title: Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S) Long-term effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria:Ten years of follow-up of Prevention of Renal and Vascular End-stage Disease Intervention Trial (PREVEND IT). Long-Term Effects of Statin Treatment in Elderly People: Extended Follow-Up of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) Long-term follow-up after tight control of blood pressure in type 2 diabetes. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial Immediate and late benefits of treating very elderly people with hypertension: results from active treatment extension to Hypertension in the Very Elderly randomised controlled trial Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects With Microalbuminuria Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Long-Term Effects of Ramipril on Cardiovascular Events and on Diabetes: Results of the HOPE Study Extension Long-term follow-up of the West of Scotland Coronary Prevention Study. Treatment of hypertension in patients 80 years of age or older. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the U.K. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. Persistence of reduction in blood pressure and mortality of participants in the Hypertension Detection and Follow-up Program. Hypertension Detection and Follow-up Program Cooperative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. Six-year follow-up of the Norwegian Multicenter Study on Timolol after Acute Myocardial Infarction. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. Long‐term Cardiac Outcomes in Renal Transplant Recipients Receiving Fluvastatin: The ALERT Extension Study Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up Long-term follow-up of moderately hypercholesterolemic hypertensive patients following randomization to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study [Clinical study of the month. The LIPID study: "long-term intervention with pravastatin in ischaemic disease"]. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
abstract: BACKGROUND The effects of cholesterol-lowering treatment with statins on mortality and risk of cancer beyond the usual 5 - 6-year trial periods are unknown . We extended post-trial follow-up of participants in the Sc and inavian Simvastatin Survival Study ( 4S ) to investigate cause-specific mortality and incidence of cancer 5 years after closure of the trial . METHODS 4S was a r and omised double-blind trial of simvastatin or placebo in patients with coronary heart disease , serum total cholesterol 5.5 - 8.0 mmol/L , and serum triglycerides 2.5 mmol/L or lower . The double-blind period lasted for a median of 5.4 years ( range for survivors 4.9 - 6.3 ) and ended in 1994 . After the trial , most patients in both groups received open-label lipid-lowering treatment . National registers were used to assess mortality and causes of death and cancer incidence in the original treatment groups for a median total follow-up time of 10.4 years ( range for survivors 9.9 - 11.3 ) . Analysis was by intention to treat . FINDINGS 414 patients originally allocated simvastatin and 468 assigned placebo  died during the 10.4-year follow-up ( relative risk 0.85 [ 95 % CI 0.74 - 0.97 ] , p=0.02 ) , a difference largely attributable to lower coronary mortality in the simvastatin group ( 238 vs 300 deaths ; 0.76 [ 0.64 - 0.90 ] , p=0.0018 ) . 85 cancer deaths arose in the simvastatin group versus 100 in the placebo group ( 0.81 [ 0.60 - 1.08 ] , p=0.14 ) , and 227 incident cancers were reported in the simvastin group versus 248 in the placebo group ( 0.88 [ 0.73 - 1.05 ] , p=0.15 ) . Incidence of any specific type of cancer did not rise in the simvastatin group . INTERPRETATION Simvastatin treatment for 5 years in a placebo-controlled trial , followed by open-label statin therapy , was associated with survival benefit over 10 years of follow-up compared with open-label statin therapy for the past 5 years only . No difference was noted in mortality from and incidence of cancer between the original simvastatin group and placebo group BACKGROUND The PREVEND IT investigated whether treatment targeted at lowering urinary albumin excretion ( UAE ) would reduce adverse cardiovascular events . We obtained extended follow-up data to approximately 10 years to investigate the long-term effects of fosinopril 20 mg and pravastatin 40 mg on cardiovascular outcomes in subjects with UAE > 15 mg per 24 hours . METHODS The original PREVEND IT consisted of 864 participants and 839 survivors after 4 years . For every survivor , the primary end point determined by the combined incidence of cardiovascular mortality and hospitalization for cardiovascular morbidity was registered in several national data bases and electronic hospital systems . RESULTS Mean total follow-up of the extended PREVEND IT was 9.5 years ( range 9.4 - 10.7 years ) . Four years of treatment with fosinopril was not associated with a reduction in the primary end point compared with placebo ( hazard ratio 0.87 , 95 % CI 0.61 - 1.24 [ P = .42 ] ) during long-term follow-up . After 9.5 years , subjects with a baseline UAE in the upper quintile ( > 50 mg/24 hours ) had a total event rate of 29.5 % and were at a higher risk for developing cardiovascular disease compared with less UAE ( hazard ratio 2.03 , 95 % CI 1.38 - 2.97 [ P ≤ .01 ] ) . In addition , 4 years of fosinopril treatment result ed in a risk reduction of 45 % ( 95 % CI 6%-75 % [ P = .04 ] ) in this group compared with placebo . Subjects originally assigned to pravastatin had no overall risk reduction in the primary end point ( P = .99 ) . CONCLUSIONS Elevated UAE is associated with increased cardiovascular mortality and morbidity after 9.5 years of follow-up , with a doubling of the risk if the UAE is > 50 mg per 24 hours . In this group , the benefits of 4-year treatment with fosinopril were sustained during posttrial follow-up for cardiovascular mortality and morbidity . We propose that UAE be used to estimate risk in the general population and that large clinical trials be design ed to confirm the hypothesis that angiotensin-converting enzyme-inhibitor treatment may be beneficial in patients with mildly elevated UAE despite the absence of other comorbidities Background The PROspect i ve Study of Pravastatin in the Elderly at Risk ( PROSPER ) , a placebo-controlled trial of pravastatin , demonstrated a 19 % reduction in coronary outcomes ( p = 0.006 ) after a mean of 3.2 years , with no impact on stroke outcomes or all-cause mortality . However , there was a suggestion of increased cancer risk . Our aim is to determine the long-term benefits and safety of pravastatin treatment in older people using post-trial follow-up of the PROSPER participants . Methods 5,804 ( 2,520 Scottish ) men and women aged 70–82 years with either pre-existing vascular disease or increased risk of such disease because of smoking , hypertension or diabetes , were r and omised to 40 mg pravastatin or matching placebo . Using record linkage to routinely collected health records , all participants ( full cohort ) were linked to death and cancer registries , and the Scottish cohort additionally to hospital admissions , to provide composite fatal/non-fatal cardiovascular outcomes ( total mean follow-up 8.6 years ) . Results Pravastatin treatment for 3.2 years reduced CHD death in the full cohort , hazard ratio ( HR ) 0.80 , 95 % confidence interval ( CI ) 0.68–0.95 , p = 0.0091 and fatal coronary events or coronary hospitalisations in the Scottish cohort ( HR 0.81 , 95 % CI 0.69–0.95 , p = 0.0081 ) over 8.6 years . There was no reduction in stroke or all-cause mortality . Cancer risk was not increased in the full cohort ( HR 1.08 , 95 % CI 0.96–1.21 , p = 0.22 ) . Conclusions Pravastatin treatment of elderly high-risk subjects for 3.2 years provided long-term protection against CHD events and CHD mortality . However , this was not associated with any increase in life expectancy , possibly due to competing mortality with deaths from other causes . There was no evidence of long-term increased risk of cancer . Trial registration IS RCT N40976937 BACKGROUND Post-trial monitoring of patients in the United Kingdom Prospect i ve Diabetes Study ( UKPDS ) examined whether risk reductions for microvascular and macrovascular disease , achieved with the use of improved blood-pressure control during the trial , would be sustained . METHODS Among 5102 UKPDS patients with newly diagnosed type 2 diabetes mellitus , we r and omly assigned , over a 4-year period beginning in 1987 , 1148 patients with hypertension to  tight or less-tight blood-pressure control regimens .  The 884 patients who underwent post-trial monitoring  were asked to attend annual UKPDS clinics for the first 5 years , but no attempt was made to maintain their previously assigned therapies . Annual question naires completed by patients and general practitioners were used to follow patients who were unable to attend the clinic in years 1 through 5 , and question naires were used for all patients in years 6 to 10 . Seven prespecified aggregate clinical end points were examined on an intention-to-treat basis , according to the previous r and omization categories . RESULTS Differences in blood pressure between the two groups during the trial disappeared within 2 years after termination of the trial . Significant relative risk reductions found during the trial for any diabetes-related end point , diabetes-related death , microvascular disease , and stroke in the group receiving tight , as compared with less tight , blood-pressure control were not sustained during the post-trial follow-up . No risk reductions were seen during or after the trial for myocardial infa rct ion or death from any cause , but a risk reduction for peripheral vascular disease associated with tight blood-pressure control became significant ( P=0.02 ) . CONCLUSIONS The benefits of previously improved blood-pressure control were not sustained when between-group differences in blood pressure were lost . Early improvement in blood-pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of complications , but it appears that good blood-pressure control must be continued if the benefits are to be maintained . ( UKPDS 81 ; Current Controlled Trials number , IS RCT N75451837 . BACKGROUND Treatment with angiotensin-converting-enzyme ( ACE ) inhibitors reduces mortality among survivors of acute myocardial infa rct ion , but whether to use ACE inhibitors in all patients or only in selected patients is uncertain . METHODS We screened 6676 consecutive patients with 7001 myocardial infa rct ions confirmed by enzyme studies . A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction ( ejection fraction , < or = 35 percent ) . On days 3 to 7 after infa rct ion , 1749 patients were r and omly assigned to receive oral tr and olapril ( 876 patients ) or placebo ( 873 patients ) . The duration of follow-up was 24 to 50 months . RESULTS During the study period , 304 patients ( 34.7 percent ) in the tr and olapril group died , as compared with 369 ( 42.3 percent ) in the placebo group ( P = 0.001 ) . The relative risk of death in the tr and olapril group , as compared with the placebo group , was 0.78 ( 95 percent confidence interval , 0.67 to 0.91 ) . Tr and olapril also reduced the risk of death from cardiovascular causes ( relative risk , 0.75 ; 95 percent confidence interval , 0.63 to 0.89 ; P = 0.001 ) and sudden death ( relative risk , 0.76 ; 95 percent confidence interval , 0.59 to 0.98 ; P = 0.03 ) . Progression to severe heart failure was less frequent in the tr and olapril group ( relative risk , 0.71 ; 95 percent confidence interval , 0.56 to 0.89 ; P = 0.003 ) . In contrast , the risk of recurrent myocardial infa rct ion ( fatal or nonfatal ) was not significantly reduced ( relative risk , 0.86 ; 95 percent confidence interval , 0.66 to 1.13 ; P = 0.29 ) . CONCLUSIONS Long-term treatment with tr and olapril in patients with reduced left ventricular function soon after myocardial infa rct ion significantly reduced the risk of overall mortality , mortality from cardiovascular causes , sudden death , and the development of severe heart failure . That mortality was reduced in a r and omized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infa rct ion BACKGROUND Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals , their efficacy and safety in elderly people is not fully established . Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with , or at high risk of developing , cardiovascular disease and stroke . METHODS We did a r and omised controlled trial in which we assigned 5804 men ( n=2804 ) and women ( n=3000 ) aged 70 - 82 years with a history of , or risk factors for , vascular disease to pravastatin ( 40 mg per day ; n=2891 ) or placebo ( n=2913 ) . Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death , non-fatal myocardial infa rct ion , and fatal or non-fatal stroke . Analysis was by intention-to-treat . FINDINGS Pravastatin lowered LDL cholesterol concentrations by 34 % and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo ( hazard ratio 0.85 , 95 % CI 0.74 - 0.97 , p=0.014 ) . Coronary heart disease death and non-fatal myocardial infa rct ion risk was also reduced ( 0.81 , 0.69 - 0.94 , p=0.006 ) . Stroke risk was unaffected ( 1.03 , 0.81 - 1.31 , p=0.8 ) , but the hazard ratio for transient ischaemic attack was 0.75 ( 0.55 - 1.00 , p=0.051 ) . New cancer diagnoses were more frequent on pravastatin than on placebo ( 1.25 , 1.04 - 1.51 , p=0.020 ) . However , incorporation of this finding in a meta- analysis of all pravastatin and all statin trials showed no overall increase in risk . Mortality from coronary disease fell by 24 % ( p=0.043 ) in the pravastatin group . Pravastatin had no significant effect on cognitive function or disability . INTERPRETATION Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals . PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people Objective To assess if very elderly people with hypertension obtain early benefit from antihypertensive treatment . Design One year open label active treatment extension of r and omised controlled trial ( Hypertension in the Very Elderly Trial ( HYVET ) ) . Setting Hospital and general practice based centres mainly in eastern and western Europe , China , and Tunisia . Participants People on double blind treatment at the end of HYVET were eligible to enter the extension . Interventions Participants on active blood pressure lowering treatment continued taking active drug ; those on placebo were given active blood pressure lowering treatment . The treatment regimen was as used in the main trial — indapamide SR 1.5 mg ( plus perindopril 2 - 4 mg if required)—with the same target blood pressure of less than 150/80 mm Hg . Main outcome measures The primary outcome was all stroke ; other outcomes included total mortality , cardiovascular mortality , and cardiovascular events . Results Of 1882 people eligible for entry to the extension , 1712 ( 91 % ) agreed to participate . During the extension period , 1682 patient years were accrued . By six months , the difference in blood pressure between the two groups was 1.2/0.7 mm Hg . Comparing people previously treated with active drug and those previously on placebo , no significant differences were seen for stroke ( n=13 ; hazard ratio 1.92 , 95 % confidence interval 0.59 to 6.22 ) or cardiovascular events ( n=25 ; 0.78 , 0.36 to 1.72 ) . Differences were seen for total mortality ( 47 deaths ; hazard ratio 0.48 , 0.26 to 0.87 ; P=0.02 ) and cardiovascular mortality ( 11 deaths ; 0.19 , 0.04 to 0.87 ; P=0.03 ) . Conclusion Very elderly patients with hypertension may gain immediate benefit from treatment . Sustained differences in reductions of total mortality and cardiovascular mortality reinforce the benefits and support the need for early and long term treatment . Trial registration Clinical trials NCT00122811 BACKGROUND In the Action in Diabetes and Vascular Disease : Preterax and Diamicron Modified Release Controlled Evaluation ( ADVANCE ) factorial trial , the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes , but intensive glucose control , targeting a glycated hemoglobin level of less than 6.5 % , did not . We now report results of the 6-year post-trial follow-up . METHODS We invited surviving participants , who had previously been assigned to perindopril-indapamide or placebo and to intensive or st and ard glucose control ( with the glucose-control comparison extending for an additional 6 months ) , to participate in a post-trial follow-up evaluation . The primary end points were death from any cause and major macrovascular events . RESULTS The baseline characteristics were similar among the 11,140 patients who originally underwent r and omization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years ( blood-pressure-lowering comparison ) or 5.4 years ( glucose-control comparison ) . Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit . The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up ; the hazard ratios were 0.91 ( 95 % confidence interval [ CI ] , 0.84 to 0.99 ; P=0.03 ) and 0.88 ( 95 % CI , 0.77 to 0.99 ; P=0.04 ) , respectively . No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the st and ard-glucose-control group ; the hazard ratios were 1.00 ( 95 % CI , 0.92 to 1.08 ) and 1.00 ( 95 % CI , 0.92 to 1.08 ) , respectively . CONCLUSIONS The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up . There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events . ( Funded by the National Health and Medical Research Council of Australia and others ; ADVANCE-ON Clinical Trials.gov number , NCT00949286 . ) Drug therapy for hypercholesterolaemia has remained controversial mainly because of insufficient clinical trial evidence for improved survival . The present trial was design ed to evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease ( CHD ) . 4444 patients with angina pectoris or previous myocardial infa rct ion and serum cholesterol 5.5 - 8.0 mmol/L on a lipid-lowering diet were r and omised to double-blind treatment with simvastatin or placebo . Over the 5.4 years median follow-up period , simvastatin produced mean changes in total cholesterol , low-density-lipoprotein cholesterol , and high-density-lipoprotein cholesterol of -25 % , -35 % , and + 8 % , respectively , with few adverse effects . 256 patients ( 12 % ) in the placebo group died , compared with 182 ( 8 % ) in the simvastatin group . The relative risk of death in the simvastatin group was 0.70 ( 95 % CI 0.58 - 0.85 , p = 0.0003 ) . The 6-year probabilities of survival in the placebo and simvastatin groups were 87.6 % and 91.3 % , respectively . There were 189 coronary deaths in the placebo group and 111 in the simvastatin group ( relative risk 0.58 , 95 % CI 0.46 - 0.73 ) , while noncardiovascular causes accounted for 49 and 46 deaths , respectively . 622 patients ( 28 % ) in the placebo group and 431 ( 19 % ) in the simvastatin group had one or more major coronary events . The relative risk was 0.66 ( 95 % CI 0.59 - 0.75 , p < 0.00001 ) , and the respective probabilities of escaping such events were 70.5 % and 79.6 % . This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more . Other benefits of treatment included a 37 % reduction ( p < 0.00001 ) in the risk of undergoing myocardial revascularisation procedures . This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients Background —Microalbuminuria is associated with increased risk of cardiovascular events . We assessed whether therapeutic intervention aim ed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects ( 15 to 300 mg/24 hours ) . Methods and Results —From the Prevention of Renal and Vascular Endstage Disease ( PREVEND ) cohort ( n=8592 ) , 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial ( PREVEND IT ) . Of these subjects , 864 were r and omized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo . The mean follow-up was 46 months , and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity . Mean age was 51±12 years ; 65 % of subjects were male , and 3.4 % had a previous cardiovascular event . Mean cholesterol level was 5.8±1.0 mmol/L , mean systolic/diastolic blood pressure was 130±18/76±10 mm Hg , and median urinary albumin excretion was 22.8 ( 15.8 to 41.3 ) mg/24 hours . The primary end point occurred in 45 subjects ( 5.2 % ) . Fosinopril  reduced urinary albumin excretion by 26 % ( P<0.001 ) . Subjects treated with fosinopril showed a 40 % lower incidence of the primary end point ( hazard ratio 0.60 [ 95 % CI 0.33 to 1.10 ] , P=0.098 , log-rank ) . Pravastatin did not reduce urinary albumin excretion , and subjects treated with pravastatin showed a 13 % lower incidence of the primary end point than subjects in the placebo group ( 0.87 [ 0.49 to 1.57 ] , P=0.649 , log-rank ) . Conclusions —In microalbuminuric subjects , treatment with fosinopril had a significant effect on urinary albumin excretion . In addition , fosinopril treatment was associated with a trend in reducing cardiovascular events  . Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events BACKGROUND Improved blood-glucose control decreases the progression of diabetic microvascular disease , but the effect on macrovascular complications is unknown . There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation . We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a r and omised controlled trial . METHODS 3867 newly diagnosed patients with type 2 diabetes , median age 54 years ( IQR 48 - 60 years ) , who after 3 months ' diet treatment had a mean of two fasting plasma glucose ( FPG ) concentrations of 6.1 - 15.0 mmol/L were r and omly assigned intensive policy with a sulphonylurea ( chlorpropamide , glibenclamide , or glipizide ) or with insulin , or conventional policy with diet . The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group , the aim was the best achievable FPG with diet alone ; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment :  any diabetes-related endpoint ( sudden death , death from hyperglycaemia or hypoglycaemia , fatal or non-fatal myocardial infa rct ion , angina , heart failure , stroke , renal failure , amputation [ of at least one digit ] , vitreous haemorrhage , retinopathy requiring photocoagulation , blindness in one eye , or cataract extraction ) ; diabetes-related death ( death from myocardial infa rct ion , stroke , peripheral vascular disease , renal disease , hyperglycaemia or hypoglycaemia , and sudden death ) ; all-cause mortality . Single clinical endpoints and surrogate sub clinical endpoints were also assessed . All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy . FINDINGS Over 10 years , haemoglobin A1c ( HbA1c ) was 7.0 % ( 6.2 - 8.2 ) in the intensive group compared with 7.9 % ( 6.9 - 8.8 ) in the conventional group -- an 11 % reduction . There was no difference in HbA1c among agents in the intensive group . Compared with the conventional group , the risk in the intensive group was 12 % lower ( 95 % CI 1 - 21 , p=0.029 ) for any diabetes-related endpoint ; 10 % lower ( -11 to 27 , p=0.34 ) for any diabetes-related death ; and 6 % lower ( -10 to 20 , p=0.44 ) for all-cause mortality . Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25 % risk reduction ( 7 - 40 , p=0.0099 ) in microvascular endpoints , including the need for retinal photocoagulation . There was no difference for any of the three aggregate endpoints between the three intensive agents ( chlorpropamide , glibenclamide , or insulin ) . Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis ( both p<0.0001 ) . The rates of major hypoglycaemic episodes per year were 0.7 % with conventional treatment , 1.0 % with chlorpropamide , 1.4 % with glibenclamide , and 1.8 % with insulin .  Weight gain was significantly higher in the intensive group ( mean 2.9 kg ) than in the conventional group ( p<0.001 ) , and patients assigned insulin had a greater gain in weight ( 4.0 kg ) than those assigned chlorpropamide ( 2.6 kg ) or glibenclamide ( 1.7 kg ) . INTERPRETATION Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications , but not macrovascular disease , in patients with type 2 diabetes . ( ABSTRACT TRUNCATED Background —We have previously demonstrated that ramipril reduces vascular events and new diagnoses of diabetes when given for a 4.5-year period . However , it is not known whether the benefits are observed in subgroups of patients at varying risk or on other proven therapies and whether the benefits are sustained beyond the current trial . The 2 aims of this investigation were to assess whether the benefits observed during the HOPE trial were ( 1 ) maintained after trial cessation during an additional 2.6 years of follow-up and ( 2 ) observed in subgroups based on risk and ancillary treatments . Methods and Results —Of the initial 267 study centers and 9297 patients , 174 centers and 4528 patients agreed to further follow-up . The rates of use of angiotensin-converting-enzyme inhibitors ( ACEIs ) in the 2 groups ( 72 % ramipril versus 68 % placebo ) were similar after the end of the trial . During the posttrial follow-up , patients allocated to ramipril had a 19 % further lower relative risk ( RR ) of myocardial infa rct ion ( 95 % confidence interval [ CI ] , 0.65 to 1.01 ) , a 16 % lower RR ( 95 % CI , 0.70 to 0.99 ) of revascularization , and a 34 % lower RR of a new diagnosis of diabetes ( 95 % CI , 0.46 to 0.95 ) . Similar RR reductions in vascular events were observed during and after the active phase of the trial , regardless of baseline risk ( RR of 0.76 , 0.89 , and 0.83 for low- , medium- , and high-risk patients , respectively ) or ancillary treatments ( RR of 0.90 for aspirin , 0.76 for & bgr;-blockers , and 0.84 for lipid-lowering medication ) . Conclusions —The benefits of ramipril observed during the active period of the HOPE trial were maintained during posttrial follow-up for cardiovascular death , stroke , and hospitalization for heart failure . Additional reductions in myocardial infa rct ion , revascularization , and the development of diabetes were observed during the follow-up phase despite similar rates of ACEI use in the 2 r and omized groups . These benefits were consistent regardless of patient risk or ancillary treatments BACKGROUND The West of Scotl and Coronary Prevention Study was a r and omized clinical trial comparing pravastatin with placebo in men with hypercholesterolemia who did not have a history of myocardial infa rct ion , with an average follow-up of approximately 5 years . The combined outcome of death from definite coronary heart disease or definite nonfatal myocardial infa rct ion was reduced from 7.9 to 5.5 % ( P<0.001 ) in the treatment group . Extended follow-up data were obtained for approximately 10 years after completion of the trial . METHODS For the survivors of the trial , all deaths , hospitalizations and deaths due to coronary events and stroke , and incident cancers and deaths from cancer were tracked with the use of a national computerized record-linkage system . The results were analyzed with time-to-event analyses and use of Cox proportional-hazards models . RESULTS Five years after the trial ended , 38.7 % of the original statin group and 35.2 % of the original placebo group were being treated with a statin . In the period approximately 10 years after completion of the trial , the risk of death from coronary heart disease or nonfatal myocardial infa rct ion was 10.3 % in the placebo group and 8.6 % in the pravastatin group ( P=0.02 ) ; over the entire follow-up period , the rate was 15.5 % in the placebo group and 11.8 % in the pravastatin group ( P<0.001 ) . Similar percentage reductions were seen in the combined rate of death from coronary heart disease and hospitalization for coronary events for both periods . The rate of death from cardiovascular causes was reduced ( P=0.01 ) , as was the rate of death from any cause ( P=0.03 ) , over the entire follow-up period . There were no excess deaths from noncardiovascular causes or excess fatal or incident cancers . CONCLUSIONS In this analysis , 5 years of treatment with pravastatin was associated with a significant reduction in coronary events for a subsequent 10 years in men with hypercholesterolemia who did not have a history of myocardial infa rct ion BACKGROUND Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear . It has been suggested that antihypertensive therapy may reduce the risk of stroke , despite possibly increasing the risk of death . METHODS We r and omly assigned 3845 patients from Europe , China , Australasia , and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide ( sustained release , 1.5 mg ) or matching placebo .  The angiotensin-converting-enzyme inhibitor perindopril ( 2 or 4 mg ) , or matching placebo , was added if necessary to achieve the target blood pressure of 150/80 mm Hg . The primary end point was fatal or nonfatal stroke . RESULTS The active-treatment group ( 1933 patients ) and the placebo group ( 1912 patients ) were well matched ( mean age , 83.6 years ; mean blood pressure while sitting , 173.0/90.8 mm Hg ) ; 11.8 % had a history of cardiovascular disease . Median follow-up was 1.8 years . At 2 years , the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group . In an intention-to-treat analysis , active treatment was associated with a 30 % reduction in the rate of fatal or nonfatal stroke ( 95 % confidence interval [ CI ] , -1 to 51 ; P=0.06 ) , a 39 % reduction in the rate of death from stroke ( 95 % CI , 1 to 62 ; P=0.05 ) , a 21 % reduction in the rate of death from any cause ( 95 % CI , 4 to 35 ; P=0.02 ) , a 23 % reduction in the rate of death from cardiovascular causes ( 95 % CI , -1 to 40 ; P=0.06 ) , and a 64 % reduction in the rate of heart failure ( 95 % CI , 42 to 78 ; P<0.001 ) . Fewer serious adverse events were reported in the active-treatment group ( 358 , vs. 448 in the placebo group ; P=0.001 ) . CONCLUSIONS The results provide evidence that antihypertensive treatment with indapamide ( sustained release ) , with or without perindopril , in persons 80 years of age or older is beneficial . ( Clinical Trials.gov number , NCT00122811 [ Clinical Trials.gov ] . ) AIMS The aim of this study was to determine the outcome benefits in those originally assigned atorvastatin in the Anglo-Sc and inavian Cardiac Outcomes Trial-8 years after closure of the lipid-lowering arm ( LLA ) of the trial ( ASCOT-LLA ) among the U.K. population . METHODS AND RESULTS ASCOT-LLA was a factorially design ed double-blind placebo-controlled trial of atorvastatin in 10 305 hypertensive patients enrolled into the ASCOT-Blood Pressure Lowering Arm ( BPLA ) of the trial and with total cholesterol concentrations , at baseline , of < 6.5 mmol/L. ASCOT-LLA was stopped prematurely after a median 3.3-year follow-up because of a 36 % relative risk reduction ( RRR ) in non-fatal myocardial infa rct ion and fatal coronary heart disease ( CHD ) ( the primary outcome ) in favour of atorvastatin and a non-significant reduction in CV deaths ( 16 % ) and all-cause mortality ( 13 % ) . After a further 2.2 years at the end of ASCOT-BPLA , despite extensive crossovers from and to statin usage , the RRR in all endpoints remained essentially unchanged . A median 11 years after initial r and omization and ∼8 years after closure of LLA , all-cause mortality ( n=520 and 460 in placebo and atorvastatin , respectively ) remained significantly lower in those originally assigned atorvastatin ( HR 0.86 , CI 0.76 - 0.98 , P=0.02 ) . CV deaths were fewer , but not significant ( HR 0.89 , CI 0.72 - 1.11 , P=0.32 ) and non-CV deaths were significantly lower ( HR 0.85 , CI 0.73 - 0.99 , P=0.03 ) in those formerly assigned atorvastatin attributed to a reduction in deaths due to infection and respiratory illness . CONCLUSION Legacy effects of those originally assigned atorvastatin may contribute to long-term benefits on all-cause mortality . An explanation for long-term benefits on non-CV deaths has not been established CONTEXT Hypertension is a leading cause of end-stage renal disease ( ESRD ) in the United States , with no known treatment to prevent progressive declines leading to ESRD . OBJECTIVE To compare the effects of 2 levels of blood pressure ( BP ) control and 3 antihypertensive drug classes on glomerular filtration rate ( GFR ) decline in hypertension . DESIGN R and omized 3 x 2 factorial trial with enrollment from February 1995 to September 1998 . SETTING AND PARTICIPANTS A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( GFR , 20 - 65 mL/min per 1.73 m(2 ) ) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years . INTERVENTIONS Participants were r and omly assigned to 1 of 2 mean arterial pressure goals , 102 to 107 mm Hg ( usual ; n = 554 ) or 92 mm Hg or less ( lower ; n = 540 ) , and to initial treatment with either a beta-blocker ( metoprolol 50 - 200 mg/d ; n = 441 ) , an angiotensin-converting enzyme inhibitor ( ramipril 2.5 - 10 mg/d ; n = 436 ) or a dihydropyridine calcium channel blocker , ( amlodipine 5 - 10 mg/d ; n = 217 ) . Open-label agents were added to achieve the assigned BP goals . MAIN OUTCOME MEASURES Rate of change in GFR ( GFR slope ) ; clinical composite outcome of reduction in GFR by 50 % or more ( or > or = 25 mL/min per 1.73 m2 ) from baseline , ESRD , or death . Three primary treatment comparisons were specified : lower vs usual BP goal ; ramipril vs metoprolol ; and amlodipine vs metoprolol . RESULTS Achieved BP averaged ( SD ) 128/78 ( 12/8 ) mm Hg in the lower BP group and 141/85 ( 12/7 ) mm Hg in the usual BP group . The mean ( SE ) GFR slope from baseline through 4 years did not differ significantly between the lower BP group ( -2.21 [ 0.17 ] mL/min per 1.73 m2 per year ) and the usual BP group ( -1.95 [ 0.17 ] mL/min per 1.73 m2 per year ; P = .24 ) , and the lower BP goal did not significantly reduce the rate of the clinical composite outcome ( risk reduction for lower BP group = 2 % ; 95 % confidence interval [ CI ] , -22 % to 21 % ; P = .85 ) . None of the drug group comparisons showed consistent significant differences in the GFR slope . However , compared with the metoprolol and amlodipine groups , the ramipril group manifested risk reductions in the clinical composite outcome of 22 % ( 95 % CI , 1%-38 % ; P = .04 ) and 38 % ( 95 % CI , 14%-56 % ; P = .004 ) , respectively . There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups . CONCLUSIONS No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal . Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline Background To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension  , we extended the double-blind placebo-controlled Systolic Hypertension in Europe ( Syst-Eur ) trial by an open-label follow-up study lasting 4 years . Methods The Syst-Eur trial included 4695 r and omized patients with minimum age of 60 years and an untreated blood pressure of 160–219 mmHg systolic and below 95 mmHg diastolic . The double-blind trial ended after a median follow-up of 2.0 years ( range 1–97 months ) . Of 4409 patients still alive , 3517 received open-label treatment consisting of nitrendipine ( 10–40 mg daily ) with the possible addition of enalapril ( 5–20 mg daily ) , hydrochlorothiazide ( 12.5–25 mg daily ) , or both add-on drugs .  Non- participants ( n = 892 ) were also followed up . Results Median follow-up increased to 6.1 years . Systolic pressure decreased to below 150 mmHg ( target level ) in 2628 participants ( 75.0 % ) . During the 4-year open-label follow-up , stroke and cardiovascular complications occurred at similar frequencies in patients formerly r and omized to placebo and those continuing active treatment . These rates were similar to those previously observed in the active-treatment group during the double-blind trial . Considering the total follow-up of 4695 r and omized patients , immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28 % ( P = 0.01 ) and 15 % ( P = 0.03 ) , respectively , with a similar tendency for total mortality ( 13 % , P = 0.09 ) . In 492 diabetic patients , the corresponding estimates of long-term benefit ( P < 0.02 ) were 60 , 51 and 38 % , respectively . Conclusions Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension . Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years . These findings underscore the necessity of early treatment of isolated systolic hypertension A multicenter double-blind r and omized study was carried out to compare the effect of timolol ( 10 mg twice daily ) with that of placebo in patients surviving acute myocardial infa rct ion . Treatment was started seven to 28 days after infa rct ion in 1884 patients ( 945 taking timolol , and 939 placebo ) , who represented 52 per cent of those evaluated for entry ; the patients were followed for 12 to 33 months ( mean , 17 ) . There were 152 deaths in the placebo group and 98 in the timolol group . When deaths that occurred during treatment or within 28 days of withdrawal were considered , the cumulated sudden-death rate over 33 months was 13.9 per cent in the placebo group and 7.7 per cent in the timolol group -- a reduction of 44.6 per cent ( P = 0.0001 ) . The cumulated reinfa rct ion rate was 20.1 per cent in the placebo group and 14.4 per cent in the timolol group ( P = 0.0006 ) . We conclude that long-term treatment with timolol in patients surviving acute myocardial infa rct ion reduces mortality and the rate of reinfa rct ion The Hypertension Detection and Follow-up Program ( HDFP ) previously described a significant reduction in five-year , all-cause mortality in its intensively treated stepped care ( SC ) group relative to its referred care ( RC ) control group . At the time this finding was described , a proportion of the SC cohort had been treated for periods as long as 6.7 years , but comparable RC and SC mortality data beyond five years were not available . These data , which are described herein , indicate that the 6.7-year life-table mortality rates were 95.1/1000 participants for SC vs 116.3/1000 participants for RC , a larger mortality difference than was observed at five years . This favorable finding for SC extended to all major subgroups , including white women and those aged 30 to 49 years at trial entry . Six months after the close of the treatment trial , a two-year posttrial surveillance study , which extended mortality follow-up to 8.3 years , was conducted . The posttrial use of antihypertensive medication declined in SC and increased in RC participants so that by the end of the posttrial period , there was little difference in the percentages of SC and RC participants taking medication . Control of blood pressure , indicated by mean diastolic blood pressure and by percent of participants with a pressure of 90 mm Hg or less , was slightly better for SC than for RC participants ( SC group , 86.5 mm Hg and 68 % controlled ; RC group , 87.8 mm Hg and 62 % controlled ) . The absolute mortality advantage found at 6.7 years persisted and increased throughout the posttrial period of follow-up despite discontinuation of the formal SC therapy program . It is postulated that regression of hypertensive end-organ changes brought about by the more effective SC treatment caused this favorable outcome BACKGROUND Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes , and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension . We assessed the effects of the routine administration of an angiotensin converting enzyme ( ACE ) inhibitor-diuretic combination on serious vascular events in patients with diabetes , irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs . METHODS The trial was done by 215 collaborating centres in 20 countries . After a 6-week active run-in period , 11 140 patients with type 2 diabetes were r and omised to treatment with a fixed combination of perindopril and indapamide or matching placebo , in addition to current therapy . The primary endpoints were composites of major macrovascular and microvascular events , defined as death from cardiovascular disease , non-fatal stroke or non-fatal myocardial infa rct ion , and new or worsening renal or diabetic eye disease , and analysis was by intention-to-treat . The macrovascular and microvascular composites were analysed jointly and separately . This trial is registered with Clinical Trials.gov , number NCT00145925 . FINDINGS After a mean of 4.3 years of follow-up , 73 % of those assigned active treatment and 74 % of those assigned control remained on r and omised treatment . Compared with patients assigned placebo , those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg . The relative risk of a major macrovascular or microvascular event was reduced by 9 % ( 861 [ 15.5 % ] active vs 938 [ 16.8 % ] placebo ; hazard ratio 0.91 , 95 % CI 0.83 - 1.00 , p=0.04 ) . The separate reductions in macrovascular and microvascular events were similar but were not independently significant ( macrovascular 0.92 ; 0.81 - 1.04 , p=0.16 ; microvascular 0.91 ; 0.80 - 1.04 , p=0.16 ) . The relative risk of death from cardiovascular disease was reduced by 18 % ( 211 [ 3.8 % ] active vs 257 [ 4.6 % ] placebo ; 0.82 , 0.68 - 0.98 , p=0.03 ) and death from any cause was reduced by 14 % ( 408 [ 7.3 % ] active vs 471 [ 8.5 % ] placebo ; 0.86 , 0.75 - 0.98 , p=0.03 ) . There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline . INTERPRETATION Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events , including death . Although the confidence limits were wide , the results suggest that over 5 years , one death due to any cause would be averted among every 79 patients assigned active therapy BACKGROUND Renal transplant recipients are at increased risk of premature cardiovascular disease . Although statins reduce cardiovascular risk in the general population , their efficacy and safety in renal transplant recipients have not been established . We investigated the effects of fluvastatin on cardiac and renal endpoints in this population . METHODS We did a multicentre , r and omised , double-blind , placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4.0 - 9.0 mmol/L. We r and omly assigned patients fluvastatin ( n=1050 ) or placebo ( n=1052 ) and follow up was for 5 - 6 years . The primary endpoint was the occurrence of a major adverse cardiac event , defined as cardiac death , non-fatal myocardial infa rct ion ( MI ) , or coronary intervention procedure . Secondary endpoints were individual cardiac events , combined cardiac death or non-fatal MI , cerebrovascular events , non-cardiovascular death , all-cause mortality , and graft loss or doubling of serum creatinine . Analysis was by intention to treat . FINDINGS After a mean follow-up of 5.1 years , fluvastatin lowered LDL cholesterol concentrations by 32 % . Risk reduction with fluvastatin for the primary endpoint ( risk ratio 0.83 [ 95 % CI 0.64 - 1.06 ] , p=0.139 ) was not significant , although there were fewer cardiac deaths or non-fatal MI ( 70 vs 104 , 0.65 [ 0.48 - 0.88 ] p=0.005 ) in the fluvastatin group than in the placebo group . Coronary intervention procedures and other secondary endpoints did not differ significantly between groups . INTERPRETATION Although cardiac deaths and non-fatal MI seemed to be reduced , fluvastatin did not generally reduce rates of coronary intervention procedures or mortality . Overall effects of fluvastatin were similar to those of statins in other population BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive  ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P<0.001 ) . Treatment with ramipril reduced the rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P<0.001 ) , myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P<0.001 ) , stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P<0.001 ) , death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P<0.001 ) , cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P<0.001 ) , and complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure The original Norwegian Multicenter Study on  Timolol after Myocardial Infa rct ion was a double-blind , r and omized study comparing the effect of timolol with that of placebo for up to 33 months after acute myocardial infa rct ion . The initial results showed that the cumulated mortality rate was 39.4 per cent lower among 945 patients r and omly assigned to  timolol  treatment than among 939 patients r and omly assigned to  placebo  ( P = 0.0003 ) . After the end of the double-blind period the majority of participating patients in the timolol group continued to receive beta-adrenergic blockade , whereas the majority of  placebo-treated patients continued without such blockade . During an extended follow-up of participating patients up to 72 months after r and omization , the mortality curves of the two groups continued to rise in parallel . Cumulated mortality rates were 32.3 per cent in the placebo group and 26.4 per cent in the timolol group ( P = 0.0028 ) . We conclude that the previously observed early beneficial effect of beta-adrenergic blocking therapy is maintained for at least six years after infa rct ion BACKGROUND It is not known whether the treatment of patients with asymptomatic left ventricular dysfunction reduces mortality and morbidity . We studied the effect of an angiotensin-converting -- enzyme inhibitor , enalapril , on total mortality and mortality from cardiovascular causes , the development of heart failure , and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure . METHODS Patients were r and omly assigned to receive either placebo ( n = 2117 ) or enalapril ( n = 2111 ) at doses of 2.5 to 20 mg per day in a double-blind trial . Follow-up averaged 37.4 months . RESULTS There were 334 deaths in the placebo group , as compared with 313 in the enalapril group ( reduction in risk , 8 percent by the log-rank test ; 95 percent confidence interval , -8 percent [ an increase of 8 percent ] to 21 percent ; P = 0.30 ) . The reduction in mortality from cardiovascular causes was larger but was not statistically significant ( 298 deaths in the placebo group vs. 265 in the enalapril group ; risk reduction , 12 percent ; 95 percent confidence interval , -3 to 26 percent ; P = 0.12 ) . When we combined patients in whom heart failure developed and those who died , the total number of deaths and cases of heart failure was lower in the enalapril group than in the placebo group ( 630 vs. 818 ; risk reduction , 29 percent ; 95 percent confidence interval , 21 to 36 percent ; P less than 0.001 ) . In addition , fewer patients given enalapril  died or were hospitalized for heart failure ( 434 in the enalapril group ; vs. 518 in the placebo group ; risk reduction , 20 percent ; 95 percent confidence interval , 9 to 30 percent ; P less than 0.001 ) . CONCLUSIONS The angiotensin-converting -- enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations , as compared with the rates in the group given placebo , among patients with asymptomatic left ventricular dysfunction . There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril Renal transplant recipients ( RTR ) have an increased risk of premature cardiovascular disease . The ALERT study is the first trial to evaluate the effect of statin therapy on cardiac outcomes following renal transplantation . Patients initially r and omized to fluvastatin or placebo in the 5–6 year ALERT study were offered open‐label fluvastatin XL 80 mg/day in a 2‐year extension to the original study . The primary endpoint was time to first major adverse cardiac event ( MACE ) . Of 1787 patients who completed ALERT , 1652 ( 92 % ) were followed in the extension . Mean total follow‐up was 6.7 years . Mean LDL‐cholesterol was 98 mg/dL ( 2.5 mmol/L ) at last follow‐up compared to a pre‐ study level of 159 mg/dL ( 4.1 mmol/L ) . Patients r and omized to fluvastatin had a reduced risk of MACE ( hazards ratio [ HR ] 0.79 , 95 % CI 0.63–0.99 , p = 0.036 ) , and a 29 % reduction in cardiac death or definite non‐fatal MI ( HR 0.71 , 95 % CI 0.55–0.93 , p = 0.014 ) . Total mortality and graft loss did not differ significantly between groups . Fluvastatin produces a safe and effective reduction in LDL‐cholesterol associated with reduced risk of MACE in RTR . The lipid‐lowering and cardiovascular benefits  of fluvastatin are comparable to those of statins in other patient groups , and support use of fluvastatin in RTR BACKGROUND The Post Coronary Artery Bypass Graft Trial , design ed to compare the effects of 2 lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery , demonstrated that aggressive lowering of LDL cholesterol ( LDL-C ) levels to < 100 mg/dL compared with a moderate reduction to 132 to 136 mg/dL decreased the progression of atherosclerosis in grafts . Low-dose anticoagulation did not significantly affect progression . METHODS AND RESULTS Approximately 3 years after the last trial visit , Clinical Center Coordinators contacted each patient by telephone to ascertain the occurrence of cardiovascular events and procedures . The National Death Index was used to ascertain vital status for patients who could not be contacted . Vital status was established for all but 3 of 1351 patients . Information on nonfatal events was available for 95 % of surviving patients . A 30 % reduction in revascularization procedures and 24 % reduction in a composite clinical end point were observed in patients assigned to aggressive strategy compared with patients assigned to moderate strategy during 7.5 years of follow-up , P=0 . 0006 and 0.001 , respectively . Reductions of 35 % in deaths and 31 % in deaths or myocardial infa rct ions with low-dose anticoagulation compared with placebo were also observed , P=0.008 and 0.003 , respectively . CONCLUSIONS -The long-term clinical benefit observed during extended follow-up in patients assigned to the aggressive strategy is consistent with the angiographic findings of delayed atherosclerosis progression in grafts observed during the trial . The apparent long-term benefit of low-dose warfarin remains unexplained OBJECTIVE To assess the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal ( total ) stroke in isolated systolic hypertension . DESIGN Multicenter , r and omized , double-blind , placebo-controlled . SETTING Community-based ambulatory population in tertiary care centers . PARTICIPANTS 4736 persons ( 1.06 % ) from 447,921 screenees aged 60 years and above were r and omized ( 2365 to active treatment , 2371 to placebo ) . Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was less than 90 mm Hg . Of the participants , 3161 were not receiving antihypertensive medication at initial contact , and 1575 were . The average systolic blood pressure was 170 mm Hg ; average diastolic blood pressure , 77 mm Hg . The mean age was 72 years , 57 % were women , and 14 % were black . INTERVENTIONS -- Participants were stratified by clinical center and by antihypertensive medication status at initial contact . For step 1 of the trial , dose 1 was chlorthalidone , 12.5 mg/d , or matching placebo ; dose 2 was 25 mg/d . For step 2 , dose 1 was atenolol , 25 mg/d , or matching placebo ; dose 2 was 50 mg/d . MAIN OUTCOME MEASURES Primary . Nonfatal and fatal ( total ) stroke . Secondary . Cardiovascular and coronary morbidity and mortality , all-cause mortality , and quality of life measures . RESULTS Average follow-up was 4.5 years . The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the active treatment group , and the 5-year average diastolic blood pressure was 72 and 68 mm Hg , respectively . The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo . The relative risk by proportional hazards regression analysis was 0.64 ( P = .0003 ) . For the secondary end point of clinical nonfatal myocardial infa rct ion plus coronary death , the relative risk was 0.73 . Major cardiovascular events were reduced ( relative risk , 0.68 ) . For deaths from all causes , the relative risk was 0.87 . CONCLUSION In persons aged 60 years and over with isolated systolic hypertension , antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36 % , with 5-year absolute benefit of 30 events per 1000 participants . Major cardiovascular events were reduced , with 5-year absolute benefit of 55 events per 1000 BACKGROUND The Long-term Intervention with Pravastatin in Ischaemic Disease ( LIPID ) study showed that pravastatin therapy over 6 years reduced mortality and cardiovascular events in patients with previous acute coronary syndromes and average cholesterol concentrations . We assessed the longer-term effects of initial treatment with pravastatin on further cardiovascular events and mortality over a total follow-up period of 8 years . METHODS In the main trial , 9014 patients with previous myocardial infa rct ion or unstable angina and a baseline plasma cholesterol concentration of 4.0 - 7.0 mmol/L were r and omly assigned  pravastatin 40 mg daily or placebo and followed up for 6 years . Subsequently , all patients were offered open-label pravastatin for 2 more years . Major cardiovascular events and adverse events were compared according to initial treatment assignment . FINDINGS 7680 ( 97 % of those still alive ) had 2 years of extended follow-up . 3766 ( 86 % ) of those assigned placebo and 3914 ( 88 % ) assigned pravastatin agreed to take open-label pravastatin . During this period , patients originally assigned pravastatin had almost identical cholesterol concentrations to those assigned placebo , but a lower risk of death from all causes ( 219 [ 5.6 % ] vs 255 [ 6.8 % ] , p=0.029 ) , coronary heart disease ( CHD ) death ( 108 [ 2.8 % ] vs 137 [ 3.6 % ] , p=0.026 ) , and CHD death or non-fatal myocardial infa rct ion ( 176 [ 4.5 % ] vs 196 [ 5.2 % ] , p=0.08 ) . Over the total 8-year period , all-cause mortality was 888 ( 19.7 % ) in the group originally assigned placebo and 717 ( 15.9 % ) in the group originally assigned pravastatin , CHD mortality was 510 ( 11.3 % ) versus 395 ( 8.8 % ) , myocardial infa rct ion was 570 ( 12.7 % ) versus 435 ( 9.6 % ; each p < 0.0001 ) , and stroke was 272 ( 6.0 % ) versus 224 ( 5.0 % ; p=0.015 ) . Stronger evidence of separate treatment benefits than in the main trial was seen in important prespecified subgroups ( women , patients aged > or = 70 years , and those with total cholesterol < 5.5 mmol/L ) . Pravastatin had no significant adverse effects . INTERPRETATION The evidence of sustained treatment benefits and safety of long-term pravastatin treatment reinforces the importance of long-term cholesterol-lowering  treatment for almost all patients with previous CHD events The authors conducted a r and omized , controlled , multicenter trial , in which they assigned well-controlled hypertensive participants aged 55 years and older with moderate hypercholesterolemia to receive pravastatin ( n=5170 ) or usual care ( n=5185 ) for 4 to 8 years , when trial therapy was discontinued . Passive surveillance using national data bases to ascertain deaths and hospitalizations continued for a total follow-up of 8 to 13 years to assess whether mortality and morbidity differences persisted or new differences developed . During the post-trial period , fatal and nonfatal outcomes were available for 98 % and 64 % of participants , respectively . The primary outcome was all-cause mortality and the secondary outcomes included cardiovascular mortality , coronary heart disease ( CHD ) , stroke , heart failure , cardiovascular disease , and end-stage renal disease . No significant differences appeared in mortality for pravastatin vs usual care ( hazard ratio [ HR ] , 0.96 ; 95 % confidence interval [ CI ] , 0.89 - 1.03 ) or other secondary outcomes . Similar to the previously reported in-trial result , there was a significant treatment effect for CHD in black patients ( HR , 0.79 ; 95 % CI , 0.64 - 0.98 ) . However , the in-trial result showing a significant treatment by race effect did not remain significant during the entire follow-up ( P=.08 ) . These findings are consistent with evidence from other large trials that show statins prevent CHD and add evidence that they are effective for CHD prevention in black patients BACKGROUND In the studies of left ventricular dysfunction ( SOLVD ) , enalapril reduced mortality in patients with symptomatic but not asymptomatic left ventricular systolic dysfunction during the trial . We did a 12-year follow-up of SOLVD to establish if the mortality reduction with enalapril among patients with heart failure was sustained , and whether a subsequent reduction in mortality would emerge among those with asymptomatic ventricular dysfunction . METHODS Of the 6797 patients previously enrolled in the SOLVD prevention and treatment trials , we ascertained the subsequent vital status of 5165 individuals who were alive when the trials had been completed . Follow-up was done through direct contacts in Belgium and linkages with national death registries and federal beneficiary or historic tax summary files in the USA and Canada . FINDINGS Follow-up was 99.8 % ( 6784/6797 ) complete . In the prevention trial , 50.9 % ( 1074/2111 ) of the enalapril group had died compared with 56.4 % ( 1195/2117 ) of the placebo group ( generalised Wilcoxon p=0.001 ) . In the treatment trial , 79.8 % ( 1025/1285 ) of the enalapril group had died compared with 80.8 % ( 1038/1284 ) of the placebo group ( generalised Wilcoxon p=0.01 ) . The reductions in cardiac deaths were significant and similar in both trials . When data for the prevention and treatment trials were combined , the hazard ratio for death was 0.90 for the enalapril group compared with the placebo group ( 95 % CI 0.84 - 0.95 , generalised Wilcoxon p=0.0003 ) . Enalapril extended median survival by 9.4 months in the combined trials ( 95 % CI 2.8 - 16.5 , p=0.004 ) . INTERPRETATION Treatment with enalapril for 3 - 4 years led to a sustained improvement in survival beyond the original trial period in patients with left ventricular systolic dysfunction , with an important increase in life expectancy The LIPID study is a placebo-controlled , double-bind , r and omized trial , performed in 9014 patients with coronary heart disease and total cholesterol levels of 155 to 271 mg/dl . After a mean follow-up of 6.1 years , patients receiving pravastatin ( 40 mg/day ) had significantly ( p < 0.001 ) lower death rate from coronary heart disease ( 24 % ) , lower overall mortality ( 22 % ) and lower incidence of all cardiovascular outcomes ( 20 to 29 % depending on the event ) . Interestingly enough , the reduction in death from coronary heart disease or nonfatal myocardial infa rct ion was observed whatever the initial cholesterol concentration , and already significant if total cholesterol was < 213 mg/dl and LDL cholesterol was < 135 mg/dl . Thus , in secondary prevention , the favourable effect of the statin on the coronary heart disease outcomes is observed even in case of initial cholesterol levels yet considered as " normal " BACKGROUND Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently . We studied the effect of an angiotensin-converting-enzyme inhibitor , enalapril , on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35 . METHODS Patients receiving conventional treatment for heart failure were r and omly assigned to receive either placebo ( n = 1284 ) or enalapril ( n = 1285 ) at doses of 2.5 to 20 mg per day in a double-bind trial . Approximately 90 percent of the patients were in New York Heart Association functional classes II and III . The follow-up averaged 41.4 months . RESULTS There were 510 deaths in the placebo group ( 39.7 percent ) , as compared with 452 in the enalapril group ( 35.2 percent ) ( reduction in risk , 16 percent ; 95 percent confidence interval , 5 to 26 percent ; P = 0.0036 ) . Although reductions in mortality were observed in several categories of cardiac deaths , the largest reduction occurred among the deaths attributed to progressive heart failure ( 251 in the placebo group vs. 209 in the enalapril group ; reduction in risk , 22 percent ; 95 percent confidence interval , 6 to 35 percent ) . There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure . Fewer patients died or were hospitalized for worsening heart failure ( 736 in the placebo group and 613 in the enalapril group ; risk reduction , 26 percent ; 95 percent confidence interval , 18 to 34 percent ; P less than 0.0001 ) . CONCLUSIONS The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions BACKGROUND Obstructive changes often occur in aortocoronary saphenous-vein bypass grafts because of atherosclerosis and thrombosis . We studied whether aggressive lowering of low-density lipoprotein ( LDL ) cholesterol levels or low-dose anticoagulation would delay the progression of atherosclerosis in grafts . METHODS We studied 1351 patients who had undergone bypass surgery 1 to 11 years before base line and who had an LDL cholesterol level between 130 and 175 mg per deciliter and at least one patent vein graft as seen on angiography . We used a two-by-two factorial design to assign patients to aggressive or moderate treatment to lower LDL cholesterol levels ( with lovastatin and , if needed , cholestyramine ) and to treatment with warfarin or placebo . Angiography was repeated an average of 4.3 years after base line . The primary angiographic outcome was the mean percentage per patient of grafts with a decrease of 0.6 mm or more in lumen diameter . RESULTS As measured annually during the study period , the mean LDL cholesterol level of patients aggressive treatment ranged from 93 to 97 mg per deciliter ; with moderate treatment , the range was from 132 to 136 mg per deciliter ( P<0.001 ) . The mean international normalized ratio was 1.4 in the warfarin group and 1.1 in the placebo group ( P<0.001 ) . The mean percentage of grafts with progression of atherosclerosis was 27 percent for patients whose LDL cholesterol level was lowered with aggressive treatment , and 39 percent for those who received moderate treatment ( P<0.001 ) . There was no significant difference in angiographic outcome between the warfarin and placebo groups . The rate of revascularization over four years was 29 percent lower in the group whose LDL cholesterol level was lowered aggressively than in the group receiving moderate treatment ( 6.5 percent vs. 9.2 percent , P= 0.03 ) . CONCLUSIONS Aggressive lowering of LDL cholesterol levels to below 100 mg per deciliter reduced the progression of atherosclerosis in grafts . Low-dose warfarin did not reduce the progression of atherosclerosis CONTEXT Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease ( CHD ) reduce CHD events . However , many of these studies were too small to assess all-cause mortality or outcomes in important subgroups . OBJECTIVE To determine whether pravastatin compared with usual care reduces all-cause mortality in older , moderately hypercholesterolemic , hypertensive participants with at least 1 additional CHD risk factor . DESIGN AND SETTING Multicenter ( 513 primarily community-based North American clinical centers ) , r and omized , nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) . PARTICIPANTS Ambulatory persons ( n = 10 355 ) , aged 55 years or older , with low-density lipoprotein cholesterol ( LDL-C ) of 120 to 189 mg/dL ( 100 to 129 mg/dL if known CHD ) and triglycerides lower than 350 mg/dL , were r and omized to  pravastatin  ( n = 5170 ) or to  usual care  ( n = 5185 ) . Baseline mean total cholesterol was 224 mg/dL ; LDL-C , 146 mg/dL ; high-density lipoprotein cholesterol , 48 mg/dL ; and triglycerides , 152 mg/dL. Mean age was 66 years , 49 % were women , 38 % black and 23 % Hispanic , 14 % had a history of CHD , and 35 % had type 2 diabetes . INTERVENTION Pravastatin , 40 mg/d , vs usual care . MAIN OUTCOME MEASURES The primary outcome was all-cause mortality , with follow-up for up to 8 years . Secondary outcomes included nonfatal myocardial infa rct ion or fatal CHD ( CHD events ) combined , cause-specific mortality , and cancer . RESULTS Mean follow-up was 4.8 years . During the trial , 32 % of usual care participants with and 29 % without CHD started taking lipid-lowering drugs . At year 4 , total cholesterol levels were reduced by 17 % with pravastatin vs 8 % with usual care ; among the r and om sample who had LDL-C levels assessed , levels were reduced by 28 % with pravastatin vs 11 % with usual care .  All-cause mortality was similar for the 2 groups ( relative risk [ RR ] , 0.99 ; 95 % confidence interval [ CI ] , 0.89 - 1.11 ; P = .88 ) , with 6-year mortality rates of 14.9 % for pravastatin vs 15.3 % with usual care .  CHD event rates were not significantly different between the groups ( RR , 0.91 ; 95 % CI , 0.79 - 1.04 ; P = .16 ) , with 6-year CHD event rates of 9.3 % for pravastatin and 10.4 % for usual care . CONCLUSIONS Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol ( 9.6 % ) and LDL-C ( 16.7 % ) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention BACKGROUND Lowering the blood cholesterol level may reduce the risk of coronary heart disease . This double-blind study was design ed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infa rct ion reduced the combined incidence of nonfatal myocardial infa rct ion and death from coronary heart disease . METHODS We r and omly assigned 6595 men , 45 to 64 years of age , with a mean ( + /- SD ) plasma cholesterol level of 272 + /- 23 mg per deciliter ( 7.0 + /- 0.6 mmol per liter ) to receive pravastatin ( 40 mg each evening ) or placebo .  The average follow-up period was 4.9 years . Medical records , electrocardiographic recordings , and the national death registry were used to determine the clinical end points . RESULTS Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent , whereas there was no change with placebo . There were 248 definite coronary events ( specified as nonfatal myocardial infa rct ion or death from coronary heart disease ) in the placebo group , and 174 in the pravastatin group ( relative reduction in risk with pravastatin , 31 percent ; 95 percent confidence interval , 17 to 43 percent ; P < 0.001 ) . There were similar reductions in the risk of definite nonfatal myocardial infa rct ions ( 31 percent reduction , P < 0.001 ) , death from coronary heart disease ( definite cases alone : 28 percent reduction , P = 0.13 ; definite plus suspected cases : 33 percent reduction , P = 0.042 ) , and death from all cardiovascular causes ( 32 percent reduction , P = 0.033 ) . There was no excess of deaths from noncardiovascular causes in the pravastatin group . We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group ( 95 percent confidence interval , 0 to 40 percent ; P = 0.051 ) . CONCLUSIONS Treatment with pravastatin significantly reduced the incidence of myocardial infa rct ion and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infa rct ion
target: Results : BP and lipid levels tended to come together soon in the post-trial period .
  Conclusion : Benefits of BPL and lipid lowering on all-cause and cardiovascular mortality were persistent , but attenuated , after discontinuation of r and omized treatment , indicating the importance of continuing therapy
background: Objective : Persistent long-term benefits after discontinuation of treatment have been suggested for blood pressure-lowering and lipid-lowering treatment .
  We conducted a systematic review to assess the long-term effects of  blood pressure ( BP ) lowering ( BPL ) and lipid lowering on all-cause and cardiovascular mortality after discontinuation of r and omized treatment .