No significant benefit of sacubitril/valsartan after acute MI: PARADISE-MI trial
USA: Sacubitril/valsartan does not significantly reduce the risk of heart failure (HF) or cardiovascular (CV) death for immediate post-myocardial infarction (MI) patients, compared with an ACE inhibitor, show findings from the PARADISE-MI trial. The study appears in the European Journal of Heart Failure.
According to the lead author, Marc A. Pfeffer, the safety and tolerability of sacubitril/valsartan in this acute MI population without a run-in was comparable to that of a proven, well-used ACE inhibitor. The prespecified observations of reductions in both the composite for CV total events, as well as investigator-reported events, support an incremental clinical benefit of sacubitril/valsartan, he noted.
Patients who survive an acute myocardial infarction (AMI) are at risk of developing symptomatic HF or premature death. Dr. Pfeffer and the team that sacubitril/valsartan, effective in the treatment of chronic HF, prevents the development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor.
PARADISE-MI is a multinational (41 countries), double-blind, active-controlled trial. The trial randomized patients within 0.5–7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Inclusion criteria included transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate <60 mL/min/1.73 m2, diabetes, prior myocardial infarction, atrial fibrillation, LVEF <30%, Killip class ≥III, ST-elevation myocardial infarction without reperfusion).
PARADISE-MI targeted 708 primary endpoints (cardiovascular death, HF hospitalization or outpatient development of HF). Randomization of 5669 patients occurred 4.3 ± 1.8 days from the presentation with index AMI. The mean age was 64 ± 12 years, 24% were women.
The majority (76%) qualified with ST-segment elevation myocardial infarction; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ± 9% and 58% were in Killip class ≥II.
Following are the key findings from the study:
- At a follow-up of 23 months, the combined endpoint of CV death, first HF hospitalization, or development of outpatient HF had occurred in 11.9% of the sacubitril/valsartan group and 13.9% of the ramipril group (HR 0.90). That translated to 7.4 events per 100 patient-years for ramipril and 6.7 events per 100 patient-years for sacubitril/valsartan.
- The components of the primary outcome all showed trends toward lower numbers of events with sacubitril/valsartan versus ramipril, but those also were not statistically significant.
- Among the 23 prespecified subgroups, only two—patients age ≥ 65 and those who received PCI—showed a trend toward greater benefit with sacubitril/valsartan than ramipril.
- For all secondary endpoints, the comparisons favored sacubitril/valsartan: CV death or HF hospitalization (HR 0.91); HF hospitalization or outpatient development of HF (HR 0.84); CV death, nonfatal MI, or nonfatal stroke (HR 0.90); CV death and total hospitalizations for HF, MI, or stroke (RR 0.84); and all-cause death (HR 0.88).
- In exploratory analysis looking at total events, however, the difference between ramipril (n = 539) and sacubitril/valsartan (n = 452) did reach statistical significance for a reduction in events (RR 0.79). Similarly, investigator-reported outcomes showed an advantage for sacubitril/valsartan over ramipril for the primary endpoint (HR 0.85), as well as for the development of outpatient HF (HR 0.69).
- Looking at adverse events, the sacubitril/valsartan group had more hypotension than did the ramipril group (28.4% vs 22.0%) but fewer reports of cough (9.0% vs 13.1%) or liver abnormalities (4.7% vs 5.9%).
- Drug discontinuation was similar in both groups, with fewer discontinuations for cough or hypotension in the sacubitril/valsartan group.
- During the trial, 242 people died in the ramipril arm and 213 died in the sacubitril/valsartan arm.
The researchers conclude that, despite the missed endpoint, sacubitril/valsartan was safe and supports an incremental clinical benefit.
Reference:
The study titled, "Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): design and baseline characteristics," is published in the European Journal of Heart Failure.
DOI: https://onlinelibrary.wiley.com/doi/full/10.1002/ejhf.2191
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