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Introduction: The relative effectiveness of the implantable cardioverter defibrillator (ICD) and antiarrhythmic drugs (AADs) varies with left ventricular ejection fraction (LVEF). However, once an ICD or AAD treatment strategy is chosen, the degree to which the LVEF influences survival is unknown. This article addresses that question., Methods and Results: Using patient data from the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, the impact of LVEF on prognosis of patients who were treated with either an ICD or AAD was assessed. Survival within each quintile of LVEF was estimated by the method of Kaplan-Meier for patients treated with either the ICD or AADs. The Cox proportional hazards model was used to investigate the prognostic value of LVEF for estimating survival after adjustment for other baseline covariates among all patients in the subgroups treated by ICD or AAD. In the highest two quintiles of LVEF, survival was comparable in AAD-treated and ICD-treated patients. In the AAD-treated patients, higher LVEF was significantly and independently associated with survival free of all-cause mortality and arrhythmic death. In the ICD-treated patients, however, the statistical significance of the association was lost and only a trend toward greater survival was present. Death due to congestive heart failure remained independently and significantly associated with survival in both AAD-treated and ICD-treated patients., Conclusion: In patients treated with AADs but not patients treated with ICDs, survival is strongly associated with LVEF. The absence of a statistically significant association in the ICD patients is likely related to the effectiveness of the ICD in treating malignant ventricular arrhythmias, but a chance lack of association cannot be excluded.

Background: Black patients with heart failure have a poorer prognosis than white patients, a difference that has not been adequately explained. Whether racial differences in the response to drug treatment contribute to differences in outcome is unclear. To address this issue, we pooled and analyzed data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, two large, randomized trials comparing enalapril with placebo in patients with left ventricular dysfunction., Methods: We used a matched-cohort design in which up to four white patients were matched with each black patient according to trial, treatment assignment, sex, left ventricular ejection fraction, and age. A total of 1196 white patients (580 from the prevention trial and 616 from the treatment trial) were matched with 800 black patients (404 from the prevention trial and 396 from the treatment trial). The average duration of follow-up was 35 months in the prevention trial and 33 months in the treatment trial., Results: The black patients and the matched white patients had similar demographic and clinical characteristics, but the black patients had higher rates of death from any cause (12.2 vs. 9.7 per 100 person-years) and of hospitalization for heart failure (13.2 vs. 7.7 per 100 person-years). Despite similar doses of drug in the two groups, enalapril therapy, as compared with placebo, was associated with a 44 percent reduction (95 percent confidence interval, 27 to 57 percent) in the risk of hospitalization for heart failure among the white patients (P<0.001) but with no significant reduction among black patients (P=0.74). At one year, enalapril therapy was associated with significant reductions from base line in systolic blood pressure (by a mean [+/-SD] of 5.0+/-17.1 mm Hg) and diastolic blood pressure (3.6+/-10.6 mm Hg) among the white patients, but not among the black patients. No significant change in the risk of death was observed in association with enalapril therapy in either group., Conclusions: Enalapril therapy is associated with a significant reduction in the risk of hospitalization for heart failure among white patients with left ventricular dysfunction, but not among similar black patients. This finding underscores the need for additional research on the efficacy of therapies for heart failure in black patients.

Objectives: The study evaluated the relationship between light-to-moderate alcohol consumption and prognosis in patients with left ventricular (LV) systolic dysfunction., Background: Although chronic consumption of large amounts of alcohol can lead to cardiomyopathy, the effects of light-to-moderate alcohol consumption in patients with LV dysfunction are unknown., Methods: The relationship between light-to-moderate alcohol consumption and prognosis was assessed in participants in the Studies of Left Ventricular Dysfunction (SOLVD), all of whom had ejection fraction values < or = 0.35. Baseline characteristics and event rates of patients who consumed 1 to 14 drinks per week (light-to-moderate drinkers, n = 2,594) were compared with those of patients who reported no alcohol consumption (nondrinkers, n = 3,719). The association between light-to-moderate alcohol consumption and prognosis was evaluated using Cox proportional hazards analysis, controlling for baseline differences and important covariates., Results: Mortality rates were lower among light-to-moderate drinkers than among nondrinkers (7.2 vs. 9.4 deaths/100 person-years, p < 0.001). Among patients with ischemic LV dysfunction, light-to-moderate alcohol consumption was independently associated with a reduced risk of all-cause mortality (RR [relative risk] 0.85, p = 0.01), particularly for death from myocardial infarction (RR 0.55, p < 0.001). The risks of cardiovascular death, death from progressive heart failure, arrhythmic death, and hospitalization for heart failure were similar for light-to-moderate drinkers and nondrinkers in this group. Among patients with nonischemic LV dysfunction, light-to-moderate alcohol consumption had no significant effect on mortality (RR 0.93, p = 0.5)., Conclusions: Light-to-moderate alcohol consumption is not associated with an adverse prognosis in patients with LV systolic dysfunction, and it may reduce the risk of fatal myocardial infarction in patients with ischemic LV dysfunction.

Objectives: The present analysis examines the prognostic implications of moderate renal insufficiency in patients with asymptomatic and symptomatic left ventricular systolic dysfunction., Background: Chronic elevations in intracardiac filling pressures may lead to progressive ventricular dilation and heart failure progression. The ability to maintain fluid balance and prevent increased intracardiac filling pressures is critically dependent on the adequacy of renal function., Methods: This is a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) Trials, in which moderate renal insufficiency is defined as a baseline creatinine clearance <60 ml/min, as estimated from the Cockroft-Gault equation., Results: In the SOLVD Prevention Trial, multivariate analyses demonstrated moderate renal insufficiency to be associated with an increased risk for all-cause mortality (Relative Risk [RR] 1.41; p = 0.001), largely explained by an increased risk for pump-failure death (RR 1.68; p = 0.007) and the combined end point death or hospitalization for heart failure (RR 1.33; p = 0.001). Likewise, in the Treatment Trial, multivariate analyses demonstrated moderate renal insufficiency to be associated with an increased risk for all-cause mortality (RR 1.41; p = 0.001), also largely explained by an increased risk for pump-failure death (RR 1.49; p = 0.007) and the combined end point death or hospitalization for heart failure (RR 1.45; p = 0.001)., Conclusions: Even moderate degrees of renal insufficiency are independently associated with an increased risk for all-cause mortality in patients with heart failure, largely explained by an increased risk of heart failure progression. These data suggest that, rather than simply being a marker of the severity of underlying disease, the adequacy of renal function may be a primary determinant of compensation in patients with heart failure, and therapy capable of improving renal function may delay disease progression.

beta-Blockers have emerged as an important therapy in patients with symptomatic left ventricular systolic dysfunction. Early studies demonstrated that beta-blocker therapy improved left ventricular function, reduced neurohumoral activity and reduced heart failure symptoms in these patients. While none of these small studies demonstrated a significant benefit in terms of overall survival, several meta-analyses suggested that beta-blocker therapy could, in fact, reduce mortality in patients with left ventricular systolic dysfunction and mild to moderate heart failure symptoms (New York Heart Association class II or III). Three large, recently completed, trials have confirmed the benefit of beta-blockade in these patients. This report reviews some of the initial clinical studies of beta-blockade in heart failure, examines the findings of the three large multicentre trials and other relevant research. Finally, ongoing trials designed to assess the relative efficacy of different beta-blockers and evaluate the utility of beta-blockade in specific subsets of patients with heart failure are discussed.

Objectives: We sought to assess the effect of baseline ejection fraction on survival difference between patients with life-threatening ventricular arrhythmias who were treated with an antiarrhythmic drug (AAD) or implantable cardioverter-defibrillator (ICD)., Background: The Antiarrhythmics Versus Implantable Defibrillators (AVID) study demonstrated improved survival in patients with ventricular fibrillation or ventricular tachycardia with a left ventricular ejection fraction (LVEF) < or =0.40 or hemodynamic compromise., Methods: Survival differences between AAD-treated and ICD-treated patients entered into the AVID study (patients presenting with sustained ventricular arrhythmia associated with an LVEF < or =0.40 or hemodynamic compromise) were compared at different levels of ejection fraction., Results: In patients with an LVEF > or =0.35, there was no difference in survival between AAD-treated and ICD-treated patients. A test for interaction was not significant, but had low power to detect an interaction. For patients with an LVEF 0.20 to 0.34, there was a significantly improved survival with ICD as compared with AAD therapy. In the smaller subgroup with an LVEF <0.20, the same magnitude of survival difference was seen as that in the 0.20 to 0.34 LVEF subgroup, but the difference did not reach statistical significance., Conclusions: These data suggest that patients with relatively well-preserved LVEF (> or =0.35) may not have better survival when treated with the ICD as compared with AADs. At a lower LVEF, the ICD appears to offer improved survival as compared with AADs. Prospective studies with larger patient numbers are needed to assess the effect of relatively well-preserved ejection fraction (> or =0.35) on the relative treatment effect of AADs and the ICDs.

Background-Treatment with diuretics has been reported to increase the risk of arrhythmic death in patients with hypertension. The effect of diuretic therapy on arrhythmic death in patients with left ventricular dysfunction is unknown. Methods and Results-We conducted a retrospective analysis of 6797 patients with an ejection fraction <0.36 enrolled in the Studies Of Left Ventricular Dysfunction (SOLVD) to assess the relation between diuretic use at baseline and the subsequent risk of arrhythmic death. Participants receiving a diuretic at baseline were more likely to have an arrhythmic death than those not receiving a diuretic (3.1 vs 1.7 arrhythmic deaths per 100 person-years, P=0.001). On univariate analysis, diuretic use was associated with an increased risk of arrhythmic death (relative risk [RR] 1.85, P=0.0001). After controlling for important covariates, diuretic use remained significantly associated with an increased risk of arrhythmic death (RR 1.37, P=0.009). Only non-potassium-sparing diuretic use was independently associated with arrhythmic death (RR 1.33, P=0.02). Use of a potassium-sparing diuretic, alone or in combination with a non-potassium-sparing diuretic, was not independently associated with an increased risk of arrhythmic death (RR 0.90, P=0.6). Conclusions-In SOLVD, baseline use of a non-potassium-sparing diuretic was associated with an increased risk of arrhythmic death, whereas baseline use of a potassium-sparing diuretic was not. These data suggest that diuretic-induced electrolyte disturbances may result in fatal arrhythmias in patients with systolic left ventricular dysfunction.

Left ventricular (LV) systolic dysfunction, as indicated by a reduced LV ejection fraction (EF) is a potent predictor of cardiovascular mortality. Radionuclide angiography accurately and reproducibly assesses LVEF; however, echocardiography is used more frequently in clinical practice. Whether these methods predict similar mortality has not been fully investigated. We performed a retrospective analysis of patients with baseline radionuclide angiographic (RNA; n = 4,330) and echocardiographic (echo; n = 1,376) based EFs < or =0.35 who were enrolled in the Studies Of Left Ventricular Dysfunction (SOLVD) to address this hypothesis. After adjusting for important prognostic variables, the risk of death (RR 1.15; 95% confidence interval 1.01 to 1.30; p = 0.03) and of cardiovascular death (RR 1.15; 95% confidence interval 1.01 to 1.32; p = 0.04) was higher for patients with ECG-based EFs. To compare the 2 techniques across a range of EF values, we divided the cohort into tertiles of EF. The adjusted risk estimates for all-cause and cardiovascular mortality were similar within each tertile. Of note, the mortality difference in patients with echo- versus RNA-based EFs was most prominent in women. Further, patients with echo-based EFs had significantly higher mortality at sites where this technique was less frequently used to assess the EF. Thus, for a given EF < or =0.35, an echo-based value was associated with a higher risk of death compared with the RNA-based method of measurement. These data suggest that EF values determined by echocardiography and radionuclide angiography predict different mortality and this may, in part, be related to technical proficiency as well as patient characteristics.

We conducted a retrospective analysis of the Studies Of Left Ventricular Dysfunction (SOLVD) trials to assess the predictive value of the baseline white blood cell (WBC) count on mortality. Mortality was higher in participants with a baseline WBC count >7,000 compared to those with a baseline WBC < or =7,000 (27% vs 21%, p <0.0001). After controlling for important covariates, each increase in WBC count of 1,000/mm3 was significantly associated with an increased risk of all-cause mortality (relative risk [RR] 1.05, p <0.001). Overall, compared with a baseline WBC count < or =7,000, a baseline WBC count >7,000 was significantly associated with an increased risk of all-cause mortality (RR 1.22, p = 0.001). In participants with ischemic left ventricular (LV) dysfunction, a WBC count >7,000 remained significantly associated with an increased risk of all-cause mortality (RR 1.26, p <0.001), whereas in participants with nonischemic LV dysfunction there was no relation between WBC count and mortality (RR 1.08, p = 0.5). Thus, baseline WBC is an independent predictor of mortality in patients with LV dysfunction, specifically in those with ischemic cardiomyopathy.

Objectives: The purpose of this study was to evaluate the relationship of baseline pulse pressure and mean arterial pressure to mortality in patients with left ventricular dysfunction., Background: Increased conduit vessel stiffness increases pulse pressure and pulsatile load, potentially contributing to adverse outcomes in patients with left ventricular dysfunction., Methods: Pulse and mean arterial pressure were analyzed for their effect on mortality, adjusting for other modifiers of risk, using Cox proportional hazards regression analysis of data collected from 6,781 patients randomized into the Studies of Left Ventricular Dysfunction trials., Results: Pulse and mean arterial pressure were related positively to each other, age, ejection fraction and prevalence of diabetes and hypertension and inversely to prior myocardial infarction and beta-adrenergic blocking agent use. Higher pulse pressure was associated with increased prevalence of female gender, greater calcium channel blocking agent, digoxin and diuretic use, lower heart rate and a higher rate of reported smoking history. Higher mean arterial pressure was associated with higher heart rate, lower calcium channel blocker and digoxin use and lower New York Heart Association functional class. Over a 61-month follow-up 1,582 deaths (1,397 cardiovascular) occurred. In a multivariate analysis adjusting for the above covariates and treatment assignment, higher pulse pressure remained an independent predictor of total and cardiovascular mortality (total mortality relative risk, 1.05 per 10 mm Hg increment; 95% confidence interval, 1.01 to 1.10; p = 0.02). Mean arterial pressure was inversely related to total and cardiovascular mortality (total mortality relative risk, 0.89; 95% confidence interval, 0.85 to 0.94; p <0.0001)., Conclusions: One noninvasive blood pressure measurement provides two independent prognostic factors for survival. Increased conduit vessel stiffness, as assessed by pulse pressure, may contribute to increased mortality in patients with left ventricular dysfunction, independent of mean arterial pressure.

Objectives: This analysis was performed to assess whether beta-adrenergic blocking agent use is associated with reduced mortality in the Studies of Left Ventricular Dysfunction (SOLVD) and to determine if this relationship is altered by angiotensin-converting enzyme (ACE) inhibitor use., Background: The ability of beta-blockers to alter mortality in patients with asymptomatic left ventricular dysfunction is not well defined. Furthermore, the effect of beta-blocker use, in addition to an ACE inhibitor, on these patients has not been fully addressed., Methods: This retrospective analysis evaluated the association of baseline beta-blocker use with mortality in 4,223 mostly asymptomatic Prevention trial patients, and 2,567 symptomatic Treatment trial patients., Results: The 1,015 (24%) Prevention trial patients and 197 (8%) Treatment trial patients receiving beta-blockers had fewer symptoms, higher ejection fractions and different use of medications than patients not receiving beta-blockers. On univariate analysis, beta-blocker use was associated with significantly lower mortality than nonuse in both trials. Moreover, a synergistic reduction in mortality with use of both a beta-blocker and enalapril was suggested in the Prevention trial. After adjusting for important prognostic variables with Cox multivariate analysis, the association of beta-adrenergic blocking agent use with reduced mortality remained significant for Prevention trial patients receiving enalapril. Lower rates of arrhythmic and pump failure death and risk of death or hospitalization for heart failure were observed., Conclusions: The combination of a beta-blocker and enalapril was associated with a synergistic reduction in the risk of death in the SOLVD Prevention trial.

Background: Population-based studies have found that black patients with congestive heart failure have a higher mortality rate than whites with the same condition. This finding has been attributed to differences in the severity, causes, and management of heart failure, the prevalence of coexisting conditions, and socioeconomic factors. Although these factors probably account for some of the higher mortality due to congestive heart failure among blacks, we hypothesized that racial differences in the natural history of left ventricular dysfunction might also have a role., Methods: Using data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, in which all patients received standardized therapy and follow-up, we conducted a retrospective analysis of the outcomes of asymptomatic and symptomatic left ventricular systolic dysfunction among black and white participants. The mean (+/-SD) follow-up was 34.2+/-14.0 months in the prevention trial and 32.3+/-14.8 months in the treatment trial among the black and white participants., Results: The overall mortality rates in the prevention trial were 8.1 per 100 person-years for blacks and 5.1 per 100 person years for whites. In the treatment trial, the rates were 16.7 per 100 person-years and 13.4 per 100 person-years, respectively. After adjustment for age, coexisting conditions, severity and causes of heart failure, and use of medications, blacks had a higher risk of death from all causes in both the SOLVD prevention trial (relative risk, 1.36; 95 percent confidence interval, 1.06 to 1.74; P=0.02) and the treatment trial (relative risk, 1.25; 95 percent confidence interval, 1.04 to 1.50; P=0.02). In both trials blacks were also at higher risk for death due to pump failure and for the combined end point of death from any cause or hospitalization for heart failure, our two predefined indicators of the progression of left ventricular systolic dysfunction., Conclusions: Blacks with mild-to-moderate left ventricular systolic dysfunction appear to be at higher risk for progression of heart failure and death from any cause than similarly treated whites. These results suggest that there may be racial differences in the outcome of asymptomatic and symptomatic left ventricular systolic dysfunction.

Objective: This study undertook to determine if the presence of atrial fibrillation in patients with asymptomatic and symptomatic left ventricular dysfunction was associated with increased mortality and, if so, whether the increase could be attributed to progressive heart failure or arrhythmic death., Background: Atrial fibrillation is a common condition in heart failure with the potential to impact hemodynamics and progression of left ventricular systolic dysfunction as well as the electrophysiologic substrate for arrhythmias. The available data do not conclusively define the effect of atrial fibrillation on prognosis in heart failure., Methods: A retrospective analysis of the Studies of Left Ventricular Dysfunction Prevention and Treatment Trials was conducted that compared patients with atrial fibrillation to those in sinus rhythm at baseline for the risk of all-cause mortality, progressive pump-failure death and arrhythmic death., Results: The patients with atrial fibrillation at baseline, compared to those in sinus rhythm, had greater all-cause mortality (34% vs. 23%, p < 0.001), death attributed to pump-failure (16.7% vs. 9.4%, p < 0.001) and were more likely to reach the composite end point of death or hospitalization for heart failure (45% vs. 33%, p < 0.001), but there was no significant difference between the groups in arrhythmic deaths. After multivariate analysis, atrial fibrillation remained significantly associated with all-cause mortality (relative risk [RR] 1.34, 95% confidence interval [CI] 1.12 to 1.62, p=0.002), progressive pump-failure death (RR 1.42, 95% CI 1.09 to 1.85, p=0.01), the composite end point of death or hospitalization for heart failure (RR 1.26, 95% CI 1.03 to 1.42, p=0.02), but not arrhythmic death (RR 1.13; 95% CI 0.75 to 1.71; p=0.55)., Conclusions: The presence of atrial fibrillation in patients with asymptomatic and symptomatic left ventricular systolic dysfunction is associated with an increased risk for all-cause mortality, largely explained by an increased risk for pump-failure death. These data suggest that atrial fibrillation is associated with progression of left ventricular systolic dysfunction.

Objectives: The aims of this study were to describe the incidence and spectrum of thromboembolic events experienced by patients with moderate to severe left ventricular systolic dysfunction in normal sinus rhythm and to study the association between ejection fraction and thromboembolic risk., Background: The annual incidence of thromboembolic events in patients with heart failure is estimated to range from 0.9% to 5.5%. Previous studies demonstrating a relation between worsening left ventricular systolic function and thromboembolic risk are difficult to interpret because of the prevalence of atrial fibrillation, an independent risk factor for thromboembolism, in the patients with a lower ejection fraction., Methods: This is a retrospective analysis of the Studies of Left Ventricular Dysfunction prevention and treatment trials data base. Patients with atrial fibrillation were excluded, resulting in 6,378 participants in sinus rhythm at the time of randomization. Thromboembolic events include strokes, pulmonary emboli and peripheral emboli. Separate analyses were conducted in each gender because there was evidence of a significant interaction between ejection fraction and gender on the risk of thromboembolic events (p = 0.04)., Results: The overall annual incidence of thromboembolic events was 2.4% in women and 1.8% in men. On univariate analysis, a decline in ejection fraction was [corrected] associated with thromboembolic risk in women (relative risk [RR] per 10% decrease in ejection fraction 1.58, 95% confidence interval [CI] 1.10 to 2.26, p = 0.01), but not in men. On multivariate analysis, a decline in ejection fraction remained independently associated with thromboembolic risk in women (RR per 10% decrease 1.53, 95% CI 1.06 to 2.20, p = 0.02), but no relation was demonstrated in men., Conclusions: In patients with left ventricular systolic dysfunction and sinus rhythm, the annual incidence of thromboembolic events is low. Ejection fraction appears to be independently associated with thromboembolic risk in women, but not in men.