Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program.

BACKGROUND: The postdischarge rehospitalization and death rates are high in patients with acute heart failure (HF) syndromes despite optimization of standard therapy for chronic HF. To the best of our knowledge, there has been no systematic analysis of the causes of death and rehospitalization in this patient population. METHODS: This was a prespecified analysis of adjudicated cause-specific all-cause mortality and cardiovascular (CV) hospitalization in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, a randomized, double-blind, placebo-controlled study in patients hospitalized with worsening HF and left ventricular ejection fraction < or =40% comparing tolvaptan, an oral vasopressin receptor antagonist to placebo, in addition to standard care. RESULTS: Of the 4,133 randomized, there were 5,239 rehospitalizations and 1,080 deaths during a median of 9.9 months. Of all deaths, 41.0% were due to HF, 26.0% due to sudden cardiac death (SCD), 2.6% due to acute myocardial infarction (MI), 2.2% due to stroke, and 13.2% due to non-CV causes. Of all hospitalizations, 39.2% were non-CV, whereas 46.3% were for HF, and a minority of hospitalizations was due to stroke, MI, arrhythmia, or other CV causes. CONCLUSIONS: Despite close follow-up and evidence-based therapy within a clinical trial, rehospitalization and death remain high. Although most deaths were from HF, one quarter of patients had SCD. In addition, there were almost as many non-CV hospitalizations as HF hospitalizations. Knowledge of the causes of death and rehospitalization may be essential for proper management and early initiation of therapy.

Mechanisms underlying improvements in ejection fraction with carvedilol in heart failure.

BACKGROUND: Reductions in heart rate (HR) with beta-blocker therapy have been associated with improvements in ejection fraction (EF). However, the relative contributions of HR reduction, positive inotropism, afterload reduction, and reverse remodeling to improvements in EF are unknown. METHODS AND RESULTS: Twenty-nine patients (63+/-12 years old) with New York Heart Association class II-III heart failure underwent serial measurements of left ventricular volumes using 3-dimensional echocardiography and blood pressures by sphygmomanometry at baseline, 2 weeks, 2, 6, and 12 months after initiation of carvedilol. From these parameters, left ventricular contractility (indexed by the end-systolic pressure-volume ratio), total peripheral resistance, and effective arterial elastance (E(a)) were derived. Overall, EF increased by 7-percentage points after 6 months of therapy (from 25+/-9 to 32+/-9, P<0.0001). This change was due to an increase in stroke volume (P<0.001) with no significant change in end-diastolic volume (P=0.15). The EF change correlated with increased contractility, decreased HR and decreased total peripheral resistance (P<0.003 in each case). In those patients whose EF increased at least 5 points, approximately 60% of the increase was due to HR reduction, approximately 30% was due to increased contractility, and <20% was due to the decrease in total peripheral resistance. CONCLUSIONS: Decreased HR, improved chamber contractility and afterload reduction each contributed significantly to improved EF with carvedilol.

Management of diuretic-refractory, volume-overloaded patients with acutely decompensated heart failure.

Fluid overload is a common presentation for decompensated heart failure, yet management strategies are poorly defined because of relatively few randomized clinical trials that delineate an optimal strategy. Patients refractory to diuretic therapy may be considered for treatment with inotropes or vasodilators, and others may be considered for venovenous ultrafiltration. The rationale for use of each therapy is reviewed.

Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials.

CONTEXT: Nesiritide improves symptoms in patients with acutely decompensated heart failure compared with placebo and appears to be safer than dobutamine. Its short-term safety relative to standard diuretic and vasodilator therapies is less clear. OBJECTIVE: To investigate the safety of nesiritide relative to noninotrope-based control therapies, primarily consisting of diuretics or vasodilators. DATA SOURCES: Primary reports of completed clinical trials as of December 2004 were obtained from the US Food and Drug Administration (FDA), the study sponsor (Scios Inc), a PubMed literature search using the terms nesiritide, clinical trials, and humans, and a manual search of annual meetings of 3 heart associations. STUDY SELECTION: Of 12 randomized controlled trials evaluating nesiritide, 3 met all inclusion criteria: randomized double-blind study of patients with acutely decompensated heart failure, therapy administered as single infusion (> or =6 hours), inotrope not mandated as control, and reported 30-day mortality. DATA EXTRACTION: Data were extracted from FDA and sponsor documents and corroborated with published articles when available. Thirty-day survival was assessed by meta-analysis using a fixed-effects model and time-dependent risk by Kaplan-Meier analysis with Cox proportional hazards regression modeling. Where deaths were described within a range of days after treatment, an extreme assumption was made favoring nesiritide over control therapy, an approach relevant to the time-dependent analyses. DATA SYNTHESIS: In the 3 trials, 485 patients were randomized to nesiritide and 377 to control therapy. Death within 30 days tended to occur more often among patients randomized to nesiritide therapy (35 [7.2%] of 485 vs 15 [4.0%] of 377 patients; risk ratio from meta-analysis, 1.74; 95% confidence interval [CI], 0.97-3.12; P = .059; and hazard ratio after adjusting for study, 1.80; 95% CI, 0.98-3.31; P = .057). CONCLUSIONS: Compared with noninotrope-based control therapy, nesiritide may be associated with an increased risk of death after treatment for acutely decompensated heart failure. The possibility of an increased risk of death should be investigated in a large-scale, adequately powered, controlled trial before routine use of nesiritide for acutely decompensated heart failure.

Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure.

BACKGROUND: Renal function is an important prognostic factor for patients with acutely decompensated heart failure (ADHF). We investigated the renal effects of nesiritide as treatment for ADHF. METHODS AND RESULTS: Randomized clinical trials comparing nesiritide with either placebo or active control for ADHF were identified by electronic and manual searches and thorough review of US Food and Drug Administration files available via the website. Worsening renal function was defined as an increase in serum creatinine >0.5 mg/dL. Relative risk across all studies was determined by meta-analysis with Mantel-Haenszel fixed-effects models (RR(MH)). Risk of dialysis and medical intervention for worsening renal function were compared between therapies. Frequency of worsening renal function was determined from 5 randomized studies that included 1269 patients. Use of Food and Drug Administration-approved doses of nesiritide (< or =0.03 microg x kg(-1) x min(-1)) significantly increased the risk of worsening renal function compared with non-inotrope-based control (RR(MH), 1.52; 95% CI, 1.16 to 2.00; P=0.003) or any control therapy, including non-inotrope- and inotrope-based therapies (RR(MH), 1.54; 95% CI, 1.19 to 1.98; P=0.001). Even low-dose nesiritide (< or =0.015 microg x kg(-1) x min(-1)) significantly increased risk (P=0.012 and P=0.006 compared with non-inotrope- and inotrope-based controls, respectively), as did nesiritide administered at any dose up to 0.06 microg x kg(-1) x min(-1) (P=0.002 and P=0.001, respectively). There was no difference in the need for dialysis between therapies. CONCLUSIONS: Nesiritide significantly increases the risk of worsening renal function in patients with ADHF. Whether worsening renal function reflects hemodynamic effect or renal injury is unknown, but the prognostic importance of worsening renal function suggests the need for further investigation in appropriately powered clinical trials.

Practical guidelines to optimize effectiveness of beta-blockade in patients postinfarction and in those with chronic heart failure.

Antiadrenergic therapy reduces the risks of death and major morbidity in patients postinfarction and in those with chronic heart failure. Despite the common perception, these benefits are not attributable to a class effect, and clinical trials reveal evidence of specific agents that provide clinical advantages. To optimize patient outcome in the postinfarction setting, propranolol or timolol should be used in the setting of preserved ventricular function, and carvedilol should be used in patients with impaired ventricular function, with or without clinical evidence of heart failure. Patients with chronic heart failure are at lower risk of death when treated with carvedilol, which is also associated with a lower incidence of developing diabetes mellitus-related adverse events. This article reviews the scientific evidence for the hierarchy of antiadrenergic agents and addresses practical issues associated with initiation of therapy and long-term management.

Eprosartan improves cardiac performance, reduces cardiac hypertrophy and mortality and downregulates myocardial monocyte chemoattractant protein-1 and inflammation in hypertensive heart disease.

OBJECTIVE: The purpose of this investigation was to determine whether angiotensin II receptor (AII1R) antagonism interferes with cardiac monocyte chemoattractant protein-1 (MCP-1) expression in hypertrophic cardiomyopathy and failure. DESIGN: We studied the effects of the AII1R antagonist eprosartan on MCP-1 expression, and on the recruitment of macrophages into the myocardium in a model of cardiac hypertrophy and morbidity/mortality. METHODS: Stroke-prone spontaneously hypertensive rats fed a high-salt, high-fat diet (SFD) developed heart failure characterized by left ventricular (LV) hypertrophy/pathology and hypocontractility. These rats received either normal diet, SFD, or SFD with the daily administration of 30 mg/kg eprosartan for 28 weeks. LV function and wall thickness was assessed by echocardiography, MCP-1 expression was measured by TaqMan real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunohistochemistry, and macrophage infiltration into the LV was determined by microscopy. RESULTS: Eprosartan reduced the rate of morbidity/mortality (P = 0.001), LV MCP-1 mRNA (P < 0.05) and protein expression (P < 0.01), and LV macrophage infiltration (P < 0.01), while preserving ventricular function (P < 0.05). Eprosartan also produced a moderate (16%; P < 0.05) decrease in blood pressure. CONCLUSIONS: These data demonstrate that AII1R antagonism in an animal model of hypertensive heart disease reduces MCP-1 expression in the myocardium that results in reduced macrophage recruitment. These effects parallel the preservation of LV systolic function and the reduction in cardiac remodeling/disease progression and reduced morbidity/mortality. Suppression of MCP-1 expression might explain in part the beneficial effects of AII1R antagonism in this model.

Neurohormonal antagonism in heart failure: what is the optimal strategy?

Pharmacologic management of chronic heart failure rests on appropriate volume management followed by neurohormonal antagonism. Despite the rationale for neurohormonal antagonists, their use remains low. Definitive studies establish that neurohormonal antagonists are effective across the spectrum of disease, from the early Stage A patient at risk of developing structural heart disease and symptomatic heart failure to the Stage D patient with symptoms at rest. Although many investigators and clinicians seem focused on the next new scientific breakthrough, published studies delineate strategies that will reduce death and disability for those at risk and those with symptomatic chronic heart failure. In essence, the broad use of neurohormonal antagonists, consistent with the reports of large-scale trials that have been reported, will markedly reduce the risk of disease progression and death. Overall prognosis however remains poor. We review the data from these trials to encourage clinicians to use these proven neurohormonal antagonists in optimizing therapeutic strategy.

Increasing organ transplantation--fairly.

Ten to 30 times as many people die as a result of end-organ failure than are fortunate enough to undergo transplantation. To date, efforts to increase the donor pool or establish an alternative to transplant have failed. The authors' goal was to define a revision to the transplant system that can use innate human motivators to lead to an increase in organ donation. People are motivated more by self-interest than by altruism. To increase organ donation, the incentive needs to be aligned with self-interests. Therefore, the authors propose that the priority to receive a transplant should be based on prior willingness to be a donor: to get, you have to be willing to give. This would replace the "time on list" as a key variable in determining priority and waiting time. The commitment to the system of transplant--being a willing donor--is the fairest way to prioritize recipient status. Such a system will encourage more donation as people on the donor list start to receive transplants themselves, especially when the transplant takes place quickly, before risk becomes excessive.

How should diuretic-refractory, volume-overloaded heart failure patients be managed?

Hospitalization is often required for patients with decompensated heart failure, usually with volume overload. Intravenous diuretics are recommended to optimize volume status; however, the management of patients refractory to diuretic therapy is not addressed in American Heart Association/American College of Cardiology, European Society of Cardiology or Heart Failure Society of America guidelines. This review focuses the invasive/interventional cardiologist on the rationale for greater involvement in the care of patients admitted to the hospital with decompensated volume overload, in particular when such patients are diuretic refractory.

New evidence from the CAPRICORN Trial: the role of carvedilol in high-risk, post-myocardial infarction patients.

The CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) trial established that the beta-blocker carvedilol reduces the risk of death in patients with left ventricular dysfunction post myocardial infarction, whether or not the infarct is complicated by clinical heart failure. Thus, the utility of the beta-blocker carvedilol is confirmed in the modern era as an adjunct to revascularization, angiotensin-converting enzyme inhibitors, aspirin, and statins. In addition, the results prompt us to review the prior studies of beta-blockers postinfarction. Critical review of CAPRICORN and earlier beta-blocker studies suggests that specific beta-blockers should be matched to specific clinical scenarios. The COMET (Carvedilol or Metoprolol European Trial) study reinforces this view by establishing that beta-blockers are not simply interchangeable agents.