Update to Chapter 39: Evaluation and Management of Non-ST-Segment Elevation Myocardial Infarction and Chapter 40: ST-Segment Elevation Myocardial Infarction

Study Summary

The prospective, multicenter, international, randomized, controlled PARADISE-MI trial evaluated the efficacy and safety of sacubitril/valsartan (target dose 97/103 mg twice-daily) versus ramipril (target dose 5 mg twice-daily) in 5661 patients with reduced left ventricular ejection fraction (LVEF; ≤40%) following acute myocardial infarction (MI). At a median follow-up of 23 months, no significant differences in the primary composite end point of cardiovascular death, heart failure (HF) hospitalization or outpatient development of HF were found between the sacubitril/valsartan and ramipril groups (11.9% [6.7 per 100 patient-years] versus 13.2% [7.4 per 100 patient-years]; HR 0.90, 95% CI 0.78-1.04; P = 0.17; see accompanying Hurst’s Central Illustration). When the totality of first and recurrent events were analyzed, sacubitril/valsartan was associated with significantly lower rates of the primary composite end point compared with ramipril (8.4 versus 10.1 per 100 patient-years; rate ratio 0.79, 95% CI 0.65-0.97; P = 0.02). Hypotension was more frequent with sacubitril/valsartan compared with ramipril but permanent study discontinuation occurred similarly in both groups (17.8% versus 18.4%). All-cause death did not significantly differ between groups (7.5% versus 8.5%; HR 0.88, 95% CI 0.73-1.05; P = 0.16).

Commentary

Study Strengths: PARADISE-MI had large sample size, double-blind design, and included a high-risk population after acute MI, enhancing both the internal and external validity of the study.

Study Limitations: The findings of PARADISE-MI may be subject to type 2 statistical error since the expected event rates were significantly lower compared to historical data of trials comparing angiotensin converting enzyme inhibitors (ACEIs) or angiotensin-II receptor blockers versus placebo.

Next Steps/Clinical Perspectives: Patients who experience reduction in LVEF following acute MI are at increased risk of morbidity and mortality after hospital discharge. These patients benefit from therapy with an ACEI when compared with placebo. Sacubitril/valsartan is an angiotensin receptor–neprilysin inhibitor (ARNI) that has previously been shown to reduce risk of cardiovascular death and rehospitalization for HF in comparison with the ACEI enalapril in patients with chronic HF with reduced LVEF in the PARADIGM-HF trial. The results of PARADISE-MI indicate that, compared with the ACEI ramipril, sacubitril/valsartan does not reduce the rates of cardiovascular death, HF-hospitalization or outpatient development of HF in patients with reduced LVEF after acute MI. In a secondary analysis incorporating both primary and recurrent events, event rates were lower with sacubitril/valsartan; however, the magnitude of the benefit appeared to be modest. Possible explanations for the discordance with the findings of PARADIGM-HF include differences in active comparator (ramipril versus enalapril), disease acuity (acute versus chronic), pathology of cardiomyopathy (entirely post-MI versus a mixture of ischemic [60%] and nonischemic [40%]), and sample size.

In conclusion, PARADISE-HF demonstrates that the ARNI sacubitril/valsartan can be used in treatment of HF with reduced LVEF after acute MI with similar safety but no superior efficacy in comparison with the ACEI ramipril. Despite a lack of superiority, sacubitril/valsartan remains significantly more expensive than ACEIs for many patients. Accordingly, at this time, ACEIs remain standard of care for patients with reduced LVEF after acute MI.

Trial Reference