Treatment with sacubitril/valsartan, a pillar of therapy for patients with chronic heart failure with below-normal ejection fraction, came suggestively close to showing efficacy for preventing cardiovascular death or heart failure events in patients who have just had an MI but have no history of heart failure in a controlled trial with more than 5,600 patients.
Although sacubitril/valsartan (Entresto) fell short of producing a significant benefit, it did show good safety that was similar to the study’s comparator treatment, ramipril, an agent from the angiotensin-converting enzyme inhibitor class that is a mainstay of treatment in these patients.
“To say that, with no run-in, sacubitril/valsartan is as well tolerated and as safe as one of the best-studied ACE inhibitors – ramipril – in acutely ill MI patients, is a big statement,” said Marc A. Pfeffer, MD, at the annual scientific sessions of the American College of Cardiology. This high level of safety without gradual uptitration of sacubitril/valsartan (Entresto) “should lower barriers” to broader use of the dual-drug formulation for its approved indication in patients with chronic heart failure, especially patients with a left ventricular ejection fraction that is below normal. In addition, results from the PARADISE-MI trial suggested that “patients seemed to benefit before they develop heart failure. We couldn’t prove that, but we should build on this, and make it easier for patients to use this treatment,” Dr. Pfeffer said during a press briefing following his talk at the sessions.
Preventing heart failures to come
Treatment with sacubitril/valsartan in acute MI patients within a few days of their event “is perhaps addressing prevention of the heart failure that’s to come,” commented Lynne W. Stevenson, MD, designated discussant for the report and professor of medicine at Vanderbilt University Medical Center in Nashville. “Patients who are destined to develop heart failure are beginning their treatment early. The subgroup analyses suggest that it’s the sicker patients who benefited the most,” she said.
But Dr. Pfeffer stressed that “I don’t think this is a subgroup discussion. I would like to pursue this, but that’s up to the sponsor,” Novartis, the company that markets sacubitril/valsartan.
‘Exceedingly reassuring’ safety
The safety data that Dr. Pfeffer reported “are exceedingly reassuring. We didn’t see a signal of harm, and in some of the exploratory endpoints there was some evidence of benefit, so we need to encourage you to continue,” commented Mary N. Walsh, MD, medical director of the heart failure and cardiac transplantation program at Ascension St. Vincent Heart Center of Indiana in Indianapolis.
The PARADISE-MI (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) trial enrolled 5,669 patients with no history of heart failure within an average of 4 days following an acute MI at 495 sites in 41 countries during 2016-2020, with 8% of enrolled patients from the United States. Patients averaged 64 years of age, about three-quarters were men, about 43% had a history of diabetes, and only 1% were Black; Dr. Pfeffer noted that this is because most patients came from countries with low Black populations. The enrollment criteria required a left ventricular ejection fraction no greater than 40%, and among the enrolled patients this averaged about 37%.