Coronary artery disease, coronary revascularization, and outcomes in chronic advanced systolic heart failure.

BACKGROUND: Associations between coronary artery disease (CAD) and outcomes in systolic heart failure (HF) and that between coronary artery bypass graft (CABG) surgery and outcomes in patients with HF and CAD have not been examined using propensity-matched designs. METHODS: Of the 2707 patients with advanced chronic systolic HF in the Beta-Blocker Evaluation of Survival Trial (BEST), 1593 had a history of CAD, of whom 782 had prior CABG. Using propensity scores for CAD we assembled a cohort of 458 pairs of CAD and no-CAD patients. Propensity scores for prior CABG in those with CAD were used to assemble 500 pairs of patients with and without CABG. Matched patients were balanced on 68 baseline characteristics. RESULTS: All-cause mortality occurred in 33% and 24% of matched patients with and without CAD respectively, during 26 months of median follow-up (hazard ratio {HR} when CAD was compared with no-CAD, 1.41; 95% confidence interval {CI}, 1.11-1.81; P=0.006). HR's (95% CIs) for CAD-associated cardiovascular mortality, HF mortality, and sudden cardiac death (SCD) were 1.53 (1.17-2.00; P=0.002), 1.44 (0.92-2.25; P=0.114) and 1.76 (1.21-2.57; P=0.003) respectively. CAD had no association with hospitalization. Among matched patients with HF and CAD, all-cause mortality occurred in 32% and 39% of those with and without prior CABG respectively (HR for CABG, 0.77; 95% CI, 0.62-0.95; P=0.015). CONCLUSIONS: In patients with advanced chronic systolic HF, CAD is associated with increased mortality, and in those with CAD, prior CABG seems to be associated with reduced all-cause mortality but not SCD.

Effects of peripheral arterial disease on outcomes in advanced chronic systolic heart failure: a propensity-matched study.

BACKGROUND: The effect of peripheral arterial disease (PAD) on outcomes in patients with chronic heart failure (HF) has not been examined in propensity-matched studies. METHODS AND RESULTS: Of the 2689 patients with advanced chronic systolic HF in the Beta-Blocker Evaluation of Survival Trial, 441 had a history of PAD. Propensity scores for a history of PAD, calculated for each patient using a multivariable logistic regression model, were used to assemble a matched cohort of 299 and 1015 patients, respectively, with and without PAD who were well balanced on 65 measured baseline characteristics. Cox regression models were used to estimate hazard ratios and 95% CIs for associations between PAD and outcomes during 4.1 years of follow-up. Patients had a mean age of 63+/-11 years, 19% were women, and 19% were black. All-cause mortality occurred in 43% and 33% of patients with and without a history of PAD, respectively (hazard ratio when PAD was compared with no history of PAD, 1.40; 95% CI, 1.14 to 1.72; P=0.001). All-cause hospitalization occurred in 75% and 63% of patients with and without PAD, respectively (hazard ratio when PAD was compared with no history of PAD, 1.36; 95% CI, 1.16 to 1.58; P<0.0001). PAD-associated hazard ratios for cardiovascular mortality, HF mortality, and HF hospitalization were 1.31 (95% CI, 1.04 to 1.63; P=0.019), 1.40 (95% CI, 0.97 to 2.02; P=0.076), and 1.05 (95% CI, 0.86 to 1.29; P=0.635), respectively. CONCLUSIONS: In a well-balanced propensity-matched population of chronic systolic HF patients, a history of PAD was independently associated with increased mortality and hospitalization.

Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: the Beta-blocker Evaluation of Survival Trial (BEST).

OBJECTIVES: The aim of this study was to determine echocardiographic predictors of outcome in patients with advanced heart failure (HF) due to severe left ventricular (LV) systolic dysfunction in the Beta-blocker Evaluation of Survival Trial (BEST). BACKGROUND: Previous studies indicate that echocardiographic measurements of LV size and function, mitral deceleration time, and mitral regurgitation (MR) predict adverse outcomes in HF. However, complete quantitative echocardiograms evaluating all of these parameters have not been reported in a prospective randomized clinical trial in the era of modern HF therapy. METHODS: Complete echocardiograms were performed in 336 patients at 26 sites and analyzed by a core laboratory. A Cox proportional-hazards regression model was used to determine which echocardiographic variables predicted the primary end point of death or the secondary end point of death, HF hospitalization, or transplant. Significant variables were then entered into a multivariable model adjusted for clinical and demographic covariates. RESULTS: On multivariable analysis adjusted for clinical covariates, only LV end-diastolic volume index predicted death (events = 75), with a cut point of 120 ml/m(2). Three echocardiographic variables predicted the combined end point of death (events = 75), HF hospitalization (events = 97), and transplant (events = 9): LV end-diastolic volume index, mitral deceleration time, and the vena contracta width of MR. Optimal cut points for these variables were 120 ml/m(2), 150 ms, and 0.4 cm, respectively. CONCLUSIONS: Echocardiographic predictors of outcome in advanced HF include LV end-diastolic volume index, mitral deceleration time, and vena contracta width. These variables indicate that LV remodeling, increased LV stiffness, and MR are independent predictors of outcome in patients with advanced HF.

Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with beta-blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST).

BACKGROUND: beta-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. METHODS AND RESULTS: Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol (r=-0.72, P<0.0001) and was the most significant multivariate predictor of change in LVEF (P=0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687+/-333 versus 420+/-246 pg/mL, P<0.05) and greater decrease in plasma norepinephrine in response to bucindolol (-249+/-171 versus -35+/-277 pg/mL, P<0.05). CONCLUSIONS: This study suggests a direct relationship between contractile reserve and improvement in LVEF with beta-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.

Digoxin.

After 200 years of use, digitalis still appears to have a place in our armamentarium for heart failure and atrial fibrillation despite the proven survival benefits with ACE inhibitors and beta-blockers. Digoxin therapy is inexpensive and well tolerated and may result in considerable savings. Digoxin is the only oral inotrope that does not increase mortality in heart failure patients, particularly if low doses are being used. Digoxin therapy should be used in patients with systolic heart failure who continue to have signs and symptoms despite therapeutic doses of ACE inhibitors or diuretics or in patients with atrial fibrillation with or without heart failure for rate control.

Treating patients with severe heart failure.

The roles of the renin-angiotensin system and the sympathetic nervous system in the pathogenesis and progression of heart failure are well established. Angiotensin-converting enzyme (ACE) inhibitors and ss-adrenergic-receptor antagonists have been shown to slow down and, in many cases, reverse the process of cardiac remodeling, thus leading to improved cardiac function and clinical outcomes in patients with heart failure. Standard treatment for heart failure consists of a diuretic, an ACE inhibitor (or angiotensin-receptor blocker if the ACE inhibitor is not well tolerated), a ss-blocker, and low-dose digoxin (if needed). Numerous clinical trials have demonstrated reductions in morbidity and mortality with this combination of medications. However, the majority of patients included in these clinical trials had New York Heart Association (NYHA) functional class II or III heart failure. Because few patients with NYHA class IV heart failure have been evaluated in clinical trials, the treatment approach in this patient population is less well defined. The purpose of this article is to review the results of clinical trials with ss-blockers that included patients with severe heart failure.

A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure.

BACKGROUND: Although beta-adrenergic-receptor antagonists reduce morbidity and mortality in patients with mild-to-moderate chronic heart failure, their effect on survival in patients with more advanced heart failure is unknown. METHODS: A total of 2708 patients with heart failure designated as New York Heart Association (NYHA) functional class III (in 92 percent of the patients) or IV (in 8 percent) and a left ventricular ejection fraction of 35 percent or lower were randomly assigned to double-blind treatment with either bucindolol (1354 patients) or placebo (1354 patients) and followed for the primary end point of death from any cause. RESULTS: The data and safety monitoring board recommended stopping the trial after the seventh interim analysis. At that time, there was no significant difference in mortality between the two groups (unadjusted P=0.16). The results presented here are based on complete follow-up at the time of study termination (average, 2.0 years). There were a total of 449 deaths in the placebo group (33 percent) and 411 deaths in the bucindolol group (30 percent; adjusted P=0.13). The risk of the secondary end point of death from cardiovascular causes was lower in the bucindolol group (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99), as was the risk of heart transplantation or death (hazard ratio, 0.87; 95 percent confidence interval, 0.77 to 0.99). CONCLUSIONS: In a demographically diverse group of patients with NYHA class III and IV heart failure, bucindolol resulted in no significant overall survival benefit.

The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.

Previous trials (Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS] II) have demonstrated a mortality benefit of beta-adrenergic blockade in patients with mild to moderate heart failure. The recent Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial has extended these results to a more advanced patient population. This trial did not, however, include patients who could not reach compensation, patients with far advanced heart failure symptoms, or a significant number of black patients. Future studies of beta-blockade may focus on these patients or patients with asymptomatic left ventricular dysfunction.