title: Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data 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. Effect of amlodipine on the survival of patients with severe chronic heart failure due to a nonischemic cardiomyopathy: results of the PRAISE-2 study (prospective randomized amlodipine survival evaluation 2). Irbesartan in patients with atrial fibrillation. Telmisartan, ramipril, or both in patients at high risk for vascular events. 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 Enalapril Decreases the Incidence of Atrial Fibrillation in Patients With Left Ventricular Dysfunction Insight From the Studies Of Left Ventricular Dysfunction (SOLVD) Trials Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study) Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial Atrial Fibrillation and Isolated Systolic Hypertension: The Systolic Hypertension in the Elderly Program and Systolic Hypertension in the Elderly Program-Extension Study Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). 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 Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: the VALUE trial Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT). Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE study. Valsartan for prevention of recurrent atrial fibrillation.
abstract: BACKGROUND The beneficial effects of beta-blockers on long-term outcome after acute myocardial infa rct ion were shown before the introduction of thrombolysis and angiotensin-converting-enzyme ( ACE ) inhibitors . Generally , the patients recruited to these trials were at low risk : few had heart failure , and none had measurements of left-ventricular function taken . We investigated the long-term efficacy of carvedilol on morbidity and mortality in patients with left-ventricular dysfunction after acute myocardial infa rct ion treated according to current evidence -based practice . METHODS In a multicentre , r and omised , placebo-controlled trial , 1959 patients with a proven acute myocardial infa rct ion and a left-ventricular ejection fraction of < /=40 % were r and omly assigned 6.25 mg carvedilol ( n=975 ) or placebo ( n=984 ) . Study medication was progressively increased to a maximum of 25 mg twice daily during the next 4 - 6 weeks , and patients were followed up until the requisite number of primary endpoints had occurred . The primary endpoint was all-cause mortality or hospital admission for cardiovascular problems . Analysis was by intention to treat . FINDINGS Although there was no difference between the carvedilol and placebo groups in the number of patients with the primary endpoint ( 340 [ 35 % ] vs 367 [ 37 % ] , hazard ratio 0.92 [ 95 % CI 0.80 - 1.07 ] ) , all-cause mortality alone was lower in the carvedilol group than in the placebo group ( 116 [ 12 % ] vs 151 [ 15 % ] , 0.77 [ 0.60 - 0.98 ] , p=0.03 ) . Cardiovascular mortality , non-fatal myocardial infa rct ions , and all-cause mortality or non-fatal myocardial infa rct ion were also lower on carvedilol than on placebo . INTERPRETATION In patients treated long-term after an acute myocardial infa rct ion complicated by left-ventricular systolic dysfunction , carvedilol reduced the frequency of all-cause and cardiovascular mortality , and recurrent , non-fatal myocardial infa rct ions . These beneficial effects are additional to those of evidence -based treatments for acute myocardial infa rct ion including ACE inhibitors BACKGROUND Atrial fibrillation is the most common supraventricular arrhythmia in patients with acute myocardial infa rct ion . Recent advances in pharmacological treatment of myocardial infa rct ion may have changed the impact of this arrhythmia . OBJECTIVE To assess the incidence and prognosis of atrial fibrillation complicating myocardial infa rct ion in a large population of patients receiving optimal treatment , including angiotensin converting enzyme ( ACE ) inhibitors .  METHODS Data were derived from the GISSI-3 trial , which included 17 944 patients within the first 24 hours after acute myocardial infa rct ion . Atrial fibrillation was recorded during the hospital stay , and follow up visits were planned at six weeks and six months . Survival of the patients at four years was assessed through census offices . RESULTS The incidence of in-hospital atrial fibrillation or flutter was 7.8 % . Atrial fibrillation was associated with indicators of a worse prognosis ( age > 70 years , female sex , higher Killip class , previous myocardial infa rct ion , treated hypertension , high systolic blood pressure at entry , insulin dependent diabetes , signs or symptoms of heart failure ) and with some adverse clinical events ( reinfa rct ion , sustained ventricular tachycardia , ventricular fibrillation ) . After adjustment for other prognostic factors , atrial fibrillation remained an independent predictor of increased in-hospital mortality : 12.6%v 5 % , adjusted relative risk ( RR ) 1.98 , 95 % confidence interval ( CI ) 1.67 to 2.34 . Data on long term mortality ( four years after acute myocardial infa rct ion ) confirmed the persistent negative influence of atrial fibrillation ( RR 1.78 , 95 % CI 1.60 to 1.99 ) . CONCLUSIONS Atrial fibrillation is an indicator of worse prognosis after acute myocardial infa rct ion , both in the short term and in the long term , even in an unselected population 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 OBJECTIVES This study was design ed to test the hypothesis of whether amlodipine reduces the risk for death in patients with heart failure due to a nonischemic cardiomyopathy . BACKGROUND A pre-specified subgroup analysis in an earlier , large-scale , placebo-controlled study suggested that amlodipine might reduce the risk for death in patients with heart failure due to a nonischemic cardiomyopathy . METHODS To evaluate this hypothesis , 1654 patients with severe heart failure due to a nonischemic cardiomyopathy ( ejection fraction < 30 % ) were r and omly assigned to amlodipine ( target dose : 10 mg/d ) or placebo added to conventional therapy for heart failure for a median of 33 months . RESULTS There were 278 deaths in the amlodipine group and 262 deaths in the placebo group ( hazard ratio : 1.09 ; 95 % confidence interval [ CI ] : 0.92 to 1.29 ; p = 0.33 ) . The differences between the 2 groups in the risks for cardiovascular death and hospitalization were also not significant . When the results from patients with a nonischemic cardiomyopathy in both the earlier trial and in the current study were combined , there was no evidence of a favorable or unfavorable effect of amlodipine on mortality ( hazard ratio : 0.97 ; 95 % CI : 0.83 to 1.13 ; p = 0.66 ) . Both trials , however , observed higher frequencies of peripheral edema and pulmonary edema and lower frequencies of uncontrolled hypertension and chest pain in patients treated with amlodipine . CONCLUSIONS These results of the current trial , viewed together with the results from the earlier study , indicate that amlodipine does not exert favorable effects on the clinical course of patients with heart failure , regardless of the presence or absence of underlying coronary artery disease . These findings indicate the need for great caution when striking benefits are observed in subgroups of patients or in trials not primarily design ed to assess such effects BACKGROUND The risk of cardiovascular events among patients with atrial fibrillation is high . We evaluated whether irbesartan , an angiotensin-receptor blocker , would reduce this risk . METHODS We r and omly assigned patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mm Hg to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo . These patients were already enrolled in one of two trials ( of clopidogrel plus aspirin versus aspirin alone or versus oral anticoagulants ) . The first co primary outcome was stroke , myocardial infa rct ion , or death from vascular causes ; the second was this composite outcome plus hospitalization for heart failure . RESULTS A total of 9016 patients were enrolled and followed for a mean of 4.1 years . The mean reduction in systolic blood pressure was 2.9 mm Hg greater in the irbesartan group than in the placebo group , and the mean reduction in diastolic blood pressure was 1.9 mm Hg greater . The first co primary outcome occurred at a rate of 5.4 % per 100 person-years in both groups ( hazard ratio with irbesartan , 0.99 ; 95 % confidence interval [ CI ] , 0.91 to 1.08 ; P=0.85 ) . The second co primary outcome occurred at a rate of 7.3 % per 100 person-years among patients receiving irbesartan and 7.7 % per 100 person-years among patients receiving placebo ( hazard ratio , 0.94 ; 95 % CI , 0.87 to 1.02 ; P=0.12 ) . The rates of first hospitalization for heart failure ( a prespecified secondary outcome ) were 2.7 % per 100 person-years among patients receiving irbesartan and 3.2 % per 100 person-years among patients receiving placebo ( hazard ratio , 0.86 ; 95 % CI , 0.76 to 0.98 ) . Among patients who were in sinus rhythm at baseline , there was no benefit of irbesartan in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded on 12-lead electrocardiography , nor was there a benefit in a subgroup that underwent transtelephonic monitoring . More patients in the irbesartan group than in the placebo group had symptomatic hypotension ( 127 vs. 64 ) and renal dysfunction ( 43 vs. 24 ) . CONCLUSIONS Irbesartan did not reduce cardiovascular events in patients with atrial fibrillation . ( Funded by Bristol-Myers Squibb and Sanofi-Aventis ; Clinical Trials.gov number , NCT00249795 . ) BACKGROUND In patients who have vascular disease or high-risk diabetes without heart failure , angiotensin-converting-enzyme ( ACE ) inhibitors reduce mortality and morbidity from cardiovascular causes , but the role of angiotensin-receptor blockers ( ARBs ) in such patients is unknown . We compared the ACE inhibitor ramipril , the ARB telmisartan , and the combination of the two drugs in patients with vascular disease or high-risk diabetes . METHODS After a 3-week , single-blind run-in period , patients underwent double-blind r and omization , with 8576 assigned to receive 10 mg of ramipril per day , 8542 assigned to receive 80 mg of telmisartan per day , and 8502 assigned to receive both drugs ( combination therapy ) . The primary composite outcome was death from cardiovascular causes , myocardial infa rct ion , stroke , or hospitalization for heart failure . RESULTS Mean blood pressure was lower in both the telmisartan group ( a 0.9/0.6 mm Hg greater reduction ) and the combination-therapy group ( a 2.4/1.4 mm Hg greater reduction ) than in the ramipril group . At a median follow-up of 56 months , the primary outcome had occurred in 1412 patients in the ramipril group ( 16.5 % ) , as compared with 1423 patients in the telmisartan group ( 16.7 % ; relative risk , 1.01 ; 95 % confidence interval [ CI ] , 0.94 to 1.09 ) . As compared with the ramipril group , the telmisartan group had lower rates of cough ( 1.1 % vs. 4.2 % , P<0.001 ) and angioedema ( 0.1 % vs. 0.3 % , P=0.01 ) and a higher rate of hypotensive symptoms ( 2.6 % vs. 1.7 % , P<0.001 ) ; the rate of syncope was the same in the two groups ( 0.2 % ) . In the combination-therapy group , the primary outcome occurred in 1386 patients ( 16.3 % ; relative risk , 0.99 ; 95 % CI , 0.92 to 1.07 ) ; as compared with the ramipril group , there was an increased risk of hypotensive symptoms ( 4.8 % vs. 1.7 % , P<0.001 ) , syncope ( 0.3 % vs. 0.2 % , P=0.03 ) , and renal dysfunction ( 13.5 % vs. 10.2 % , P<0.001 ) . CONCLUSIONS Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema . The combination of the two drugs was associated with more adverse events without an increase in benefit . ( Clinical Trials.gov number , NCT00153101 [ Clinical Trials.gov ] . ) 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 Background Atrial fibrillation ( AF ) is frequently encountered in patients with heart failure ( HF ) and is also a predictor of morbidity and mortality in this population . Recent experimental studies have shown electrical and structural atrial remodeling with increased fibrosis in animals with HF and have suggested a preventive effect of ACE inhibitors ( ACEi ) on the development of AF . To verify the hypothesis that ACEi prevent the development of AF in patients with HF , we conducted a retrospective analysis of the patients from the Montreal Heart Institute ( MHI ) included in the Studies Of Left Ventricular Dysfunction ( SOLVD ) . Methods and Results Clinical charts were review ed and serial ECGs interpreted by a single cardiologist blinded to drug allocation . Patients with AF or flutter on the baseline ECG were excluded . Baseline characteristics were obtained from the SOLVD data bases . The mean follow‐up was 2.9±1.0 years . Of the 391 patients r and omly assigned at MHI , 374 were in sinus rhythm at the time of r and om assignment , with 186 taking enalapril and 188 taking placebo .  Baseline characteristics were similar in the two groups except for a higher incidence of previous myocardial infa rct ion in the enalapril group . Fifty‐five patients had AF during the follow‐up : 10 ( 5.4 % ) in the enalapril group and 45 ( 24 % ) in the placebo group ( P<0.0001 ) . By Cox multivariate analysis , enalapril was the most powerful predictor for risk reduction of AF ( hazard ratio , 0.22 ; 95 % CI , 0.11 to 0.44 ; P<0.0001 ) . Conclusions Treatment with the ACEi enalapril markedly reduces the risk of development of atrial fibrillation in patients with left ventricular dysfunction . ( Circulation . 2003;107:2926‐2931 . Abstract Objective To investigate whether a low dose of the angiotensin converting enzyme ( ACE ) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria . Design R and omised , double blind , parallel group trial comparing ramipril ( 1.25 mg/day ) with placebo ( on top of usual treatment ) for cardiovascular and renal outcomes for at least three years . Setting Multicentre , primary care study conducted mostly by general practitioners in 16 European and north African countries . Participants 4912 patients with type 2 diabetes aged > 50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria ( urinary albumin excretion 20 mg/l in two consecutive sample s ) , and serum creatinine ≤ 150 μmol/l . Main outcome measures The primary outcome measure was the combined incidence of cardiovascular death , non-fatal myocardial infa rct ion , stroke , heart failure leading to hospital admission , and end stage renal failure . Results Participants were followed for 3 to 6 ( median 4 ) years . There were 362 primary events among the 2443 participants taking ramipril ( 37.8 per 1000 patient years ) and 377 events among the 2469 participants taking placebo ( 38.8 per 1000 patient years ; hazard ratio 1.03 ( 95 % confidence interval 0.89 to 1.20 , P = 0.65 ) ) . None of the components of the primary outcome was reduced . Ramipril  lowered systolic and diastolic blood pressures ( by 2.43 and 1.06 mm Hg respectively after two years ) and favoured regression from microalbuminuria ( 20 - 200 mg/l ) or proteinuria ( > 200mg/l ) to normal level ( < 20 mg/l ) or microalbuminuria ( P < 0.07 ) in 1868 participants who completed the study . Conclusions Low dose ( 1.25 mg ) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria , despite a slight decrease in blood pressure and urinary albumin . The cardiovascular benefits of a daily higher dose ( 10 mg ) ramipril observed elsewhere are not found with an eightfold lower daily dose BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors have been used for more than a decade to treat high blood pressure  , despite the lack of data from r and omised intervention trials to show that such treatment affects cardiovascular morbidity and mortality . The Captopril Prevention Project ( CAPPP ) is a r and omised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension . METHODS CAPPP was a prospect i ve , r and omised , open trial with blinded endpoint evaluation . 10,985 patients were enrolled at 536 health centres in Sweden and Finl and . Patients aged 25 - 66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were r and omly assigned captopril or conventional antihypertensive treatment ( diuretics , beta-blockers ) . Analysis was by intention-to-treat . The primary endpoint was a composite of fatal and non-fatal myocardial infa rct ion , stroke , and other cardiovascular deaths . FINDINGS Of 5492 patients assigned captopril and 5493 assigned conventional therapy , 14 and 13 , respectively , were lost to follow-up . Primary endpoint events occurred in 363 patients in the captopril group ( 11.1 per 1000 patient-years ) and 335 in the conventional-treatment group ( 10.2 per 1000 patient-years ; relative risk 1.05 [ 95 % CI 0.90 - 1.22 ] , p=0 - 52 ) . Cardiovascular mortality was lower with captopril than with conventional treatment ( 76 vs 95 events ; relative risk 0.77 [ 0.57 - 1 - 04 ] , p=0.092 ) , the rate of fatal and non-fatal myocardial infa rct ion was similar ( 162 vs 161 ) , but fatal and non-fatal stroke was more common with captopril ( 189 vs 148 ; 1.25 [ 1 - 01 - 1 - 55 ] . p=0.044 ) . INTERPRETATION Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality . The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients r and omised to conventional therapy We performed a post hoc analysis of the Systolic Hypertension in the Elderly Program data base to assess the incidence of atrial fibrillation in the elderly hypertensive population , its influence on cardiovascular events , and whether antihypertensive treatment can prevent its onset . The Systolic Hypertension in the Elderly Program was a double-blind placebo-controlled trial in 4736 subjects with isolated systolic hypertension aged ≥60 years . Atrial fibrillation was an exclusion criterion from the trial . Participants were r and omly assigned to stepped care treatment with chlorthalidone and atenolol ( n=2365 ) or placebo ( n=2371 ) . The occurrence of atrial fibrillation and cardiovascular events over 4.7 years as well as the determination of cause of death at 4.7 and 14.3 years were followed . Ninety-eight subjects ( 2.06 % ) developed atrial fibrillation over 4.7 years mean follow-up , without significant difference between treated and placebo groups . Atrial fibrillation increased the risk for : total cardiovascular events ( RR 1.69 ; 95 % CI 1.21 to 2.36 ) , rapid death ( RR 3.29 ; 95 % CI 1.08 to 10.00 ) , total ( RR 5.10 ; 95 % CI 3.12 to 8.37 ) and nonfatal left ventricular failure ( RR 5.31 ; 95 % CI 3.09 to 9.13 ) . All-cause and total cardiovascular death were significantly increased in the atrial fibrillation group at 4.7 years ( HR 3.44 ; 95 % CI 2.18 to 5.42 ; HR 2.39 ; 95 % CI 1.05 to 5.43 ) and 14.3 years follow-up ( HR 2.33 ; 95 % CI 1.83 to 2.98 ; HR 2.21 ; 95 % CI 1.54 to 3.17 ) . Atrial fibrillation increased the risk for total cardiovascular events , rapid death , and left ventricular failure . All-cause mortality and total cardiovascular mortality were significantly increased in hypertensives with atrial fibrillation at 4.7 and 14.3 years follow-up AIMS Large r and omized trials have shown that beta-blockers reduce mortality and hospital admissions in patients with heart failure . The effects of beta-blockers in elderly patients with a broad range of left ventricular ejection fraction are uncertain . The SENIORS study was performed to assess effects of the beta-blocker , nebivolol , in patients > /=70 years , regardless of ejection fraction . METHODS AND RESULTS We r and omly assigned 2128 patients aged > /=70 years with a history of heart failure ( hospital admission for heart failure within the previous year or known ejection fraction < /=35 % ) , 1067 to nebivolol  ( titrated from 1.25 mg once daily to 10 mg once daily ) , and 1061 to placebo . The primary outcome was a composite of all cause mortality or cardiovascular hospital admission ( time to first event ) . Analysis was by intention to treat . Mean duration of follow-up was 21 months . Mean age was 76 years ( SD 4.7 ) , 37 % were female , mean ejection fraction was 36 % ( with 35 % having ejection fraction > 35 % ) , and 68 % had a prior history of coronary heart disease . The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg . The primary outcome occurred in 332 patients ( 31.1 % ) on nebivolol compared with 375 ( 35.3 % ) on placebo [ hazard ratio ( HR ) 0.86 , 95 % CI 0.74 - 0.99 ; P=0.039 ] . There was no significant influence of age , gender , or ejection fraction on the effect of nebivolol on the primary outcome . Death ( all causes ) occurred in 169 ( 15.8 % ) on nebivolol and 192 ( 18.1 % ) on placebo ( HR 0.88 , 95 % CI 0.71 - 1.08 ; P=0.21 ) . CONCLUSION Nebivolol , a beta-blocker with vasodilating properties , is an effective and well-tolerated treatment for heart failure in the elderly 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 Background Atrial fibrillation ( AF ) is the most common arrhythmia and increases cardiovascular risk in hypertensive patients . Therefore , in the Valsartan Antihypertensive Long-term Use Evaluation ( VALUE ) a prespecified objective was to compare the effects of valsartan and amlodipine on new-onset AF . Methods A total of 15 245 hypertensive patients at high cardiovascular risk received valsartan 80–160 mg/day or amlodipine 5–10 mg/day combined with additional antihypertensive agents . Electrocardiograms were obtained every year and analyzed central ly for evidence of left ventricular hypertrophy and new-onset AF . Results At baseline ,  AF was diagnosed in 2.6 % of 7649 valsartan recipients and 2.6 % of 7596 amlodipine recipients . During antihypertensive treatment the incidence of at least one documented occurrence of new-onset AF was 3.67 % with valsartan and 4.34 % with amlodipine { unadjusted hazard ratio 0.843 , [ 95 % confidence interval ( CI ) : 0.713 , 0.997 ] , P = 0.0455}. The incidence of persistent AF was 1.35 % with valsartan and 1.97 % with amlodipine [ unadjusted hazard ratio 0.683 ( 95 % CI : 0.525 , 0.889 ) , P = 0.0046 ] . Conclusions Valsartan-based treatment reduced the development of new-onset AF , particularly sustained AF in hypertensive patients , compared with amlodipine-based therapy . These findings suggest that angiotensin II receptor blockers may result in greater benefits than calcium antagonists in hypertensive patients at risk of new-onset AF In 1972 - -1973 , 785 symptom-free men , aged 40 to 49 years , without target organ damage , with systolic blood pressures between 150 and 179 mm Hg and diastolic blood pressure below 110 mm Hg , were assigned at r and om to one of two groups : ( 406 to a drug treatment group and 379 to a control group ) for a five-year controlled drug treatment trial to evaluate the effect of therapy on cardiovascular complications . Drug treatment started with hydrochlorothiazide . If systolic blood pressure remained above 140 mm Hg and /or diastolic blood pressure above 90 mm Hg , alphamethyldopa was added . If there were side effects , methyldopa was replaced with propranolol . The control group was not given a placebo . The mean observation time was 66 months ( range 60 to 78 months ) . A difference in blood pressure between groups of about 17 mm Hg systolic and 10 mm Hg diastolic was maintained throughout the study . The study protocol had a rather low " ethical " blood pressure roof , 180 mm Hg systolic and /or 110 mm Hg diastolic . Seventeen percent of the control group had an increase in blood pressure above this level during the trial , and drug treatment was started . There was no effect on major cardiovascular morbidity comparing groups as established by r and omization , with 18 events in the treatment group and 20 events in the control group . There was no difference between the groups in total mortality and mortality from cardiovascular events . However , in the subgroups with diastolic blood pressure greater than or equal to 100 mm Hg before r and omization , there was a probable reduction in total morbidity from cardiovascular events in favor or the group receiving drug therapy , 7.6 and 16.4 percent events in the treated and control groups , respectively . Cerebrovascular events occurred only in the control group , 7 versus 0 . Two cases of fatal aortic aneurysms also occurred in the control group . Other " pressure " complications , such as marked left ventricular hypertrophy in the electrocardiogram and left ventricular failure , occurred only in the control group . However , regarding coronary heart disease , including sudden death , the incidence tended to be higher in the treated group , although it was not statistically significant . Only 13 men ( 1.7 percent ) failed to meet for regular examinations . At the end of the study these men were also followed up with regard to possible cardiovascular events OBJECTIVES Whether beta-blockers reduce atrial arrhythmias and , when added to an angiotensin-converting enzyme ( ACE ) inhibitor , ventricular arrhythmia is unknown . BACKGROUND Ventricular and atrial arrhythmias are common after acute myocardial infa rct ion ( AMI ) and are associated with a poor prognosis . Angiotensin-converting enzyme inhibitors reduce the incidence of both types of arrhythmia . METHODS The antiarrhythmic effect of carvedilol was examined in a placebo-controlled multicenter trial , the Carvedilol Post-Infa rct Survival Control in Left Ventricular Dysfunction ( CAPRICORN ) study , which enrolled 1,959 patients with reduced left ventricular systolic function after AMI , 98 % of whom were treated with an ACE inhibitor .  RESULTS The incidence of atrial fibrillation/flutter was 53 to 984 ( 5.4 % ) in the placebo group and 22 to 975 ( 2.3 % ) in the carvedilol group , giving a carvedilol/placebo  hazard ratio ( HR ) of 0.41 ( 95 % confidence interval [ CI ] 0.25 to 0.68 ; p = 0.0003 ) . The corresponding rates of ventricular tachycardia/flutter/fibrillation were 38 to 984 ( 3.9 % ) and 9 to 975 ( 0.9 % ) ( HR 0.24 , 95 % CI 0.11 to 0.49 ; p < 0.0001 ) . CONCLUSIONS Carvedilol has a powerful antiarrhythmic effect after AMI , even in patients already treated with an ACE inhibitor . Carvedilol suppresses atrial as well as ventricular arrhythmias in these patients BACKGROUND  Atrial fibrillation ( AF ) in heart failure ( HF ) is generally considered a negative prognostic factor . Recent studies indicate that the incidence of AF might be decreased by renin angiotensin aldosterone system inhibitors . The identification of a treatment to prevent its occurrence is likely to improve patients outcome . The aims of these subanalyses of Val-HeFT were to assess ( a ) the effects of valsartan in the prevention of AF , ( b ) the independent predictors of this event , and ( c ) the prognostic role of AF occurrence . METHODS AND RESULTS The occurrence of AF was evaluated based on adverse event reports in the patients with HF enrolled in Val-HeFT . Patients were r and omized to valsartan or placebo  on top of their prescribed treatments for HF . During the mean 23 months of follow-up , AF was reported in 287/4395 patients ( 6.53 % ) in sinus rhythm at baseline , of whom 113/2205 ( 5.12 % ) were allocated to valsartan and 174/2190 ( 7.95 % ) to placebo ( P = .0002 ) . Multivariable analysis showed that brain natriuretic peptide ( BNP ) levels at baseline above the median value ( HR 2.28 , 95 % CI 1.75 - 2.98 ) , age over 70 years ( HR 1.51 , 95 % CI 1.17 - 1.95 ) , male sex ( HR 1.53 , 95 % CI 1.07 - 2.18 ) , and the valsartan treatment ( HR 0.63 , 95 % CI 0.49 - 0.81 ) were independently associated with AF occurrence . Cox multivariable regression analysis showed that occurrence of AF was independently associated with a worse prognosis , with the adjusted hazard risks for all-cause mortality and combined mortality/morbidity of 1.40 ( 95 % CI 1.16 - 1.58 ) and 1.38 ( 95 % CI 1.12 - 1.70 ) , respectively . CONCLUSIONS The results of the present study demonstrate that ( a ) adding valsartan to prescribed therapy for HF significantly reduces the incidence of AF by 37 % ; ( b ) BNP level and advanced age were the strongest independent predictors for AF occurrence ; and ( c ) AF occurrence further worsens the outcome in patients with HF BACKGROUND The level to which systolic blood pressure should be controlled in hypertensive patients without diabetes remains unknown . We tested the hypothesis that tight control compared with usual control of systolic blood pressure would be beneficial in such patients . METHODS In this r and omised open-label trial undertaken in 44 centres in Italy , 1111 non-diabetic patients with systolic blood pressure 150 mm Hg or greater were r and omly assigned to a target systolic blood pressure of less than 140 mm Hg ( usual control ; n=553 ) or less than 130 mm Hg ( tight control ; n=558 ) . After stratification by centre , we used a computerised r and om function to allocate patients to either group . Observers who were unaware of r and omisation read electrocardiograms and adjudicated events . Open-label agents were used to reach the r and omised targets . The primary endpoint was the rate of electrocardiographic left ventricular hypertrophy 2 years after r and omisation . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00421863 . RESULTS Over a median follow-up of 2.0 years ( IQR 1.93 - 2.03 ) , systolic and diastolic blood pressure were reduced by a mean of 23.5/8.9 mm Hg ( SD 10.6/7.0 ) in the usual-control group and by 27.3/10.4 mm Hg ( 11.0/7.5 ) in the tight-control group ( between-group difference 3.8 mm Hg systolic [ 95 % CI 2.4 - 5.2 ] , p<0.0001 ; and 1.5 mm Hg diastolic [ 0.6 - 2.4 ] ; p=0.041 ) . The primary endpoint occurred in 82 of 483 patients ( 17.0 % ) in the usual-control group and in 55 of 484 patients ( 11.4 % ) of the tight-control group ( odds ratio 0.63 ; 95 % CI 0.43 - 0.91 ; p=0.013 ) . A composite cardiovascular endpoint occurred in 52 ( 9.4 % ) patients in the usual-control group and in 27 ( 4.8 % ) in the tight-control group ( hazard ratio 0.50 , 95 % CI 0.31 - 0.79 ; p=0.003 ) . Side-effects were rare and did not differ significantly between the two groups . INTERPRETATION Our findings lend support to a lower blood pressure goal than is recommended at present in non-diabetic patients with hypertension . FUNDING Boehringer-Ingelheim , Sanofi-Aventis , Pfizer Background Event adjudication in r and omized controlled trials is thought to be a necessary step to remove noise and potential bias from the results [ 1,2 ] . However , this hypothesis has not been widely evaluated . We conducted a meta- analysis of a series of cardiovascular outcomes trials and estimated the effect of adjudication on treatment estimates and on the number of outcomes included the trials . Methods Data were retrieved from all cardiovascular outcomes trials conducted at the Population Health Research Institute ( PHRI ) between 1993 and 2006 . These data included 10 trials with over 9000 events from 95 038 individuals . Differences in the log odds ratios between adjudicated and reported outcomes were analyzed and summarized using a ratio of odds ratios . Both masked and unmasked trials were included in this analysis . Results There were no effects of event adjudication on the estimates of treatment effect for the primary outcomes , myocardial infa rct ion ( MI ) , stroke , or cardiovascular/vascular death . For the trial primary outcomes , the effect of adjudication vs. reported events was OR ratio = 1.00 [ 95 % confidence interval ( CI ) : 0.97—1.02 ] . There were also no significant differences in the number of outcomes included in the trials . Results were the same for masked and unmasked trials . Limitations The number of unmasked trials were small , and this analysis was restricted to cardiovascular endpoints reported from trials managed by a single coordinating center , with similar sets of procedures . Individual patient data were not used for the analysis . Conclusions This systematic meta- analysis failed to detect any effect of event adjudication on study conclusions and the numbers of events included in the final analyses were minimally changed . Given the considerable effort required to perform adjudication , there is a need to demonstrate that this process does indeed increase the sensitivity of trials . There is a need to conduct more systematic analyses of the effect of event adjudication in other trials to determine if this process is truly worthwhile BACKGROUND Atrial fibrillation ( AF ) is frequent in patients with chronic heart failure ( CHF ) . Experimental and small patient studies have demonstrated that blocking the renin-angiotensin-aldosterone system may prevent AF . In the CHARM program , the effects of the angiotensin receptor blocker c and esartan on cardiovascular mortality and morbidity were evaluated in a broad spectrum of patients with symptomatic CHF . CHARM provided the opportunity to prospect ively determine the effect of c and esartan on the incidence of new AF in this CHF population . METHODS 7601 patients with symptomatic CHF and reduced or preserved left ventricular systolic function were r and omized to c and esartan ( target dose 32 mg once daily , mean dose 24 mg ) or placebo in the 3 component trials of CHARM . The major outcomes were cardiovascular death or CHF hospitalization and all-cause mortality . The incidence of new AF was a prespecified secondary outcome . Median follow-up was 37.7 months . A conditional logistic regression model for stratified data was used . RESULTS 6379 patients ( 83.9 % ) did not have AF on their baseline electrocardiogram . Of these , 392 ( 6.15 % ) developed AF during follow-up , 177 ( 5.55 % ) in the c and esartan group and 215 ( 6.74 % ) in the placebo group ( odds ratio 0.812 , 95 % CI 0.662 - 0.998 , P = .048 ) . After adjustment for baseline covariates , the odds ratio was 0.802 ( 95 % CI 0.650 - 0.990 , P = .039 ) . There was no heterogeneity of the effects of c and esartan in preventing AF between the 3 component trials ( P = .57 ) . CONCLUSIONS Treatment with the angiotensin receptor blocker c and esartan reduced the incidence of AF in a large , broadly-based , population of patients with symptomatic CHF AIMS The aim of this study was to investigate serious clinical outcomes associated with atrial fibrillation ( AF ) and the effects of routine blood pressure lowering on such outcomes in the presence or absence of AF , among individuals with type 2 diabetes . METHODS AND RESULTS About 11 140 patients with type 2 diabetes ( 7.6 % of whom had AF at baseline ) were r and omized to a fixed combination of perindopril and indapamide or placebo in the Action in Diabetes and Vascular Disease : preterAx and diamicroN-MR Controlled Evaluation ( ADVANCE ) study . We compared total mortality and cardiovascular disease outcomes and effects of r and omized treatment for 4.3 years on such outcomes between patients with and without AF at baseline . After multiple adjustments , AF was associated with a 61 % ( 95 % confidence interval 31 - 96 , P < 0.0001 ) greater risk of all-cause mortality and comparable higher risks of cardiovascular death , stroke , and heart failure ( all P < 0.001 ) . Routine treatment with a fixed combination of perindopril and indapamide produced similar relative , but greater absolute , risk reductions for all-cause and cardiovascular mortalities in patients with AF , compared with those without AF . The number of patients needed to be treated with perindopril-indapamide for 5 years to prevent one cardiovascular death was 42 for patients with AF and 120 for patients without AF at baseline . CONCLUSION Atrial fibrillation is relatively common in type 2 diabetes and is associated with substantially increased risks of death and cardiovascular events in patients with type 2 diabetes . This arrhythmia identifies individuals who are likely to obtain greater absolute benefits from blood pressure-lowering treatment . Atrial fibrillation in diabetic patients should be regarded as a marker of particularly adverse outcome and prompt aggressive management of all risk factors BACKGROUND Atrial fibrillation is the most common cardiac arrhythmia , and no current therapy is ideal for control of this condition . Experimental studies suggest that angiotensin II-receptor blockers ( ARBs ) can influence atrial remodeling , and some clinical studies suggest that they may prevent atrial fibrillation . METHODS We conducted a large , r and omized , prospect i ve , placebo-controlled , multicenter trial to test whether the ARB valsartan could reduce the recurrence of atrial fibrillation . We enrolled patients who were in sinus rhythm but had had either two or more documented episodes of atrial fibrillation in the previous 6 months or successful cardioversion for atrial fibrillation in the previous 2 weeks . To be eligible , patients also had to have underlying cardiovascular disease , diabetes , or left atrial enlargement . Patients were r and omly assigned to receive valsartan or placebo . The two primary end points were the time to a first recurrence of atrial fibrillation and the proportion of patients who had more than one recurrence of atrial fibrillation over the course of 1 year . RESULTS A total of 1442 patients were enrolled in the study .  Atrial fibrillation recurred in 371 of the 722 patients ( 51.4 % ) in the valsartan group , as compared with 375 of 720 ( 52.1 % ) in the placebo group ( adjusted hazard ratio , 0.97 ; 96 % confidence interval [ CI ] , 0.83 to 1.14 ; P=0.73 ) . More than one episode of atrial fibrillation occurred in 194 of 722 patients ( 26.9 % ) in the valsartan group and in 201 of 720 ( 27.9 % ) in the placebo group ( adjusted odds ratio , 0.89 ; 99 % CI , 0.64 to 1.23 ; P=0.34 ) . The results were similar in all predefined subgroups of patients , including those who were not receiving angiotensin-converting-enzyme inhibitors . CONCLUSIONS Treatment with valsartan was not associated with a reduction in the incidence of recurrent atrial fibrillation . ( Clinical Trials.gov number , NCT00376272 .
target: Antihypertensive therapy reduces the risk of atrial fibrillation modestly but benefits appear to be larger in patients with heart failure , with no clear evidence of benefit in patients without heart failure .
  Previous suggestions of class-specific effects could not be confirmed in this more comprehensive analysis
background: AIMS High blood pressure is known to be associated with future risk of atrial fibrillation .
  Whether such risks can be reduced with antihypertensive therapy is less clear .
  We conducted a systematic review and meta- analysis of large-scale r and omized trials that have reported the effect of antihypertensive agents on atrial fibrillation .