At the 70th annual American College of Cardiology (ACC) 2021 meeting, results were presented for the PARADISE-MI trial, which investigated whether Entresto (sacubitril/valstartan) decreases the risk of heart failure (HF) or cardiovascular (CV) death compared to an angiotensin-converting enzyme (ACE) inhibitor, Ramipril, in the enhanced risk of acute myocardial infarction (AMI) population. Evidence from previous trials had demonstrated that Entresto was superior to the ACE inhibitor, Ramipril, for patients who have symptomatic HF with reduced ejection faction (HFrEF), in terms of reducing HF events and total mortality. PARADISE-MI missed its primary endpoint of a 15% reduction in HF events needed to demonstrate the superiority of Entresto, first-in-class angiotensin receptor neprilysin inhibitor (ARNI) over Ramipril, in the AMI participant population. However, overall, there was an observed 10% reduction (p=0.17) in the Entresto group and positive reports of a reduced number of HF events by investigators of the trial. From these results, it remains to be observed whether physicians are likely to prescribe the drug to a broader patient group and whether the incremental benefit has actual clinical value to drive the already low uptake of Entresto. GlobalData predicts that Novartis’s Entresto, currently approved for the chronic HF market, will likely remain at its current low uptake among physicians due to the lack of significant clinical data demonstrating wider potential application of the drug in the AMI population. Furthermore, the superiority of the established ACE inhibitor for treating Chronic HF patients will likely remain as Entresto uptake has had pricing and access issues, coupled with a modest clinical benefit over much cheaper standard of care from ACE inhibitors and clinical trial faults that have all created doubt among prescribers.
PARADISE-MI enrolled 5,669 participants from 41 countries who had previously had an AMI within the last 7 days (mean 4.3 days). None of these patients had a previous history of HF, but they all had transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional risk factor for HF or death from age ≥70 years, estimated glomerular filtration rate <60mL/min/1.73m2, diabetes, prior MI, atrial fibrillation, LVEF <30, Killip class ≥III, or ST-elevation myocardial infarction (STEMI) without reperfusion. Of each study cohort 92% were on dual antiplatelet therapy, 85% were on a beta-blocker, and 78% were on an ACE inhibitor or angiotensin receptor blocker (ARB). Patients were randomized to either Ramipril, which had a target dose of 5mg BID, or Entresto, which had a target dose of 97/103mg BID, with three matching blinded dose titrations. At a follow-up of 23 months the combined endpoint of CV death, first HF hospitalisation or development of outpatient HF occurred in 11.9% of the Entresto group and 13.9% of the Ramipril group (HR 0.90; 95% CI 0.78–1.04). This approximately equated to 6.7 events per 100 patient-years for Entresto and 7.4 events per 100 patient-years for Ramipril.
Components of the primary outcome all demonstrated trends towards a lower number of HF events with Entresto directly compared against Ramipril, but these were not statistically significant. Two patients aged ≥65 and those who received the percutaneous coronary intervention (PCI) showed a trend toward greater benefit with Entresto than with Ramipril. For all secondary endpoints, the comparisons were favourable towards sacubitril/valsartan, CV death or HF hospitalisation (HR 0.91; 95% CI 0.78–1.07), HF hospitalisation or outpatient development of HF (HR 0.84; 95% CI 0.70–1.02), CV death, nonfatal MI, or nonfatal stroke (HR 0.90; 95% CI 0.77–1.05), CV death and total hospitalisations for HF, MI, or stroke (RR 0.84; 95% CI 0.70–1.00) and all-cause death (HR 0.88; 95% CI 0.73–1.05).
In an exploratory analysis looking at total events, the difference between Ramipril (n = 539) and Entresto (n = 452) did reach statistical significance in terms of reduction of events (RR 0.79; 95% CI 0.65–0.97). Similarly, investigator-reported outcomes demonstrated an advantage for Entresto over Ramipril when looking at the primary endpoint (HR 0.85; 95% CI 0.75–0.96), as well as for preventing the development of outpatient HF (HR 0.69; 95% CI 0.54–0.88).
Trial results from the PARADISE-MI demonstrate that treatment with Entresto did not result in significantly reducing the rate of CV death, HF hospitalisation, or outpatient HF requiring treatment in the AMI population in comparison to established ACE inhibitor Ramipril. Entresto will likely require further long-term studies to determine if it’s an effective treatment regimen for enhanced risk AMI patient populations There is also the opportunity to capture a significant share of the growing HF market, as the reservoir of MI survivors increases, leading to a steadily increasing demand for clinically beneficial therapies that improve long-term outcomes and quality of life years, as well as CV function.