Jean-Lucien Rouleau

Rhythm control versus rate control for atrial fibrillation and heart failure.

BACKGROUND It is common practice to restore and maintain sinus rhythm in patients with atrial fibrillation and heart failure. This approach is based in part on data indicating that atrial fibrillation is a predictor of death in patients with heart failure and suggesting that the suppression of atrial fibrillation may favorably affect the outcome. However, the benefits and risks of this approach have not been adequately studied. METHODS We conducted a multicenter, randomized trial comparing the maintenance of sinus rhythm (rhythm control) with control of the ventricular rate (rate control) in patients with a left ventricular ejection fraction of 35% or less, symptoms of congestive heart failure, and a history of atrial fibrillation. The primary outcome was the time to death from cardiovascular causes. RESULTS A total of 1376 patients were enrolled (682 in the rhythm-control group and 694 in the rate-control group) and were followed for a mean of 37 months. Of these patients, 182 (27%) in the rhythm-control group died from cardiovascular causes, as compared with 175 (25%) in the rate-control group (hazard ratio in the rhythm-control group, 1.06; 95% confidence interval, 0.86 to 1.30; P=0.59 by the log-rank test). Secondary outcomes were similar in the two groups, including death from any cause (32% in the rhythm-control group and 33% in the rate-control group), stroke (3% and 4%, respectively), worsening heart failure (28% and 31%), and the composite of death from cardiovascular causes, stroke, or worsening heart failure (43% and 46%). There were also no significant differences favoring either strategy in any predefined subgroup. CONCLUSIONS In patients with atrial fibrillation and congestive heart failure, a routine strategy of rhythm control does not reduce the rate of death from cardiovascular causes, as compared with a rate-control strategy. (ClinicalTrials.gov number, NCT00597077.)

Comparison of Candesartan, Enalapril, and Their Combination in Congestive Heart Failure Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study: The RESOLVD Pilot Study Investigators

BACKGROUND We investigated the effects of candesartan (an angiotensin II antagonist) alone, enalapril alone, and their combination on exercise tolerance, ventricular function, quality of life (QOL), neurohormone levels, and tolerability in congestive heart failure (CHF). METHODS AND RESULTS Seven hundred sixty-eight patients in New York Heart Association functional class (NYHA-FC) II to IV with ejection fraction (EF) <0.40 and a 6-minute walk distance (6MWD) <500 m received either candesartan (4, 8, or 16 mg), candesartan (4 or 8 mg) plus 20 mg of enalapril, or 20 mg of enalapril for 43 weeks. There were no differences among groups with regard to 6MWD, NYHA-FC, or QOL. EF increased (P=NS) more with candesartan-plus-enalapril therapy (0.025+/-0.004) than with candesartan alone (0.015+/-0.004) or enalapril alone(0.015+/-0.005). End-diastolic (EDV) and end-systolic (ESV) volumes increased less with combination therapy (EDV 8+/-4 mL; ESV 1+/-4 mL; P<0.01) than with candesartan alone (EDV 27+/-4 mL; ESV 18+/-3 mL) or enalapril alone (EDV 23+/-7 mL; ESV 14+/-6 mL). Blood pressure decreased with combination therapy (6+/-1/4+/-1 mm Hg) compared with candesartan or enalapril alone (P<0.05). Aldosterone decreased (P<0.05) with combination therapy (23.2+/-5.3 pg/mL) at 17 but not 43 weeks compared with candesartan (0.7+/-7.8 pg/mL) or enalapril (-0.8+/-11. 3 pg/mL). Brain natriuretic peptide decreased with combination therapy (5.8+/-2.7 pmol/L; P<0.01) compared with candesartan (4. 4+/-3.8 pmol/L) and enalapril alone (4.0+/-5.0 pmol/L). CONCLUSIONS Candesartan alone was as effective, safe, and tolerable as enalapril. The combination of candesartan and enalapril was more beneficial for preventing left ventricular remodeling than either candesartan or enalapril alone.

Effect of Nesiritide in Patients with Acute Decompensated Heart Failure

BACKGROUND Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE)

Background—Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone. Methods and Results—We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, n=2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, n=2886) for a mean of 14.5 months. The primary end point—the combined risk of death or hospitalization for heart failure requiring intravenous treatment—was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03, P =0.187)—a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (P =0.024) and a 6% lower risk of death (P =0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal P =0.012). Conclusion—Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study.

Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril.

BACKGROUND Left ventricular enlargement after myocardial infarction increases the likelihood of an adverse outcome. In an echocardiographic substudy of the Survival and Ventricular Enlargement (SAVE) Trial, we assessed whether captopril would attenuate progressive left ventricular enlargement in patients with left ventricular dysfunction after acute myocardial infarction and, if so, whether this would be associated with improved clinical outcome. METHODS AND RESULTS Two-dimensional transthoracic echocardiograms were obtained in 512 patients at a mean of 11.1 +/- 3.2 days after infarction and were repeated at 1 year in 420 survivors. Left ventricular size was assessed as left ventricular cavity areas at end diastole and end systole and left ventricular function as percent change in cavity area from end diastole to end systole. Patients were randomly assigned to placebo or captopril, and the incidence of adverse cardiovascular events consisting of cardiovascular death, heart failure requiring either hospitalization or open-label angiotensin-converting enzyme inhibitor therapy, and recurrent infarction were determined over a follow-up period averaging 3.0 +/- 0.6 years. Irrespective of treatment assignment, baseline left ventricular systolic area and percent change in area were strong predictors of cardiovascular mortality and adverse cardiovascular events. At 1 year, left ventricular end-diastolic and end-systolic areas were larger in the placebo than in the captopril group (P = .038, P = .015, respectively), and percent change in cavity area was greater in the captopril group (P = .005). One hundred eleven of the 420 1-year survivors with 1-year echo measurements (26.4%) experienced a major adverse cardiovascular event, and these patients had more than a threefold greater increase in left ventricular cavity areas than those with an uncomplicated course. Sixty-nine patients with adverse cardiovascular events were in the placebo group compared with 42 patients in the captopril-treated group (a risk reduction of 35%, P = .010). CONCLUSIONS Two-dimensional echocardiography provides important and independent prognostic information in patients after infarction. Left ventricular enlargement and function after infarction are associated with the development of adverse cardiac events. Attenuation of ventricular enlargement with captopril in these patients was associated with a reduction in adverse events. This study demonstrates the linkage between attenuation of left ventricular enlargement by captopril after infarction and improved clinical outcome.

Coronary-Artery Bypass Surgery in Patients with Left Ventricular Dysfunction

BACKGROUND The role of coronary-artery bypass grafting (CABG) in the treatment of patients with coronary artery disease and heart failure has not been clearly established. METHODS Between July 2002 and May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). The primary outcome was the rate of death from any cause. Major secondary outcomes included the rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. RESULTS The primary outcome occurred in 244 patients (41%) in the medical-therapy group and 218 (36%) in the CABG group (hazard ratio with CABG, 0.86; 95% confidence interval [CI], 0.72 to 1.04; P=0.12). A total of 201 patients (33%) in the medical-therapy group and 168 (28%) in the CABG group died from an adjudicated cardiovascular cause (hazard ratio with CABG, 0.81; 95% CI, 0.66 to 1.00; P=0.05). Death from any cause or hospitalization for cardiovascular causes occurred in 411 patients (68%) in the medical-therapy group and 351 (58%) in the CABG group (hazard ratio with CABG, 0.74; 95% CI, 0.64 to 0.85; P<0.001). By the end of the follow-up period (median, 56 months), 100 patients in the medical-therapy group (17%) underwent CABG, and 555 patients in the CABG group (91%) underwent CABG. CONCLUSIONS In this randomized trial, there was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary end point of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; STICH ClinicalTrials.gov number, NCT00023595.).

Sphygmomanometrically Determined Pulse Pressure Is a Powerful Independent Predictor of Recurrent Events After Myocardial Infarction in Patients With Impaired Left Ventricular Function

BACKGROUND There is increasing evidence of a link between conduit vessel stiffness and cardiovascular events, although the association has never been tested in a large post-myocardial infarction patient population. METHODS AND RESULTS We evaluated the relationship between baseline pulse pressure, measured by sphygmomanometry 3 to 16 days after myocardial infarction, and subsequent adverse clinical events in the 2231 patients enrolled in the SAVE Trial. Increased pulse pressure was associated with increased age, left ventricular ejection fraction, female sex, history of prior infarction, diabetes, and hypertension and use of digoxin and calcium channel blockers. Over a 42-month period, there were 503 deaths, 422 cardiovascular deaths, and 303 myocardial infarctions. Pulse pressure was significantly related to each of these end points as a univariate predictor. In a multivariate analysis, pulse pressure remained a significant predictor of total mortality (relative risk, 1.08 per 10 mm Hg increment in pulse pressure; 95% CI, 1.00 to 1.17; P<.05) and recurrent myocardial infarction (relative risk, 1.12; 95% CI, 1.01 to 1.23; P<.05) after control for age; left ventricular ejection fraction; mean arterial pressure; sex; treatment arm (captopril or placebo); smoking history; history of prior myocardial infarction, diabetes, or hypertension; and treatment with beta-blockers, calcium channel blockers, digoxin, aspirin, or thrombolytic therapy. CONCLUSIONS These data provide strong evidence for a link between pulse pressure, which is related to conduit vessel stiffness, and subsequent cardiovascular events after myocardial infarction in patients with left ventricular dysfunction.

Identification of Serum Soluble ST2 Receptor as a Novel Heart Failure Biomarker

Background—Using genomic technology, we previously identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes. The soluble receptor form of ST2 is secreted and detectable in human serum. This study tested the hypothesis that soluble ST2 levels in the serum of patients with severe chronic heart failure are increased in patients with neurohormonal activation. Methods and Results—Serum samples, clinical variables, and neurohormone levels from the PRAISE-2 heart failure trial (NYHA functional class III-IV; end point, mortality or transplantation) were analyzed. ST2 serum measurements were performed with ELISA on samples from 161 patients obtained at trial enrollment and from 139 of the same patients obtained 2 weeks after trial enrollment. Baseline ST2 levels were correlated with baseline B-type natriuretic peptide (BNP) levels (r =0.36, P <0.0001), baseline proatrial natriuretic peptide (ProANP) levels (r =0.36, P <0.0001), and baseline norepinephrine levels (r =0.39, P <0.0001). The change in ST2 was significant as a univariate predictor of subsequent mortality or transplantation (P =0.048), as was baseline BNP (P <0.0001) and baseline ProANP (P <0.0001). In multivariate models including BNP and ProANP, the change in ST2 remained significant as a predictor of mortality or transplantation independent of BNP and ProANP. Conclusions—Serum soluble ST2 is a novel biomarker for neurohormonal activation in patients with heart failure. In patients with severe chronic NYHA class III to IV heart failure, the change in ST2 levels is an independent predictor of subsequent mortality or transplantation.

Expression and Regulation of ST2, an Interleukin-1 Receptor Family Member, in Cardiomyocytes and Myocardial Infarction

Background—We identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes and hypothesized that ST2 participates in the acute myocardial response to stress and injury. Methods and Results—ST2 mRNA was induced in cardiac myocytes by mechanical strain (4.7±0.9-fold) and interleukin-1&bgr; (2.0±0.2-fold). Promoter analysis revealed that the proximal and not the distal promoter of ST2 is responsible for transcriptional activation in cardiac myocytes by strain and interleukin-1&bgr;. In mice subjected to coronary artery ligation, serum ST2 was transiently increased compared with unoperated controls (20.8±4.4 versus 0.8±0.8 ng/mL, P <0.05). Soluble ST2 levels were increased in the serum of human patients (N=69) 1 day after myocardial infarction and correlated positively with creatine kinase (r =0.41, P <0.001) and negatively with ejection fraction (P =0.02). Conclusions—These data identify ST2 release in response to myocardial infarction and suggest a role for this innate immune receptor in myocardial injury.

Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. SAVE Investigators.

BACKGROUND In the Survival and Ventricular Enlargement (SAVE) trial, recurrent myocardial infarction (MI) was the most important predictor of a poor outcome and conferred a sevenfold increase in risk of death. The purpose of this study was to determine the predictors of recurrent MI in study participants and to examine the influence of the angiotensin-converting enzyme inhibitor captopril on this and other myocardial ischemic events. METHODS AND RESULTS The 2231 patients had survived the acute phase of MI (3 to 16 days) and had a radionuclide ventricular ejection fraction < or = 40%. Patients were randomly assigned to receive double-blind treatment with either placebo or captopril and were followed for an average of 42 months. The influence of captopril on recurrent MI, cardiac revascularization procedures, and hospitalization with unstable angina was examined. The likelihood of recurrent MI was greater in patients with an MI or functional disability before the index infarction and higher systolic pressure (all P < .001) but was not influenced by baseline left ventricular ejection fraction. Therapy with captopril reduced the risk of development of recurrent MI by 25% (95% confidence intervals, 5% to 40%; P = .015) and the risk of death after recurrent MI by 32% (95% confidence intervals, 4% to 51%; P = .029). Captopril-assigned patients were also less likely to require cardiac revascularization procedures (P = .010), but hospitalization for unstable angina was unaltered. When all three of these major coronary ischemic events were considered together, captopril therapy reduced the risk (14% risk reduction; 95% confidence intervals, 0% to 26%; P = .047). CONCLUSIONS In post-MI patients with asymptomatic left ventricular dysfunction, long-term administration of captopril reduced recurrence of MI and the need for cardiac revascularization but had no influence on the rate of hospitalization with a discharge diagnosis of unstable angina. The finding that the recurrence of MI was independent of left ventricular ejection fraction suggests that captopril could be useful in preventing recurrent MI in patients with more preserved left ventricular function. The need for cardiac revascularization was reduced in patients receiving long-term captopril therapy, suggesting either an anti-ischemic effect or the ability of the angiotensin-converting enzyme inhibitor to modify the atherosclerotic process in survivors of MI.