Review of the PARADISE-MI Trial

Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction

NEJM 2021:385:1845-55.

Background Over two decades had passed since the publications of the seminal trials comparing ACE inhibitors with placebo in post-MI patients with LV dysfunction and congestive heart failure (SAVE, AIRE and TRACE). The VALIANT trial, published in 2003, found that the ARB drug Valsartan was as effective as Captopril in improving survival and reducing cardiovascular morbidity in this patient population. Thus, for many years, a cornerstone of managing post-MI patients with LV dysfunction and heart failure involved afterload reduction with ACE inhibitors or ARBs.

Then in 2014, the landscape of heart failure management changed with the publication of the PARADIGM-HF trial which found that Entresto, a drug combining the ARB Valsartan and the neprilysin inhibitor Sacubitril, significantly reduced death and heart failure hospitalizations. We will review PARDIGM-HF later since it enrolled patients with chronic, stable heart failure and not post-MI patients. The rationale for the combination drug is that it simultaneously blocks the renin-angiotensin system and inhibits of the breakdown of several vasoactive peptides including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), serving to enhance vasodilation and reduce blood volume.

The PARADISE-MI trial sought to test the hypothesis that early initiation of Sacubitril-Valsartan in post-MI patients with LV dysfunction and congestive heart failure would reduce cardiovascular death or incident heart failure compared to the ACE inhibitor Ramipril.

Patients Adults without a history of heart failure who had a spontaneous MI within 0.5 to 7 days before presentation who had either a LVEF of </= 40%, pulmonary congestion requiring intravenous treatment, or both AND at least 1 of 8 prespecified risk augmenting features including: age >/= 70 years, diabetes, previous MI, eGFR <60, atrial fibrillation, LVEF <30%, Killip class III or IV, or a STEMI without reperfusion within 24 hours of presentation. Key exclusion criteria included clinical instability defined as receiving intravenous diuretics, vasodilators, inotropes or vasopressors within 24 hours of randomization; an eGFR <30; serum potassium >5.2 mmol/L; a history of angioedema or inability to take an ACEi or an ARB.

Baseline characteristics The average age of patients was 64 years and nearly 70% were men. Sixteen percent of patients had a prior MI, more than 40% had diabetes and two-thirds had hypertension. The average ejection fraction was 36% and two-thirds of patients had an anterior MI. Almost 60% had a Killip class of II or above. Patients were hemodynamically stable with an average blood pressure slightly above 120/70 mmHg and heart rate of 77 beats per minute. The average eGFR was 72. Almost 90% of patients underwent percutaneous coronary intervention and 80% received a drug eluting stent for the primary MI. At the time of randomization, nearly 80% of patients were on an ACE inhibitor or ARB, over 40% were on a MRA, 85% were on a beta blocker and 44% were on a diuretic.

Procedures Patients were randomized 1:1 to receive either Sacubitril-Valsartan or Ramipril. Treatment with ACE inhibitors or ARBs was discontinued at randomization. Clinical evaluations were scheduled for weeks 1, 2, and 4 and then at 2 and 4 months and every 4 months thereafter. Three doses of each drug were available to the investigators to use at their own discretion (1.25 mg, 2.5 mg, or 5 mg of ramipril administered twice daily; or 24 mg of sacubitril plus 26 mg of valsartan, 49 mg of sacubitril plus 51 mg of valsartan, or 97 mg of sacubitril plus 103 mg of valsartan administered twice daily), with the highest dose of each drug as the target.

Endpoints The primary study endpoint was a composite of cardiovascular death or incident heart failure, whichever occurred first. Incident heart failure was defined as hospitalization for heart failure or outpatient episodes of symptomatic heart failure treated with intravenous or sustained oral diuretic therapy.

Secondary endpoints were a composite of death from cardiovascular causes or hospitalization for heart failure; a composite of hospitalization for heart failure or an outpatient episode of symptomatic heart failure; a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; and the total number of (first or recurrent) nonfatal cardiovascular events (hospitalizations for heart failure, myocardial infarction, or stroke). Additional secondary outcomes included the number of deaths from cardiovascular causes and the total number of deaths. All prespecified outcomes were adjudicated by a clinical outcome committee blinded to treatment-group assignment.

Data on all reported adverse events and serious adverse events were compiled for safety assessments. Hypotension, hyperkalemia, renal dysfunction, cough, and angioedema were prespecified adverse events of interest, with reports of angioedema adjudicated by a separate committee.

PARADISE-MI was an event driven trial. The investigators estimated that 708 primary-outcome events would provide the trial with 80% power to detect a hazard ratio of 0.81 for the primary composite outcome in a time-to-event analysis, with the use of a two-sided alpha level of 0.05. They estimated that following 5650 patients for a mean of 19 months would provide the target number of primary events. That number represented an upward revision from the original plan that called for enrollment of 4650 patients. This was done on the basis of a prespecified blinded assessment of cumulative incidence that was performed when approximately half the patients had undergone randomization and had reached the 3-month time point.

Results 5661 patients were included in the final analysis; 2831 in the ramipril group and 2830 in the sacubitril-valsartan group. The mean follow-up time was 1.8 years or 22 months. Compared to ramipril, sacubitril-valsartan did not significantly reduce the composite primary endpoint of cardiovascular death or incident heart failure (12% vs 13%; HR 0.90; 95% CI 0.78-1.04) or any of the secondary endpoints including all-cause death (8% vs 9%; HR 0.88; 95% CI 0.73-1.05).

Serious adverse events (SAE) occurred in 40.3% of patients in the sacubitril-valsartan group compared to 39.8% in the ramipril group (p=0.58) and those leading to treatment discontinuation occurred in 12.6% vs 13.4%, respectively (p=0.39). Hypotension was significantly increased in the sacubitril-valsartan group (28.3% vs 21.9%; p<0.001) whereas cough was increased in the ramipril group (9.0% vs 13.1%; p<0.001). There were no other notable significant differences in other serious adverse events.

The average time to randomization in the trial was 4.3 days. At the final assessment, 67.5% of the sacubitril-valsartan group were receiving the target dose of 97-103 mg twice daily and 76.5% of the ramipril group were receiving the target dose of 5 mg twice daily.

Conclusions In patients with AMI complicated by a LVEF </= 40% or pulmonary congestion and at least 1 risk enhancing feature, sacubitril-valsartan did not significantly reduce cardiovascular death or incident heart failure compared to ramipril.

Hypotension was significantly increased with sacubitril-valsartan, with a number needed to harm of approximately 16 patients, and is likely what limited achievement of target dosing of the drug in the trial compared to ramipril (67.5% vs 76.5%).

The PARADISE-MI trial does not provide justification for use of sacubitril-valsartan over ACE inhibitors or valsartan alone in post-MI patients who would meet the inclusion criteria of the trial.