Effect of a Strategy of Comprehensive Vasodilation vs Usual Care on Mortality and Heart Failure Rehospitalization Among Patients With Acute Heart Failure: The GALACTIC Randomized Clinical Trial

Abstract

Importance: Short-term infusions of single vasodilators, usually given in a fixed dose, have not improved outcomes in patients with acute heart failure (AHF).

Objective: To evaluate the effect of a strategy that emphasized early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with AHF.

Design, setting, and participants: Randomized, open-label blinded-end-point trial enrolling 788 patients hospitalized for AHF with dyspnea, increased plasma concentrations of natriuretic peptides, systolic blood pressure of at least 100 mm Hg, and plan for treatment in a general ward in 10 tertiary and secondary hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Enrollment began in December 2007 and follow-up was completed in February 2019.

Interventions: Patients were randomized 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 was a comprehensive pragmatic approach of maximal and sustained vasodilation 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.

Main outcomes and measures: The primary end point was a composite of all-cause mortality or rehospitalization for AHF at 180 days.

Results: Among 788 patients randomized, 781 (99.1%; median age, 78 years; 36.9% women) completed the trial and were eligible for primary end point analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary end point, 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 end point, 2.8% [95% CI, -3.7% to 9.3%]; adjusted hazard ratio, 1.07 [95% CI, 0.83-1.39]; P = .59). The most common clinically significant adverse events with early intensive and sustained vasodilation vs 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 and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT00512759.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Goudev reported receiving personal fees (speaking honoraria and advisory board membership) from Pfizer, Novartis, AstraZeneca, and Amgen. Dr Walter reported receiving grants from the Swiss Heart Foundation and the Swiss Academy of Medical Sciences. Dr Gualandro reported receiving personal fees from Servier. Dr Wenzel reported receiving personal fees from Novartis, Bayer, the German Federal Ministry for Education and Research, and Abbott Vascular and nonfinancial support from Servier. Dr Pfister reported receiving personal fees from Novartis, Vifor Pharma, and Merck Sharp & Dohme and grants from Sanofi and Boehringer Ingelheim. Dr Conen reported receiving personal fees from Servier Canada. Dr Kobza reported receiving grants from Biosense Webster, Biotronik, Medtronic, Abbott, SIS Medical, and Boston Scientific. Dr Münzel reported being the principal investigator of the DZHK (German Center for Cardiovascular Research) Partner Site Rhine-Main. Dr Mueller reported receiving grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the Foundation for Cardiovascular Research Basel, and the Stanley Johnson Foundation; grants, personal fees, and nonfinancial support from Roche Diagnostics, Singulex, and Brahms; personal fees from Novartis, Cardiorentis, and Boehringer Ingelheim; and grants and nonfinancial support from Abbott. No other disclosures were reported.

Figures

Figure 1.. Flow of Participants Through the GALACTIC Trial

aThe number of patients assessed for eligibility is not reported because it was not collected at all sites. bNo further follow-up data were obtained. All information up to withdrawal of consent was used in analysis.

Figure 2.. Kaplan-Meier Estimates of the Primary End Point of Cumulative All-Cause Mortality or Acute Heart Failure Rehospitalization Within 180 Days Among Patients Treated With Early Intensive and Sustained Vasodilation vs Usual Care

Median observation time, 180 days (interquartile range, 136-180 days) in the early intensive and sustained vasodilation group vs 180 days (interquartile range, 141-180 days) in the usual care group.

Figure 3.. Risk of All-Cause Death or Acute Heart Failure Rehospitalization Within 180 Days in Prespecified Subgroups Among Patients Treated With Early Intensive and Sustained Vasodilation vs Usual Care

BNP indicates B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction. Data on LVEF were not available for 47 of 399 patients in the usual care group and 48 of 382 patients in the intervention group. BNP measurements were not available for 179 of 399 patients in the usual care group and 215 of 382 patients in the intervention group. In those patients, the biological equivalent concentration of BNP was estimated as their N-terminal pro–BNP concentration × 0.2.

Figure 4.. Post Hoc Analysis of Medication Doses and Weight Reduction and Prespecified Exploratory Analysis of Blood Pressure in Early Intensive and Sustained Vasodilation vs Usual Care Groups

ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ARN, angiotensin receptor–neprilysin. Yellow boxes indicate early intensive and sustained vasodilation; blue boxes, usual care. Bars indicate medians; box bottoms and tops, 25th and 75th percentiles; whiskers, upper and lower adjacent values; dots, outliers. Upper adjacent value is defined as the largest observation less than or equal to third quartile + 1.5 × interquartile range (IQR). Lower adjacent value is the smallest observation equal to first quartile − 1.5 × IQR. Significant differences (P < .05) were found between groups for nitroglycerin doses throughout hospitalization, for hydralazine doses from day 1 to day 3, for furosemide-equivalent doses on day 4, for ACE inhibitor, ARB, and ARN inhibitor doses from day 3 to day of discharge, for systolic and diastolic blood pressure on day 2 and day 3, and for weight reduction from day 2 to day 7. aFurosemide-equivalent dose on day 1 corresponds to intravenous furosemide application and on day 2 through 180-day follow-up corresponds to prescribed furosemide and/or torasemide dose × 4. bAbsolute increases of percentage target dose of ACE inhibitors, ARBs, and ARN inhibitors are reported starting on day 2. Absolute decreases of percentage target dose are expressed as a negative number (eg, a decrease of ramipril dose from 5 mg/d to 2.5 mg/d corresponds to −25% absolute increase of percentage target dose of ramipril at 10 mg/d). cWeight reduction is reported starting on day 2. In most patients, weight on day 1 was a self-reported estimate and not a measurement.