 ACTION patients were hypertensive . Some 80 % were on a β blocker ; hypertensives were more often treated with other blood pressure-lowering drugs . Mean baseline blood pressure was 122/74 mmHg among normotensives and 151/85 mmHg among hypertensives . Follow-up blood pressures were reduced by nifedipine ( P < 0.001 ) on the average by 3.9/2.4 and 6.6/3.5 mmHg among normotensives and hypertensives , respectively . Nifedipine GITS significantly ( P < 0.05 ) reduced the combined incidence of all-cause mortality , myocardial infa rct ion , refractory angina , heart failure , stroke and peripheral revascularization by 13 % in hypertensives only . Nifedipine significantly reduced the incidence of any stroke or transient ischemic attack by almost 30 % in both subgroups and the need for coronary angiography by 21 % in normotensives and 16 % in hypertensives . Among hypertensives , the incidence of new overt heart failure was significantly reduced by 38 % and of debilitating stroke by 33 % . Among normotensives , the need for coronary bypass grafting was significantly reduced by 32 % . Nifedipine did not affect all-cause death , cardiovascular death and myocardial infa rct ion in either normo- or hypertensives , but increased the need for peripheral revascularization . Conclusion The salutary effects of the addition of nifedipine GITS to the basic regimen of patients with concurrent stable symptomatic coronary artery disease and hypertension emphasize the need for blood pressure control 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 Background It is unclear whether the carotid intima – media thickness can be influenced by antihypertensive treatment and whether some antihypertensive agents , such as calcium antagonists , may have a greater effect on this parameter than others , such as diuretics . The present paper reports the principal results of the ultrasound sub study of the r and omized , prospect i ve , controlled , Verapamil in Hypertension and Atherosclerosis Study ( VHAS ) . Design and methods In 498 hypertensive patients in eight Italian centres , r and omized to either verapamil ( 240 mg once a day ) or chlorthalidone ( 25 mg once a day ) , a B-mode ultrasound scan was performed according to a st and ardized procedure at baseline and after 3 , 12 , 24 , 36 and 48 months of treatment . The maximum intima – media thicknesses of the far walls of common , bifurcation and internal carotid arteries were measured bilaterally , and the following indices calculated : the mean thickness at the six measured sites , the mean thickness at the common and bifurcation sites and the single maximum thickness . The primary endpoint for treatment efficacy was the slope of the change over 4 years ( rate of change , mm/year ) , corrected by using the initial mean over the six sites ( baseline + 3 months ) as a covariate ( mm/year per mm ) . The patients were also classified into three strata according to their baseline single maximum thickness : those with normal carotid arteries ( single maximum ( 1 mm ) , those with thickened carotid arteries ( single maximum > 1 and ≤ 1.5 mm and those with carotid plaques ( single maximum > 1.5 mm ) . Results Among the 456 patients with satisfactory baseline ultrasound readings , 33 % were classified with normal carotid arteries , 27 % with thickened carotid arteries and 40 % with plaques . In the intention-to-treat population ( 377 patients with ultrasound measurements taken on at least three different occasions over a period of at least 2 years ) , the rate of change in the mean thickness at the six sites measured was rather small ( 0.015 mm/year ) , but significantly ( P < 0.05 ) smaller in patients with plaques ( 0.003 mm/year ) than in patients with thickened or with normal carotids ( 0.023 and 0.025 mm/year , respectively ) . When related to initial values , the rate of change in the mean thickness at the six sites had a negative slope ( −0.059 mm/year per mm , P < 0.01 ) . Although rates of change in the carotid intima – media thickness in unstratified patients were not different in those treated with verapamil or with chlorthalidone , when changes in the mean thickness of six sites were related to the initial value , the slope of this relationship was significantly different in the two treatment groups ( verapamil −0.082 versus chlorthalidone −0.037 mm/year per mm , P < 0.02 ) . The blood pressure-lowering effect of the two r and omized treatments was similar . Taking fatal and nonfatal , major and minor cardiovascular events together , there were 19 events in the verapamil group and 35 in the chlorthalidone group , with a significantly ( P < 0.01 ) greater incidence in patients with plaques , and among patients with plaques in those who were r and omized to chlorthalidone ( P < 0.05 ) . Conclusions In accord with evidence from animal models of atherosclerosis , the calcium antagonist verapamil was more effective than the diuretic chlorthalidone in promoting regression of thicker carotid lesions . Changes in the carotid intima – media thickness were small in both groups , and the differences between the changes under the two treatments were consequently small , but the observation that these small differences in carotid wall changes were paralleled by differences in the incidence of cardiovascular events ( better intima – media thickness regression with verapamil paralleled by a lower cardiovascular event rate ) suggests that even small effects on carotid plaques may have clinical and prognostic relevance OBJECTIVE To compare the rate of progression of mean maximum intimal-medial thickness ( IMT ) in carotid arteries , using quantitative B-mode ultrasound imaging , during  antihypertensive therapy with isradipine vs hydrochlorothiazide . DESIGN R and omized , double-blind , positive-controlled trial . SETTING Nine medical center clinics . POPULATION A total of 883 patients with baseline mean + /- SD systolic and diastolic blood pressure ( SBP and DBP , respectively ) of 149.7 + /- 16.6 and 96.5 + /- 5.1 mm Hg , age of 58.5 + /- 8.5 years , and maximum IMT of 1.17 + /- 0.20 mm . INTERVENTIONS Twice daily doses of isradipine ( 2.5 - 5.0 mg ) or hydrochlorothiazide ( 12.5 - 25 mg ) . MAIN OUTCOME MEASURE ( PRIMARY END POINT ) : Rate of progression of mean maximum IMT in 12 carotid focal points over 3 years . RESULTS There was no difference in the rate of progression of mean maximum IMT between isradipine and hydrochlorothiazide over 3 years ( P=.68 ) . There was a higher incidence of major vascular events ( eg , myocardial infa rct ion , stroke , congestive heart failure , angina , and sudden death ) in isradipine ( n=25 ; 5.65 % ) vs hydrochlorothiazide ( n=14 ; 3.17 % ) ( P=.07 ) , and a significant increase in nonmajor vascular events and procedures ( eg , transient ischemic attack , dysrhythmia , aortic valve replacement , and femoral popliteal bypass graft ) in isradipine ( n=40 ; 9.05 % ) vs hydrochlorothiazide ( n=23 ; 5.22 % ) ( P=.02 ) . At 6 months , mean DBP decreased by 13.0 mm Hg in both groups , and mean SBP decreased by 19.5 mm Hg in hydrochlorothiazide and 16.0 mm Hg in isradipine ( P=.002 ) ; the difference in SBP between the 2 groups persisted throughout the study but did not explain the increased incidence of vascular events in patients treated with isradipine . CONCLUSION The rate of progression of mean maximum IMT in carotid arteries , the surrogate end point in this study , did not differ between the 2 treatment groups . The increased incidence of vascular events in patients receiving isradipine compared with hydrochlorothiazide is of concern and should be studied further Background Isolated systolic hyprtension occurs in around 8 % of Chinese people aged 60 years or older . In 1988 , the Systolic Hypertension in China ( Syst-China ) Collaborative Group started to investigate whether active treatment could reduce the incidence of stroke and other cardiovascular complications in older patients with isolated systolic hypertension . Methods All patients were initially started on masked placebo . After stratification for centre , sex and previous cardiovascular complications , alternate patients ( n = 1253 ) were assigned nitrendipine at 10–40 mg daily , with the addition of captopril at 12.5–50.0 mg daily or hydrochlorothiazide at 12.5–50.0 mg daily , or both , if a sufficient blood pressure fall was not obtained . In the remaining 1141 control patients , matching placebos were administered similarly . Results At entry , sitting blood pressure averaged 170.5 mmHg systolic and 86.0 mmHg diastolic , age averaged 66.5 years and total serum cholesterol was 5.1 mmol/l . After 2 years of follow-up , sitting systolic and diastolic blood pressures had fallen by 10.9 mmHg and 1.9 mmHg in the placebo group and by 20.0 mmHg and 5.0 mmHg in the active treatment group . The intergroup differences were 9.1 mmHg systolic ( 95 % confidence interval 7.6–10.7 mmHg ) and 3.2 mmHg diastolic ( 95 % confidence interval 2.4–4.0 ) . Active treatment reduced total strokes by 38 % ( from 20.8 to 13.0 endpoints per 1000 patient-years , P = 0.01 ) , all-cause mortality by 39 % ( from 28.4 to 17.4 endpoints per 1000 patient-years , P = 0.003 ) , cardiovascular mortality by 39 % ( from 15.2 to 9.4 endpoints per 1000 patient-years , P = 0.03 ) , stroke mortality by 58 % ( from 6.9 to 2.9 endpoints per 1000 patient-years , P = 0.02 ) , and all fatal and nonfatal cardiovascular endpoints by 37 % ( from 33.3 to 21.4 endpoints per 1000 patient-years , P = 0.004 ) . Conclusions Antihypertensive treatment prevents stroke and other cardiovascular complications in older Chinese patients with isolated systolic hypertension . Treatment of 1000 Chinese patients for 5 years could prevent 55 deaths , 39 strokes or 59 major cardiovascular endpoints BACKGROUND Isolated systolic hypertension occurs in about 15 % of people aged 60 years or older . In 1989 , the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension . Fatal and non-fatal stroke combined was the primary endpoint . METHODS All patients ( > 60 years ) were initially started on masked placebo .  At three run-in visits 1 month apart , their average sitting systolic blood pressure was 160 - 219 mm Hg with a diastolic blood pressure lower than 95 mm Hg . After stratification for centre , sex , and previous cardiovascular complications , 4695 patients were r and omly assigned to nitrendipine 10 - 40 mg daily , with the possible addition of enalapril 5 - 20 mg daily and hydrochlorothiazide 12.5 - 25.0 mg daily , or matching placebos . Patients withdrawing from double-blind treatment were still followed up . We compared occurrence of major endpoints by intention to treat . FINDINGS At a median of 2 years ' follow-up , sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group ( n = 2297 ) and by 23 mm Hg and 7 mm Hg in the active treatment group ( n = 2398 ) . The between-group differences were systolic 10.1 mm Hg ( 95 % CI 8.8 - 11.4 ) and diastolic , 4.5 mm Hg ( 3.9 - 5.1 ) . Active treatment reduced the total rate of stroke from 13.7 to 7.9 endpoints per 1000 patient-years ( 42 % reduction ; p = 0.003 ) . Non-fatal stroke decreased by 44 % ( p = 0.007 ) . In the active treatment group , all fatal and non-fatal cardiac endpoints , including sudden death , declined by 26 % ( p = 0.03 ) . Non-fatal cardiac endpoints decreased by 33 % ( p = 0.03 ) and all fatal and non-fatal cardiovascular endpoints by 31 % ( p < 0.001 ) . Cardiovascular mortality was slightly lower on active treatment ( -27 % , p = 0.07 ) , but all-cause mortality was not influenced ( -14 % ; p = 0.22 ) . INTERPRETATION Among elderly patients with isolated systolic hypertension , antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications . Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints
target: In a pooled analysis of data of 31 RCTs measuring the effect of CCBs  on stroke  , CCBs  reduced stroke more than placebo and β-adrenergic blockers , but were not different than ACEIs and diuretics .
background: BACKGROUND Hypertension is a major risk factor for the development of stroke .
  It is well known that lowering blood pressure decreases the risk of stroke in people with moderate to severe hypertension .
  However , the specific effects of calcium channel blockers ( CCBs ) against stroke in patients with hypertension as compared to no treatment and other antihypertensive drug classes are not known .