Impact of Sacubitril/Valsartan Compared With Ramipril on Cardiac Structure and Function After Acute Myocardial Infarction: The PARADISE-MI Echocardiographic Substudy

Abstract

Background: Angiotensin-converting enzyme inhibitors attenuate left ventricular (LV) enlargement after acute myocardial infarction (AMI). Preclinical data suggest similar benefits with combined angiotensin receptor neprilysin inhibition, but human data are conflicting. The PARADISE-MI Echo Study (Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction) tested the effect of sacubitril/valsartan compared with ramipril on LV function and adverse remodeling after high risk-AMI.

Methods: In a prespecified substudy, 544 PARADISE-MI participants were enrolled in the Echo Study to undergo protocol echocardiography at randomization and after 8 months. Patients were randomized within 0.5 to 7 days of presentation with their index AMI to receive a target dose of sacubitril/valsartan 200 mg or ramipril 5 mg twice daily. Echocardiographic measures were performed at a core laboratory by investigators blinded to treatment assignment. The effect of treatment on change in echo measures was assessed with ANCOVA with adjustment for baseline value and enrollment region. The primary end points were change in LV ejection fraction (LVEF) and left atrial volume (LAV), and prespecified secondary end points included changes in LV end-diastolic and end-systolic volumes.

Results: Mean age was 64±12 years; 26% were women; mean LVEF was 42±12%; and LAV was 49±17 mL. Of 544 enrolled patients, 457 (84%) had a follow-up echo at 8 months (228 taking sacubitril/valsartan, 229 taking ramipril). There was no significant difference in change in LVEF (P=0.79) or LAV (P =0.62) by treatment group. Patients randomized to sacubitril/valsartan demonstrated less increase in LV end-diastolic volume (P=0.025) and greater decline in LV mass index (P=0.037), increase in tissue Doppler e'_lat (P=0.005), decrease in E/e'_lat (P=0.045), and decrease in tricuspid regurgitation peak velocity (P=0.024) than patients randomized to ramipril. These differences remained significant after adjustment for differences in baseline characteristics. Baseline LVEF, LV end-diastolic volume, LV end-systolic volume, LV mass index, LAV, and Doppler-based diastolic indices were associated with risk of cardiovascular death or incident heart failure.

Conclusions: Treatment with sacubitril/valsartan compared with ramipril after AMI did not result in changes in LVEF or LAV at 8 months. Patients randomized to sacubitril/valsartan had less LV enlargement and greater improvement in filling pressure. Measures of LV size, systolic function, and diastolic properties were predictive of cardiovascular death and incident heart failure after AMI in this contemporary, well-treated cohort.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT02924727.

Keywords: echocardiography; heart failure; myocardial infarction.

Figure 1.

Consort diagram of patient flow for the PARADISE-MI Echo sub-study.

Figure 2.

Changes in primary and secondary study endpoints from randomization to 8 months by treatment arm. Bar graphs show mean and 95% CI. Model 1 is adjusted for baseline value and region. Model 2 is adjusted for baseline value, region, age, history of prior PCI or CABG, AF, PAD, eGFR, and use of MRA at randomization. LVEF – left ventricular ejection fraction; LAV – left atrial volume; LVEDV – LV end-diastolic volume; LVESV – LV end-systolic volume; LVEDVi – LV end-diastolic volume index; LVESVi – LV end-systolic volume index

Figure 3.

Associations of baseline measures of cardiac structure and function with incidence of the composite of investigator-reported CV death, HF hospitalization, or outpatient HF. Hazard ratios are shown per standard deviation of measure to enable comparability between measures, as follows: LVEF – per 11.5% decrease; LVEDV – per 42.8 ml increase; LVESV – per 37.1 ml increase; MWT – per 0.16 cm increase; LVMi – per 24.9 g/m² increase; LA volume – per 17.2 ml increase; E wave – per 23.2 cm/s increase; TDI e’_ave – per 1.8 cm/s increase; E/e’_ave – per 4.9 unit increase; TR velocity – per 0.36 m/s increase.

Figure 4.

Linear continuous associations of (A) LVEF, (B) LVEDV, (C) LAV, and (D) E/e’ with incidence of investigator reported CV death, HF hospitalization, or outpatient HF. Fitted lines, hazard ratios, and p values are adjusted for age, sex, and randomized treatment assignment.