Sacubitril/Valsartan Compared to Ramipril in High-Risk Post-Myocardial Infarction Patients Stratified According to Use of Mineralocorticoid Receptor Antagonists: Insight from the PARADISE MI Trial

Morten Schou; Brian Claggett; Zi Michael Miao; Alberto Fernández; Gerasimos Filippatos; Christopher B. Granger; Karola Jering; Aldo P. Maggioni; Finnian R. Mc Causland; Jean‐Lucien Rouleau; Freny Vaghaiwalla Mody; Peter van der Meer; Dragoş Vinereanu; Martina M. McGrath; Yinong Zhou; Douglas L. Mann; Scott D. Solomon; Philippe Gabríel Steg; Eugene Braunwald; John J.V. McMurray; Marc A. Pfeffer; Lars Køber

doi:10.1002/ejhf.3079

Why the study?

It was unknown whether the safety and clinical endpoints of sacubitril/valsartan are affected by mineralocorticoid receptor antagonists in high-risk myocardial infarction patients.

Does baseline mineralocorticoid receptor antagonist (MRA) use modify the clinical efficacy and safety of sacubitril/valsartan compared to ramipril in high-risk post-myocardial infarction patients with left ventricular systolic dysfunction and/or pulmonary congestion?

Structured PICO

Does baseline mineralocorticoid receptor antagonist (MRA) use modify the clinical efficacy and safety of sacubitril/valsartan compared to ramipril in high-risk post-myocardial infarction patients with left ventricular systolic dysfunction and/or pulmonary congestion?

P

Population

5,661 adults (aged ≥18 years, 24% female) without prior heart failure hospitalized for acute myocardial infarction (0.5–7 days prior to randomization) complicated by left ventricular systolic dysfunction (LVEF ≤40%), pulmonary congestion requiring IV treatment, or both, plus at least one risk-enrichment factor (age ≥70 years, diabetes mellitus, previous MI, eGFR <60 ml/min/1.73m², atrial fibrillation, LVEF <30%, Killip class III or IV, or STEMI without reperfusion within 24 hours), stratified by baseline mineralocorticoid receptor antagonist (MRA) use (n=2,338 [41%] with MRA; n=3,323 [59%] without MRA). Multinational cohort (69% Europe and North America, 31% outside Europe and North America). Exclusions: hemodynamic instability within 24 hours, eGFR <30 ml/min/1.73m², serum potassium >5.2 mmol/L, history of angioedema.

I

Intervention

Sacubitril/valsartan (uptitrated to 97–103 mg twice daily) initiated without a run-in phase, evaluated with and without baseline mineralocorticoid receptor antagonist (MRA) background therapy

C

Comparator

Ramipril (uptitrated to 5 mg twice daily) initiated without a run-in phase, evaluated with and without baseline mineralocorticoid receptor antagonist (MRA) background therapy (prior ACE inhibitors or ARBs discontinued at randomization; other background therapy at physician discretion)

O

Outcome

Composite of first occurrence of cardiovascular death or incident heart failure (hospitalization for heart failure or outpatient symptomatic heart failure treated with IV or sustained oral diuretic therapy), adjudicated by Clinical Endpoint Committee (CEC) or investigator-reportedcomposite

Concomitant use of a mineralocorticoid receptor antagonist does not modify the efficacy or safety profile (including hyperkalemia and drug discontinuation) of initiating sacubitril/valsartan versus ramipril in high-risk post-MI patients with left ventricular dysfunction or congestion.

Limitations

Post-hoc exploratory subgroup analysis of a trial that did not meet its primary endpoint, with no adjustment for multiple comparisons
Non-randomized allocation of MRA (prescribed at clinician discretion), introducing potential confounding by indication
Inability to differentiate between specific MRA agents (spironolactone vs. eplerenone) and lack of precise data on MRA doses or exact date of initiation
Potential lack of statistical power for subgroup interaction analyses
Limited generalizability due to underrepresentation of women (24%) and patients outside Europe and North America (31%), as well as careful clinical trial monitoring that may not reflect daily practice risks of hyperkalemia and renal dysfunction

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Implication

MRA co-use did not modify ARNI safety or efficacy vs ramipril post-MI; leaves open confirmation in dedicated prospective trials.

Abstract

Aim It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor–neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high-risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. Methods and results Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77–1.19 and HRMRA– 0.87, 95% CI 0.71–1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator-reported endpoints were evaluated (p = 0.61 for interaction). Conclusions Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post-MI setting in patients with LVSD and/or congestion.

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Cite This Study

Schou et al. (2023) studied this question.

synapsesocial.com/papers/6a7ddfa0b590a867d6a13fea https://doi.org/10.1002/ejhf.3079

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Sacubitril/Valsartan Compared to Ramipril in High-Risk Post-Myocardial Infarction Patients Stratified According to Use of Mineralocorticoid Receptor Antagonists: Insight from the PARADISE MI Trial

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Sacubitril/Valsartan Compared to Ramipril in High-Risk Post-Myocardial Infarction Patients Stratified According to Use of Mineralocorticoid Receptor Antagonists: Insight from the PARADISE MI Trial

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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