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Sacubitril-valsartan provides no mortality benefit compared with ramipril in acute MI with reduced ejection fraction

26th November 2021

Sacubitril-valsartan offers no mortality advantage in acute MI patients and a reduced ejection fraction compared with ramipril alone

Using sacubitril-valsartan in those experiencing an acute myocardial infarction (MI) and an ejection fraction lower then 40% appears to offer no mortality benefit over the use of ramipril alone. This was the conclusion of a trial by the PARADISE-MI researchers at the Cardiovascular Division, Brigham and Women’s Hospital, Boston, US.

The mortality benefits achieved from the use of angiotensin converting enzyme (ACE) inhibitors in randomised, placebo-controlled trials among patients with left-ventricular dysfunction or heart failure, is well established and is independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Moreover, the beneficial effects of ACE inhibitors also extents to the angiotensin-receptor blocker drugs such as valsartan.

Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds which have a favourable effect on the pathogenesis of heart failure. Inhibition of neprilysin with sacubitril, therefore maintains natriuretic peptides and the combination of sacubitril-valsartan has been approved for the management of patients with chronic heart failure and a reduced ejection fraction.

Nevertheless, whether this combination would be effective among patients suffering an acute MI without prior heart failure but with a reduced ejection fraction was the subject of the present study by the US team. They conducted the Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction (PARADISE-MI), which was an international, randomised, double-blind, active comparator trial, comparing sacubitril-valsartan with ramipril alone. The trial recruited patients with a spontaneous MI within 0.5 to 7 days before presentation in association with a reduced ejection fraction (< 40%), pulmonary congestion or both. Included patients were randomised 1:1 to sacubitril-valsartan or ramipril 5mg, both given twice daily in addition to any recommended therapy. The composite primary outcome was death from cardiovascular causes or incident heart failure.


A total of 5661 patients with an average age of 63.7 years (24.1% women) and a mean ejection fraction of 36%, were randomised to either therapy and followed up for a median duration of 22 months. There were 338 (11.9%) primary outcome events in the sacubitril-valsartan group and 373 (13.2%)in the ramipril group and this difference was non-significant (hazard ratio, HR = 0.90, 95% CI 0.78 – 1.04, p = 0.17). Similarly, death due to cardiovascular causes was also not different (HR = 0.91, 95% CI 0.78 – 1.07), as was hospitalisation for heart failure or outpatient heart failure (HR = 0.84, 95% CI 0.70 – 1.02) and death due to any cause (HR = 0.88, 95% CI 0.73 – 1.05).

The authors concluded that sacubitril-valsartan offered no benefit survival benefit among those with an acute MI and a reduced ejection fraction.


Pfeffer MA. et al. Angiotensin Receptor–Neprilysin Inhibition in Acute Myocardial Infarction. N Eng J Med 2021