Sacubitril/Valsartan Does Not Outperform ACE Inhibitor after Heart Attack

Trial finds favorable safety but no significant reduction in subsequent heart failure or death

Contact: Nicole Napoli,, 202-669-1465

WASHINGTON (May 15, 2021) -

The heart failure drug sacubitril/valsartan did not significantly reduce the rate of heart failure or cardiovascular death following a heart attack compared to ramipril, an angiotensin converting enzyme (ACE) inhibitor proven effective in improving survival following heart attacks. Findings from the PARADISE-MI trial were presented at the American College of Cardiology’s 70th Annual Scientific Session.

The study is the first large trial to examine whether sacubitril/valsartan can reduce heart failure and associated hospitalizations and deaths in patients post-heart attack who face a high risk of developing heart failure. Patients taking sacubitril/valsartan were about 10% less likely than those taking ramipril to experience the study’s primary endpoint—a composite of cardiovascular death, heart failure hospitalization or development of symptomatic heart failure—falling short of the prespecified threshold of a 15% reduction required to demonstrate statistically significant improvement. However, according to the researchers, the trial found sacubitril/valsartan was well-tolerated, had a favorable safety profile and was associated with a trend toward improvement in the trial’s secondary endpoints, which included cardiovascular death or heart failure hospitalization; heart failure hospitalization or outpatient treatment for heart failure; cardiovascular death, non-fatal heart attack or non-fatal stroke; cardiovascular death and total hospitalizations for heart failure, heart attack or stroke; and death from any cause.

“Although we did not significantly reduce our primary endpoint, there were consistent findings that sacubitril/valsartan could represent an incremental improvement over ramipril,” said Marc Pfeffer, MD, PhD, Distinguished Dzau Professor of Medicine at Harvard Medical School and cardiologist at Brigham and Women’s Hospital, and the study’s lead author. “The results are encouraging, especially when considering recurrent heart failure events and not just the first heart failure events, but the study is not definitive. We did notice several aspects of heart failure development that were lessened with sacubitril/valsartan but to investigate these observations would require further evaluations.”

Heart failure is a condition in which the heart becomes too weak or too stiff to pump blood effectively to the rest of the body, causing fatigue, swelling and shortness of breath. While a heart attack does not always lead to heart failure, heart attack survivors are eight times more likely to develop heart failure than those who have not had a heart attack, which has led to an increased emphasis on preventing heart failure in these patients.

The PARADISE-MI trial enrolled 5,669 patients in 41 countries who had survived a heart attack less than a week before enrolling in the study. None of the patients had heart failure, but all were considered to face a high risk of developing it based on a measure of their heart’s pumping ability or fluid buildup in the lungs as well as at least one of eight additional risk-enhancing factors. Most patients were already taking medications to reduce heart disease risk before their heart attack, including antiplatelet therapy, blood pressure lowering medications and cholesterol lowering medications.

Half of the participants were randomly assigned to receive sacubitril/valsartan and half received ramipril. Most achieved the full dose of their assigned medication and kept taking it throughout the trial, which had a median follow-up period of 23 months.

The rate of the composite primary endpoint was 10% lower in patients taking sacubitril/valsartan compared with those taking ramipril. In an exploratory analysis of the total burden of heart failure including recurrent events, there was a 21% reduction observed with sacubitril/valsartan compared to ramipril. 

The rate of adverse events was equivalent in both groups, with no significant differences in the rates of allergic swelling of the airways (angioedema), abnormal potassium levels, renal impairment or liver abnormalities. Patients taking sacubitril/valsartan showed a slightly higher rate of hypotension while patients taking ramipril were slightly more likely to report coughing. These findings offer further reassurance that sacubitril/valsartan is safe to use for patients with heart failure, the indication for which it has been approved, researchers said.

“We found sacubitril/valsartan was as safe and well-tolerated as one of the best proven ACE inhibitors, even in an acutely ill population,” Pfeffer said. “This trial may not change guidelines, but it should make physicians even more comfortable using sacubitril/valsartan in their patients with heart failure.”

The study was funded by Novartis Pharmaceuticals.

Pfeffer will be available to the media in a virtual press conference on Saturday, May 15, at 10:15 a.m. ET / 14:15 UTC.

Pfeffer will present the study, “Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction (PARADISE-MI),” on Saturday, May 15, at 9 a.m. ET / 13:00 UTC, virtually.

ACC.21 will take place May 15-17 virtually, bringing together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow @ACCinTouch, @ACCMediaCenter and #ACC21 for the latest news from the meeting.

The American College of Cardiology envisions a world where innovation and knowledge optimize cardiovascular care and outcomes. As the professional home for the entire cardiovascular care team, the mission of the College and its 54,000 members is to transform cardiovascular care and to improve heart health. The ACC bestows credentials upon cardiovascular professionals who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. The College also provides professional medical education, disseminates cardiovascular research through its world-renowned JACC Journals, operates national registries to measure and improve care, and offers cardiovascular accreditation to hospitals and institutions. For more, visit


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