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The selection of end points for clinical trials of heart failure is challenging, with important implications for patients, the medical community, and regulatory agencies. The standards used in clinical research on patients with heart failure influence the effectiveness and value of future clinical trials, and the extent to which they can be translated into clinical practice.

Importance: Hospitalizations for heart failure (HHF) represent a major health burden, with high rates of early postdischarge rehospitalization and mortality. Objective: To investigate whether aliskiren, a direct renin inhibitor, when added to standard therapy, would reduce the rate of cardiovascular (CV) death or HF rehospitalization among HHF patients. Design, Setting, and Participants: International, double-blind, placebo-controlled study that randomized hemodynamically stable HHF patients a median 5 days after admission. Eligible patients were 18 years or older with left ventricular ejection fraction (LVEF) 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥400 pg/mL or N-terminal pro-BNP [NT-proBNP] ≥1600 pg/mL), and signs and symptoms of fluid overload. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012. Intervention: All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months. Main Outcome Measures: Cardiovascular death or HF rehospitalization at 6 months and 12 months. Results: In total, 1639 patients were randomized, with 1615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL, respectively. At randomization, patients were receiving diuretics (95.9%), β-blockers (82.5%), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (84.2%), and mineralocorticoid receptor antagonists (57.0%). In total, 24.9% of patients receiving aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76-1.12; P=.41). At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations; HR, 0.93; 95% CI, 0.79-1.09; P=.36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo. Conclusion and Relevance: Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge. Trial Registration: clinicaltrials.gov Identifier: NCT00894387. ©2013 American Medical Association. All rights reserved.

The risks and benefits of anticoagulation for patients with both heart failure and atrial fibrillation are unclear. We hypothesized that anticoagulation was associated with improved clinical outcomes of heart failure patients with atrial fibrillation independent of other risk factors. We conducted a retrospective cohort study of clinical registry data linked to Medicare claims for new users of oral anticoagulation (warfarin) without contraindications, discharged home alive, and stratified by CHADS2 score. Outcomes of interest were propensity score-adjusted estimates of the effects of warfarin at discharge on all-cause mortality, thromboembolic events, major adverse cardiovascular events, and bleeding events. Among 10,494 patients with heart failure and atrial fibrillation, the 2249 patients newly treated with warfarin had lower 1-year mortality (27.7% vs 39.3% for CHADS2 score ≤ 3 [P < .001]; 31.6% vs 41.8% for CHADS2 score > 3 [P < .001]) than patients not treated with warfarin. There was no significant difference in thromboembolic events, major adverse cardiovascular events, or bleeding events at 1 year. After multivariate adjustment, exposed individuals in both CHADS2 subgroups had lower adjusted 1-year mortality (CHADS2 ≤ 3: hazard ratio, 0.78 [95% confidence interval, 0.69-0.89]; CHADS 2 > 3: 0.78 [0.66-0.93]). In conclusion, warfarin use in heart failure patients with atrial fibrillation was associated with improved survival at 1 year independent of baseline CHADS2 score. However, there was no significant reduction in clinical events, such as thromboembolic or major adverse cardiovascular events at 1 year that might simply explain the survival benefit associated with warfarin.

Heart failure (HF) is a leading cause of hospitalization and readmission. As evidence-based treatments for the management of HF with reduced ejection fraction have evolved, the ability to reduce the HF readmission risk has improved. Clinical trials have shown measurable improvements in patient-centered outcomes through exercise, pharmacologic, and device therapies. In contrast, for HF with preserved ejection fraction, no medical therapy has been identified that improves survival, though aldosterone antagonists may reduce HF hospitalization risk. Thirty-day readmission rates have become a metric for hospital quality and financial penalties in the United States; however, reducing all preventable hospitalizations, improving health status, and prolonging survival should be the goal for HF patients. Nearly half of repeat hospitalizations for HF are secondary to noncardiovascular conditions. Careful attention to complicating comorbid conditions should be assessed before discharge for an acute decompensation. Optimizing the outpatient management of HF and providing careful transitions from the hospital to the outpatient setting are critical to minimizing readmission risk and improving patient-centered outcomes.