May 15, 2021— Sacubitril-valsartan was no better than the angiotensin-converting enzyme (ACE) inhibitor ramipril for prevention of major cardiovascular adverse events, when initiated in the days following an acute myocardial infarction (MI) in patient with heart failure. Findings were presented at the virtual annual meeting of the American College of Cardiology, which took place from May 15 to 17.
Previous research has demonstrated that the combination of sacubitril and valsartan was more beneficial than an ACE inhibitor for patients with symptomatic heart failure and reduced ejection fraction. “With that, we ask the question of whether sacubitril-valsartan would be superior to an ACE inhibitor if used in patients with acute MI,” said Marc A. Pfeffer, MD, PhD, of Harvard University in Boston, during his presentation of the data.
For the multinational PARADISE-MI trial, 5661 patients at high-risk of cardiovascular death and heart failure were randomized to receive sacubitril-valsartan 97 mg-103 mg twice a day (n = 2830) or the ACE inhibitor ramipril 5 mg twice a day (n = 2831). All patients had experienced an acute MI 0.5 to 7 days previously and had a left ventricular ejection fraction (LVEF) ≤ 40% and/or transient pulmonary congestion, in addition to having at least another cardiovascular risk factor. Patients with prior heart failure, who were clinically unstable, or who had impaired kidney function were excluded.
The primary endpoint was the composite of cardiovascular death, heart failure hospitalization, or outpatient development of heart failure. Secondary endpoints included cardiovascular death or first heart failure hospitalization.
Baseline characteristics of the patients were similar in both groups. Overall, their mean age was 64 years, 24% were women, and 43% had diabetes. Patients had the index acute MI within 4.3 days of starting therapy, on average.
After a median follow-up of 23 months, there were 338 primary outcome events in the sacubitril-valsartan group, compared with 373 with ramipril, for a hazard ratio 0.90 (95% confidence interval 0.78−1.04, P = .17). Similarly, each of the individual primary endpoint components showed a nonsignificant trend toward risk reduction with sacubitril-valsartan.
The pattern was similar for the secondary endpoint, with nonsignificant trends favoring sacubitril-valsartan for cardiovascular death or first heart failure hospitalization (308 vs 335 events, P = 025), heart failure hospitalization or outpatient heart failure (201 vs 237 events, P = .07), cardiovascular death, nonfatal MI, or nonfatal stroke (315 vs 349 events, P = .18), and all-cause death (213 vs 242 events, P = .16). Only the outcome of cardiovascular death and total hospitalizations for heart failure, MI, or stroke was significantly superior with sacubitril-valsartan (591 vs 692 events; hazard ratio 0.84, 95% confidence interval 0.70−1.00, P = .045).
A prespecified exploratory analysis examined the first and recurrent clinical endpoint committee adjudicated events, which comprised heart failure hospitalization, outpatient heart failure, and cardiovascular death. The risk reduction was significant with sacubitril-valsartan, compared with ramipril (rate ratio 0.79, 95% confidence interval 0.65−0.97, P = .02). In addition, investigator-reported outcomes for cardiovascular death, heart failure hospitalization, and outpatient heart failure also favored sacubitril-valsartan, compared with ramipril, with a hazard ratio of 0.85 (95% confidence interval 0.75−0.96, P = .01).
Just over 80% of patients in both groups experienced adverse events, with a serious adverse event rate of about 40% in each. The most common adverse event was hypotension, which occurred in 28.4% taking sacubitril-valsartan and 22.0% taking ramipril. Angioedema occurred 0.5% of patients on sacubitril-valsartan and 0.6% on ramipril. Laboratory values that included creatinine, potassium, and liver enzymes showed no difference between the two groups.
About 18% of patients in each group discontinued the drug, and 13% in each group discontinued due to adverse events, usually cough, hypotension, renal impairment, or hyperkalemia.
“We conclude, in this vigorously managed, enhanced risk, acute MI population, compared to active therapy with ramipril, sacubitril-valsartan did not result in a lower rate of cardiovascular death, heart failure hospitalization, or outpatient heart failure”, said Dr. Pfeffer. He pointed out that mortality rates in this population have been dramatically reduced in the last 15 to 20 years due to the use of evidence-based medicine. “We are trying to keep moving this this bar down, and it is becoming harder and harder, but it is a task we all need to continue to pursue”, he said.
PARADISE-MI was supported by Novartis.