Reference: N Engl J Med. 2019 Oct 24;381(17):1609-1620 (level 2 [mid-level] evidence)
Heart failure (HF) is a common condition, often associated with significant morbidity and mortality. Heart failure is broadly categorized as patients with reduced ejection fraction (EF)—less than 40%— or preserved EF—greater than 50%. Among patients with reduced EF, the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, has led to a reduced risk of hospitalization or death from cardiovascular causes (NEJM 2014 Sep 11). However, the effects of this drug in patients with preserved EF or near preserved EF is uncertain. The study to be reviewed offers evidence to address its efficacy in this population.
A recent randomized, double-blind, active-comparator trial was performed to evaluate the efficacy of ARNI in patients with heart failure with preserved ejection fraction (NEJM 2019 Oct). 5,746 adults ≥ 50 years old with NYHA class II-IV heart failure who had an ejection fraction ≥ 45%, elevated natriuretic peptides, structural heart disease (left atrial enlargement or left ventricular hypertrophy on echocardiography), and were on diuretic therapy entered a run-in period during which they received half the target dose of valsartan for 1-2 weeks followed by half the target dose of sacubitril/valsartan (neprilysin inhibitor) for 2-4 weeks. 4,822 adults (mean age 72 years) who did not develop unacceptable side effects during the run-in period were randomized to sacubitril/valsartan target dose 97 mg/103 mg twice daily vs. valsartan target dose 160 mg twice daily. Primary outcome was a composite of cardiovascular mortality and total hospitalizations for heart failure (first and recurrent). Secondary outcomes included change from baseline to 8 months in the clinical summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ) (100-point scale with higher score indicating fewer symptoms and limitations) and the New York Heart Association (NYHA) class, first signs of renal decline (decrease in estimated glomerular filtration rate [eGFR] >50%, development of end-stage renal disease [ESRD], or death due to renal failure), and mortality from any other cause. Patients were followed for a median of 35 months.
There were 894 primary events (690 hospitalizations for HF and 204 deaths from cardiovascular causes) in 526 patients in the sacubitril/valsartan group compared to 1,009 primary events (797 hospitalizations for HF and 212 deaths from cardiovascular causes) in 557 patients in the valsartan group (rate ratio 0.87, 95% CI 0.75-1.01). Incidence of cardiovascular death was 8.5% in the sacubitril/valsartan group and 8.9% in the valsartan group (hazard ratio 0.95, 95% CI 0.79-1.16). In a subgroup analysis based on percentage of left ventricular ejection fraction (LVEF), sacubitril/valsartan was associated with reduced rate of the primary outcome compared to valsartan in patients with a LVEF of 45%-57%, but no significant difference among patients with LVEF > 57%. Among secondary outcomes, improvement in NYHA class occurred in 15% of patients in the sacubitril/valsartan group compared to 12.6% of patients in the valsartan group (odds ratio 1.45, 95% CI 1.13-1.86) and renal decline occurred in 1.4% of patients in the sacubitril/valsartan group compared to 2.7% of patients in the valsartan group (hazard ratio 0.5, 95% CI 0.33-0.77). There were no statistically significant differences in KCCQ score or death from any cause between the two groups.
The combination medication sacubitril/valsartan appears to be beneficial in a subgroup of patients with an EF in the lower part of the range studied (45%-57%), showing reduced risk of cardiovascular mortality and hospitalization for HF compared to valsartan alone in adult patients. However, benefit may not persist in patients with EF in the upper range (>57%) and showed no significant benefit overall in patients with preserved EF.There were a few limitations in the study. One potential limitation included the lack of differentiating patients based on other cardiovascular diseases known to have higher EF but diminished responses to standard treatment, such as amyloidosis. The initial run-in period could have also influenced results since both groups did receive a lower dose of the experimental drug prior to randomization. Subgroup analysis also removes randomization of patients and potentially could introduce confounding variables. Given the scarcity of clinical trials, more research is needed to further assess and understand the benefits of ARNIs in the subgroup of patients with heart failure with mid-range ejection fraction.
For more information, see Heart Failure with Preserved Ejection Fraction in DynaMed.
Brett Prestia is a current second year Family Medicine resident at Memorial University Medical Center in Savannah, Georgia. Prior to his residency he graduated medical school in North Carolina and received an undergraduate history degree from the College of William & Mary in Virginia. After residency he plans on pursuing a Hospice & Palliative care fellowship. He currently serves on the ACOFP Resident Council, the HCA Journal of Medicine Advisory Board, and is Chair-elect of the Osteopathic Medicine Interest Group of the AAHPM. When not at work he enjoys spending time with his family, tasting local cuisine, touring historical sites, and going on long runs.
Dr. Marvin Sineath is the faculty advisor for Dr. Prestia.