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Comprehensive Vasodilation vs. Usual Care—Mortality and Rehospitalization for Heart Failure
Study Questions:
What is the effect of early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with acute heart failure (AHF)?
Methods:
The study was a randomized, open-label, blinded endpoint trial enrolling 788 patients hospitalized for AHF with shortness of breath, increased plasma concentrations of natriuretic peptides, systolic blood pressure of ≥100 mm Hg. The study investigators randomized patients 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization (n = 386) or usual care (n = 402). Early intensive and sustained vasodilation included combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril-valsartan. The primary endpoint was a composite of all-cause mortality or rehospitalization for AHF at 180 days. Sample size was calculated for superiority hypothesis testing based on outcomes observed in a prior AHF study. A hypothesized 20% reduction of the composite endpoint of death or AHF rehospitalization within 180 days and an event rate of 48% in the usual care group was expected to require 385 patients per treatment group to obtain, with a probability of 80%, a log-rank test result that was statistically significant at the 0.05 level.
Results:
About 99.1% (n = 781) of the 788 patients (median age, 78 years; 36.9% women) randomized completed the trial and were eligible for primary endpoint analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary endpoint, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 117 patients (30.6%) in the intervention group (including 55 deaths [14.4%]) and in 111 patients (27.8%) in the usual care group (including 61 deaths [15.3%]) (absolute difference for the primary endpoint, 2.8%; 95% confidence interval [CI], −3.7% to 9.3%; adjusted hazard ratio, 1.07; 95% CI, 0.83-1.39; p = 0.59). This was confirmed in a post hoc analysis using mixed-effects modeling with site as a random effect (adjusted hazard ratio, 1.07; 95% CI, 0.83-1.39; p = 0.61). There was no significant difference in key secondary endpoints, including all-cause deaths through day 180 (55 [14.4%] with the intervention vs. 61 [15.3%] with usual care; absolute difference, 0.9%; 95% CI, −4.3% to 6.1%) and median length of stay (9 days in both groups; absolute difference, 0 days; 95% CI, −1 to +1 day). The most common clinically significant adverse events with early intensive and sustained vasodilation versus usual care were hypokalemia (23% vs. 25%), worsening renal function (21% vs. 20%), headache (26% vs. 10%), dizziness (15% vs. 10%), and hypotension (8% vs. 2%).
Conclusions:
Among patients with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, did not significantly improve a composite outcome of all-cause mortality and AHF rehospitalization at 180 days.
Perspective:
Acute heart failure is a very heterogeneous condition, with varying degrees of renal and cardiac involvement and varying degrees of neurohormonal responses (such as varying degrees of secondary hyperaldosteronism), making standardization of therapy a challenge and in this study vasodilators did not significantly improve outcomes. More research is required in patients with cardiorenal syndrome.
Clinical Topics: Cardiovascular Care Team, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Acute Heart Failure
Keywords: Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Dyspnea, Geriatrics, Headache, Heart Failure, Hydralazine, Hyperaldosteronism, Hypokalemia, Hypotension, Length of Stay, Natriuretic Peptides, Nitrates, Renal Insufficiency, Vasodilation, Vasodilator Agents
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