Mixed Results with ARNI Therapy for Post-MI Heart Failure Prevention

For heart attack survivors with left ventricular dysfunction, sacubitril/valsartan (Entresto) was no better than ramipril at reducing heart failure (HF) events in the strictest sense in the PARADISE-MI trial, but several signals nevertheless pointed to potential benefit in some patients.

Acute MI patients shared similar rates of the primary outcome — cardiovascular death, HF hospitalization, or outpatient development of HF over a median 23 months — whether they had been randomized to sacubitril/valsartan or the angiotensin-converting enzyme (ACE) inhibitor (11.9% vs 13.2%, HR 0.90, 95% CI 0.78-1.04), according to Marc Pfeffer, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

Each individual component of the composite endpoint numerically favored angiotensin receptor-neprilysin inhibition (ARNI) therapy without reaching statistical significance, Pfeffer said at the American College of Cardiology (ACC) virtual meeting.

Notably, several pre-specified analyses of the more than 5,600 people in the trial suggested incremental clinical benefits of sacubitril/valsartan over ramipril post-MI:

• On subgroup analysis, people ages 65 and older (P=0.007 for interaction) and those who received percutaneous coronary intervention (PCI; P=0.005 for interaction) showed benefit for the primary endpoint
• Secondary analysis by total recurrent adjudicated events showed the primary outcome to be reduced with sacubitril/valsartan (8.4% vs 10.1%, RR 0.79, 95% CI 0.65-0.97)
• Counting all investigator-reported events (without clinical events committee adjudication) resulted in significant benefit of sacubitril/valsartan for the primary outcome (9.1% vs 10.8%, HR 0.85, 95% CI 0.75-0.96)

Pfeffer reported that safety and tolerability of sacubitril/valsartan in the trial was generally comparable to that of the ACE inhibitor. Hypotension was elevated among sacubitril/valsartan recipients (28.4% vs 22.0%), however.

Nevertheless, the data do support sacubitril/valsartan being safe, and time will tell if there are subgroups of post-MI patients who could use this drug, commented ACC session co-chair Athena Poppas, MD, of Brown University School of Medicine and the Lifespan Cardiovascular Institute in Providence, Rhode Island.

It was thought that ARNI therapy could also work for this population given that valsartan preserved most of the mortality benefit of captopril in VALIANT, and that sacubitril/valsartan reduced heart events compared with enalapril in PARADIGM-HF.

Pfeffer noted that mortality rates of acute MI survivors with left ventricular dysfunction had been in the 30% range at the inception of this field before ACE inhibitors proved their survival benefit in studies like SAVE in the 1990s. These medications have been a mainstay in therapy ever since.

“The last 15 to 20 years, we have had a dramatic improvement in mortality rate. Now we’re down to a third of where we were just 2 decades ago. That’s because of the use of evidence-based medicines. We’re trying to move this bar down, it’s becoming harder and harder, but it’s a task we need to pursue,” Pfeffer said.

“Of course it would be hard to show benefit on top of [ACE inhibitors],” agreed ACC panelist Lynne Stevenson, MD, of Vanderbilt University Medical Center in Nashville.

PARADISE-MI participants were 5,661 people randomized to sacubitril/valsartan or ramipril in 41 countries, mostly in Europe.

All were people enrolled within days of an acute MI who had left ventricular ejection fraction (LVEF) 40% or below and/or pulmonary congestion. In addition, patients were required to have a risk enhancer such as older age, diabetes, or atrial fibrillation.

The two groups shared comparable baseline characteristics, with a mean age of 64, fewer than a quarter being women, and whites accounting for three-quarters of the cohort.

Panelist Anne Curtis, MD, of University of Buffalo in New York, pointed out that there were few Black participants and women in the trial.

“That’s what happens when you go to 41 countries,” Pfeffer said in acknowledging the race issue. However, he said sex makeup of the study cohort is reflective of the acute MI population.

PARADISE-MI participants had survived a ST-segment elevation in three out of four cases. Nearly 90% of people had received PCI and were enrolled on average 4.3 days post-MI. Mean LVEF was 37%.