No Survival Gain From Aggressive Vasodilator Strategy in Acute HF: GALACTIC

December 26, 2019

Early vasodilator therapy, even when aggressive, does little to improve survival or other clinical outcomes for patients hospitalized with acute heart failure (HF), suggests only the latest randomized trial to downplay the role of vasodilators in that setting.

The GALACTIC trial showed no difference in death or acute-HF rehospitalization at 6 months among patients who received usual care compared to those who received an intensive strategy based on early initiation of multiple vasodilators. Patients with hypotension had been excluded.

The regimen included sublingual and transdermal nitrates, oral hydralazine, and "rapidly uptitrated" renin-angiotensin system (RAS) inhibitors that sometimes included sacubitril/valsartan (Entresto, Novartis), write Nikola Kozhuharov, MD, University Hospital Basel, Switzerland, and associates in a report published December 17 in the Journal of the American Medical Association.

GALACTIC is consistent with and adds to a number of earlier trials that tested treatment with short-term IV vasodilators for stabilized patients with acute HF, senior author Christian Mueller, MD, University of Basel, told theheart.org | Medscape Cardiology.

"Overall, the hypothesis that vasodilation provides incremental value on top of IV diuretic therapy has been consistently rejected in these studies," he said. On the other hand, "I was a strong believer in the incremental value of early and sustained vasodilation in these acute-HF patients until we had obtained the findings from our statistician."

The previous trials that also found little or no clinical improvement from early vasodilator-focused management included the TRUE-AHF trial of ularitide (Cardiorentis), the RELAX-AHF-2 trial of serelaxin (Novartis), and ASCEND-HF, which evaluated nesiritide (Natrecor, Scios/Johnson & Johnson).

In contrast to those trials, each of which focused on one fixed-dose vasodilator used in conjunction with usual care, "GALACTIC is unique in examining commonly available and inexpensive vasodilators, not novel compounds developed by the pharmaceutical industry to be sold for a very high price," Mueller said.

The results, along with other recent studies, "highlight the high value of IV furosemide, possibly in combination with oral metolazone, as the preferred strategy to lower filling pressures and reduce volume overload in the vast majority of acute HF patients," he said.

"Collectively, the results of these four clinical trials suggest that in the absence of hypertension, use of early intensive vasodilator therapy in acute heart failure due to fluid overload may not provide clinically significant benefit compared with standard therapy with loop diuretics to reverse congestion," agreed JAMA deputy editor Gregory Curfman, MD, Harvard Medical School, Boston, in an accompanying editorial.

"The trials failed to demonstrate benefit in either short-term, symptomatic endpoints or longer-term outcomes, including cardiovascular mortality. In patients with pulmonary congestion who are normotensive, emphasis should be placed on adequate diuresis, with vasodilators reserved for patients whose clinical improvement has stalled," Curfman writes.

GALACTIC randomly assigned 788 patients hospitalized for acute HF who had elevated natriuretic peptide levels and a systolic blood pressure of at least 100 mmHg at 10 centers in Brazil, Bulgaria, Germany, Spain, and Switzerland; 37% were women. Patients with severe renal dysfunction were excluded.

Randomized therapy was open-label, but clinical events were independently and blindly adjudicated, the report notes.

The 404 patients in the usual-care arm received standard low-dose vasodilator therapy and other treatments at physicians' discretion. The 386 patients assigned to intensive vasodilator therapy initially received sublingual or oral-spray nitrates and were later given high-dose, "maximally tolerated" nitrates by transdermal patch, along with low-dose oral hydralazine for 48 hours. Angiotensin converting enzyme inhibitors, angiotensin-receptor blockers, or sacubitril valsartan — by physicians' choice — were "rapidly uptitrated" to a systolic blood pressure target of 90 to 110 mmHg.

Nitrates were tapered off starting on the third day, but RAS inhibitors were continued until discharge at by guideline-recommended dosages for chronic HF and reduced ejection fraction.

The two groups did not differ significantly in median length of hospital stay, rate of improvement of dyspnea on day 2 or day 6, reductions in natriuretic peptide levels, or all-cause mortality by day 180.

Nor was there a significant difference reflected in the hazard ratio, intensive vasodilators vs usual care, for the primary endpoint of death from any cause or rehospitalization for acute HF at 180 days: 1.07 (95% CI 0.83 – 1.39, P = .59).

"Intravenous nitrates are part of the standard of care in patients with acute pulmonary edema. The neutral findings of the GALACTIC study and the other recent studies do not alter the role of IV nitrates in this dramatic acute-HF phenotype," Mueller observed.

"However, the recent studies clearly show that early vasodilation does not improve outcomes when applied to the much more common phenotype of rather stable acute HF patients."

Kozhuharov has disclosed no relevant financial relationships. Mueller reports receiving 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. Disclosures for other coauthors are listed in the original article. Curfman has disclosed no relevant financial relationships.

JAMA. Published online December 17, 2019. Abstract, Editorial

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