In a prespecified pooled analysis, sacubitril and valsartan dual therapy was associated with a reduction in cardiovascular (CV) and renal events in the setting of heart failure (HF) with mildly reduced or preserved ejection fraction, compared with valsartan monotherapy. These findings were published in the European Heart Journal.
Data for this study were sourced from the multicenter, double-blind, randomized, active-controlled trials PARAGLIDE-HF (ClinicalTrials.gov Identifier: NCT03988634) and PARAGON-HF (ClinicalTrials.gov Identifier: NCT01920711).
Patients with HF with mildly reduced or preserved ejection fraction, defined as a left ventricular ejection fraction (LVEF) of greater than 40% (PARAGLIDE-HF) or 45% or greater (PARAGON-HF) were randomly assigned to receive sacubitril/valsartan (n=541) or valsartan (n=547) within 30 days of a worsening HF event.
The primary outcome for this prespecified analysis was the composite event of initial and recurrent HF hospitalizations, emergency department visits, and CV mortality.
The sacubitril/valsartan and valsartan recipients were aged mean 70.5 (SD, 10.4) and 71.2 (SD, 10.2) years, 48.4% and 45.9% were men, 77.8% and 79.2% were White, had a mean LVEF of 56.6% (SD, 8.1%) and 56.1% (SD, 8.0%), 97.8% and 99.1% used loop diuretics, 83.5% and 83.0% used angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and 81.5% and 79.0% used beta-blockers, respectively.
The sacubitril/valsartan cohort was associated with a lower rate of the primary composite outcome (mean, 27.5 events per 100 patient-years [PY]) compared with the valsartan monotherapy group (mean, 34.5 events per 100 PY), indicating a significant reduction (rate ratio [RR], 0.78; 95% CI, 0.61-0.99; P =.042) among total worsening HF events and CV mortality.
In addition, the dual therapy regimen was associated with a significant reduction in total HF hospitalizations and CV mortality (RR, 0.76; 95% CI, 0.60-0.97; P =.029) and worsening renal function (RR, 0.71; 95% CI, 0.54-0.94; P =.017) compared with the monotherapy regimen.
Among the entire PARAGLIDE-HF and PARAGON-HF populations, not just those randomly assigned within 30 days of a worsening HF event, sacubitril/valsartan (n=2640) was favored over valsartan (n=2622) for reducing risk for the primary composite outcome (RR, 0.86; 95% CI, 0.75-0.98; P =.027); the composite of total HF hospitalizations and CV mortality (RR, 0.87; 95% CI, 0.76-0.99; P =.040); the composite of 50% decline or greater in estimated glomerular filtration rate, end-stage renal disease, or renal mortality (hazard ratio [HR], 0.60; 95% CI, 0.44-0.83; P =.002); and worsening renal function (odds ratio [OR], 0.72; 95% CI, 0.63-0.82; P <.001).
However, dual therapy was associated with increased risk for symptomatic hypotension compared with monotherapy (OR, 1.50; 95% CI, 1.31-1.72; P <.001).
In subgroup analyses, no significant group interactions were observed. However, when stratified by LVEF, dual therapy had a significant effect for reducing the primary outcome among patients with LVEF of 60% or less in the primary analysis group (RR, 0.70) or full cohort (RR, 0.78), but no significant effect was observed for those with higher LVEF (RR range, 1.04-1.09).
This analysis was limited by differences among the included parent studies, missing patient-reported outcome measures for certain endpoints, and reliance on investigator-reported data regarding renal mortality.
The study authors concluded, “These pre-specified pooled analyses of PARAGON-HF and PARAGLIDE-HF including over 5,000 participants worldwide strengthen the current evidence base supporting the use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, especially among those with an LVEF below normal, and irrespective of care setting.”
Disclosures: This research was supported by Novartis Pharmaceuticals Corporation. One or more study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Vaduganathan M, Mentz RJ, Claggett BL, et al. Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF. Eur Heart J. Published online May 21, 2023. doi:10.1093/eurheartj/ehad344