PARIS – A practical strategy of early and aggressive vasodilation and optimization of long-term medication for acute heart failure did not budge all-cause mortality or 180-day readmission rates, according to results of a pragmatic trial presented at the annual congress of the European Society of Cardiology.
“To our great disappointment, the curves were superimposable” between intervention and control arms in the GALACTIC (Goal-directed Afterload Reduction in Acute Congestive Cardiac Decompensation) trial, said lead investigator Christian Eugen Mueller, MD. “There was no signal of a benefit” for those receiving the targeted intervention: the adjusted hazard ratio was 1.07 for the composite primary endpoint of all-cause mortality or 6-month readmission for acute heart failure (P = 0.59).
GALACTIC, explained Dr. Mueller, was the largest investigator-initiated, randomized, controlled trial of pharmacologic therapy for acute heart failure (AHF).
“It is different in that it did not investigate a single drug, but a strategy of early, intensive, and sustained vasodilation. It is also unique in that it used individual doses of well-characterized, widely available, and mostly inexpensive drugs,” said Dr. Mueller, director of the Cardiovascular Research Institute at the University Hospital, Basel, Switzerland. “So this would have the beauty that, if it has a positive finding, you – in whatever country you come from – would be immediately able to apply it once you’re back home in your institution.”
The study attempted to address the gap between symptom amelioration and long-term outcomes when patients arrive in the ED with AHF. “Despite symptomatic improvement achieved from loop diuretics, mortality and morbidity remain unacceptably high,” said Dr. Mueller, with 40%-50% of AHF patients experiencing rehospitalization or death within 180 days of discharge.
Much remains unknown about the optimal treatment strategy for AHF. Aggressive vasodilation has been shown to improve outcomes in less-severe AHF, and intravenous nitrates are known to improve outcomes in AHF where severe pulmonary edema is present – “a phenotype representing only about 5% of patients,” noted Dr. Mueller. Still, “it is unknown whether aggressive vasodilation also improves outcomes in the much more common less-severe phenotype.”
Also, previous trials that ran intravenous vasodilators at a fixed dose for 48 hours did not improve AHF outcomes, so a one-size-fits-all strategy was not one the GALACTIC investigators sought to pursue.
In addition to a flexible regimen, “any strategy applied needs to take into consideration that the vast majority of patients with acute heart failure, after initial treatment in the ED, are then treated in a general cardiology ward,” added Dr. Mueller.
This meant that intravenous nitrate infusion was not part of the GALACTIC trial; rather, sublingual and transdermal nitrates were used, explained Dr. Mueller. “Transdermal application has the beauty that if you have an adverse effect – and hypotension is the most dangerous one – you can immediately remove the patch, and thereby avoid any further harm.”
The two-part strategy tested in GALACTIC involved reducing cardiac filling pressures by maintaining or increasing organ perfusion, while also increasing “long-term lifesaving therapy” targeting the renin-angiotensin-aldosterone system during hospitalization, with a goal to continue optimal treatment long term.
ACE inhibitors or angiotensin receptor blockers were added on the second day of hospitalization for the intervention group, said Dr. Mueller, and “in the ideal setting, up-titrated very aggressively from day to day.
“However, as you know, up-titration to target dose is sometimes wishful thinking in this frail population,” he said, so the GALACTIC trial protocol included a scheme to back dosing off for hypotension, hypokalemia, or worsening renal function. Systolic BP guided how aggressively vasodilation and ACE inhibitor/angiotensin receptor blocker therapy were escalated.
In the end, 382 patients randomized to the intervention arm received early, intensive, and sustained vasodilation, and the 399 patients in the control arm received standard-of-care treatment according to ESC guidelines. These figures omit two patients in the standard-of-care arm who withdrew consent, but follow-up was otherwise complete, said Dr. Mueller. Physicians treating patients in both study arms had discretion to use such other therapies as loop diuretics, beta-blockers, aldosterone antagonists, and cardiac devices.
Adult patients coming to the ED with acute dyspnea classified as New York Heart Association class III or IV were eligible if they had brain natriuretic peptide (BNP) levels of at least 500 ng/L, or N-terminal of the prohormone BNP (NT-proBNP) levels of at least 2,000 ng/L.
Overall, patients enrolled in GALACTIC were in their late 70s, and women made up 37% of the population.
The actual median BNP for enrollees was about 1,250 ng/L, and the median NT-proBNP was just under 6,000 ng/L. The median left ventricular ejection fraction was 37%. About a third of patients had diabetes, and 85% had hypertension. Over half had known chronic heart failure, about a third had prior history of MI, and half of patients had atrial fibrillation at baseline.
“Signs of congestion were present in all patients, and over 90% had rales on physical examination,” said Dr. Mueller.
Patients who were destined for the ICU, those who had systolic BP below 100 mm Hg or marked creatinine elevation, or who required cardiopulmonary resuscitation were excluded. Also excluded were patients with known structural defects such as severe valvular stenosis, congenital heart disease, or hypertrophic obstructive cardiomyopathy. GALACTIC also excluded patients with isolated right ventricular failure caused by pulmonary hypertension.
Prespecified subgroup analyses compared women with men, and those younger than 75 years with older participants. Women saw a significantly higher hazard ratio for readmission or death, indicating a potential harm from the intervention, said Dr. Mueller. An additional analysis stratified patients by left ventricular ejection fraction. Aside from the intervention’s negative effect on women participating in the trial, no other subgroups benefited or were harmed by an early vasodilation strategy.
Dr. Alexandre Mebazaa
Alexandre Mebazaa, MD, the designated discussant for the presentation, said that, although the GALACTIC trial was neutral, it represents “an important step forward in acute heart failure.
“Congratulations: First, because we know that in the critically ill condition it’s very difficult to do trials,” and the GALACTIC investigators succeeded in enrolling patients within the first 5 hours of presentation to EDs, noted Dr. Mebazaa, professor of anesthesiology and critical care medicine at the Paris Diderot School of Medicine.
He added that GALACTIC succeeded in continuing vasodilator use beyond the 48-hour mark. “For the first time, you had the courage to go a little bit further down, and we see that patients got the drug with vasodilator properties for 2 days or more.”
However, the long recruitment period for GALACTIC – first enrollment began in 2007 – meant that the study design reflected a thought process about AHF that doesn’t necessarily reflect current practice, noted Dr. Mebazaa. “The trial was designed many years ago, and at that time, we were still thinking that giving very aggressive treatment in the first hours could have an impact.
“Now, when we will be treating patients with vasodilators with acute heart failure – at least myself and my group – I would really wonder whether there is still evidence in the world to support the use of those agents.”
Dr. Mueller noted limitations of the GALACTIC trial, including the lack of generalizability to patients with systolic hypotension or severe renal dysfunction, since these populations were excluded. Also, “the open-label design, which was mandated by the aim to test a strategy, not a single drug, may have introduced a bias in the unblinded assessment of dyspnea” during inpatient stay.
The study was funded by several Swiss research institutions and had no industry support. Dr. Mueller reported no relevant conflicts of interest. Dr. Mebazaa reported financial relationships with Roche, Service, Novartis, AstraZeneca, S-Form Pharma, 4Teen$4, Adrenomed, and Sphingotec.
SOURCE: Mueller C. ESC 2019, Hot Line Session 3.