By Jamie L. W. Kennedy, MD, FACC

Associate Professor, Division of Cardiology, Advanced Heart Failure & Transplant Cardiology, University of California, San Francisco

Dr. Kennedy reports no financial relationships relevant to this field of study.

SYNOPSIS: The authors of the GALACTIC trial found no benefit from an aggressive vasodilation approach for patients hospitalized with acute decompensated heart failure.

SOURCE: Kozhuharov N, Goudev A, Flores D, et al. 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. JAMA 2019;322:2292-2302.

Acute decompensated heart failure is exceedingly common. Still, evidence to guide management is scant. The authors of three recent large trials studied novel vasodilating compounds: nesiritide in ASCEND-HF, ularitide in TRUE-AHF, and serelaxin in RELAX-AHF-2. Unfortunately, all three produced disappointing results. In the GALACTIC trial, Kozhuharov et al sought to examine the benefit of a treatment approach emphasizing aggressive vasodilation in the first three days of heart failure hospitalization.

The authors enrolled patients hospitalized with acute decompensated heart failure (systolic or diastolic). The median time from presentation to study enrollment was five hours. The intensive vasodilation treatment algorithm included transdermal nitrates and hydralazine on the day of admission, followed by gradual transition to angiotensin-converting enzyme/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitors (ACE/ARB/ARNI) over the following days. Diuretics, beta-blockers, and other medical management was at the discretion of the treating physician. The primary endpoint was a combination of mortality and heart failure rehospitalization at 180 days.

Investigators enrolled 789 patients at 10 centers in five European countries between December 2007 and February 2018 (386 in the treatment arm, 402 usual care). The average age was 78 years, and 37% were female. A little more than half of the patients presented with systolic heart failure with left ventricular ejection fraction (LVEF) < 40%. The mean LVEF overall was 37%. Comorbid conditions were common: 60% had coronary disease, half had atrial fibrillation, and one-third had diabetes. Symptoms were New York Heart Association class III in 55% of patients and class IV in 45%.

The primary endpoint (death or rehospitalization for heart failure) occurred in 30.6% of the treatment arm vs. 27.8% usual care. Death occurred in 14.4% of the treatment arm vs. 15.3% usual care. The results of a subgroup analysis suggested women fared better with usual care than aggressive vasodilation; no differences were seen based on chronicity of heart failure, LVEF, age, renal function, coronary disease, baseline blood pressure, or BNP. There was no difference between the groups in patient-reported dyspnea on days 2 or 6, and no difference in NT-proBNP at enrollment or discharge.

The treatment assignments were not blinded, and the medications used in the intervention arm are widely available. Thus, it is possible there was not much difference between the intervention and usual care arms. To investigate this, the authors reported the average doses of medications received by treatment arm and hospital day. As prescribed by the intervention algorithm, high doses of nitroglycerin and hydralazine were used during hospital days 1 through 3 in the treatment group, but not the usual care group.

As expected, blood pressure was significantly lower in the treatment group on hospital day 2, and hypotension occurred in 8% of the intervention patients vs. 2% usual care. At the time of discharge, blood pressure was similar in both groups, with systolic levels about 10 mmHg lower than at admission. Similar diuretic doses were used, with similar weight loss during the hospitalization. On discharge, the treatment arm was prescribed a higher average dose of ACE/ARB/ARNI; this difference had disappeared at 180 days. Headache and dizziness were more common in the intervention arm; otherwise, adverse events were similar between groups. The authors concluded that treating acute decompensated heart failure with aggressive vasodilation does not improve the composite of mortality and heart failure hospitalization at 180 days.

COMMENTARY

The duration of enrollment speaks to the difficulty in studying this patient population. The patients enrolled are representative of heart failure patients clinicians treat regularly. The 15% mortality at 180 days confirms a “sick” population. The authors achieved aggressive vasodilation in the first few days of the hospital stay, as seen in lower blood pressure and more hydralazine and nitroglycerin used in the intervention arm. Sadly, this did not translate to better outcomes. Perhaps enrolling patients with both preserved and reduced ejection fraction contributed to the observed outcome. Interventions with proven benefit in systolic heart failure have failed to demonstrate benefit in heart failure with preserved ejection fraction trials (ACE inhibitors, ARBs, and, recently, ARNIs). The authors attempted to address this concern with a LVEF subgroup analysis, which did not suggest heterogeneity.

The GALACTIC trial highlights two areas in heart failure that warrant further investigation: the management of acutely decompensated patients, and the integration of multiple evidence-based therapies. Unfortunately, the long duration of the trial and the final negative outcome may deter investigators from pursuing additional trials of this nature. Going forward, my inpatient management of heart failure will focus on adequate diuresis and initiation/uptitration of evidence-based heart failure therapies, including sacubitril/valsartan based on the results of PIONEER-HF. I will continue to use short-acting vasodilators, such as hydralazine, nitroglycerin, and nitroprusside, for significantly hypertensive patients and for acutely dyspneic patients who are trending toward intubation and mechanical ventilation.