Lower Rehospitalization, Mortality Seen From Sacubitril/Valsartan Use for HFrEF

Entresto (sacubitril/valsartan) was first approved for use in heart failure with reduced ejection fraction (HFrEF) in 2015.

A high 3-month adherence rate to the angiotensin receptor neprilysin inhibitor (ARNI) Entresto (sacubitril/valsartan; Novartis) was seen among patients with heart failure with reduced ejection fraction (HFrEF) and Medicare coverage, in a recent study, and may be responsible for decreased hospitalization and mortality rates also seen among the cohort.

These findings appeared in a new issue of JACC: Heart Failure.

Despite the American College of Cardiology having the ARNI as its top treatment recommendation for HFrEF and that its benefits are well known among patients with HF, prescription rates and adherence remain low, which “may attenuate the clinical benefits,” the authors of this most recent analysis wrote. The primary goal of their retrospective observational cohort analysis was to close information gaps regarding possible associations between HF-related outcomes and rehospitalization and sacubitril/valsartan adherence.

“Recent data suggest that only 14% of US outpatients with HFrEF are prescribed sacubitril/valsartan and <10% of patients with HFrEF who are eligible for sacubitril/valsartan received a prescription at discharge from acute HF hospitalization,” the authors added.

Of the 897-patient cohort, close to 33% (n = 295) who had a sacubitril/valsartan prescription at discharge had at least an 80% proportion of days covered (PDC) rate, meaning that for at least 80% of the days in the ensuing 3 months after discharge, they adhered to that prescription regimen. In contrast, just over 67% (n = 602) had a PDC lower than 80%.

Follow-up periods were 90 days for medication adherence and 1 year for rehospitalization and mortality risk. Patient data were derived from the Get With the Guidelines–Heart Failure registry and linked with Medicare claims for at least 1 acute HF hospitalization from October 2015 to September 2018. All patients included in the final analysis had a hospital discharge with sacubitril/valsartan.

Among those with the higher PDC, at 90 days there was a 34% (HR, 0.66; 95% CI, 0.48-0.89) lower risk of all-cause rehospitalization and a 58% (HR, 0.42; 95% CI, 0.22-0.79) lower risk of death vs those with the lower PDC. At the 1-year mark, despite slight increases, these numbers were still reduced in the group with a PDC of at least 80%, by 31% (HR, 0.69; 95% CI, 0.56-0.86) and 47% (HR, 0.53; 95% CI, 0.38-0.74), respectively.

Individuals were excluded if they had a left ventricular assist device or a history of heart/lung transplantation.

In addition, 1-year rates of rehospitalization and mortality continued to drop, by 2% (HR, 0.98; 95% CI, 0.97-0.99) and 4% (HR, 0.96; 95% CI, 0.94-0.97), respectively, with each 5-percentage-point jump in PDC.

Medicare coverage for the patients in the study comprised fee-for-service and Part D prescription medication coverage for at least 6 months prior to their index hospitalization through at least 90 days post index hospitalization discharge.

The median (interquartile range) patient age in both groups was close to equal—77 (71-82) and 76 (70-82) years in the groups with less than 80% PDC and at least 80% PDC, respectively—and more than 60% of each group were male. Their median ejection fraction was 25% (20%-33%), 86% of the group with less than 80% PDC and 89% of the group with at least 80% PDC had a history of HF, the most common comorbidities were hyperlipidemia and hypertension, and 93% each were on beta-blockers at discharge.

Between-group differences also show that treatment with sacubitril/valsartan was initiated in more of the group with at least 80% PDC before their index hospitalization, there was a greater history of stroke/transient ischemic attack among patients with less than 80% PDC, and more of those with at least 80% PDC were on mineralocorticoid receptor antagonists (46.4% vs 36.5%).

Two additional measures show the following for outcomes after the adherence ascertainment period:

  • At 30 days, the group with at least 80% PDC had a 41% (HR, 0.59; 95% CI, 0.38-0.92) lower all-cause rehospitalization risk and a 58% (HR, 0.42; 95% CI, .021-0.87) lower HF-related hospitalization risk compared with the group with PDC less than 80%.
  • Among the 76.7% of patients with 1-year continuous Medicare Part D eligibility following their index hospitalization, 89.8% who began with less than 80% PDC stayed there and 48.2% of those who began with at least 80% PDC were at less than 80% PDC by the 1-year mark.

The authors note that with their findings possibly being “the first to describe the relationship between postdischarge sacubitril/valsartan adherence and subsequent clinical outcomes,” these data could be predictive of 1-year clinical outcomes and add to the current evidence that heart failure medication adherence needs to be targeted to improve patient outcomes.

“Patients with higher sacubitril/valsartan adherence within 90 days after discharge had lower adjusted risk of all-cause death and all-cause rehospitalization at 1 year, compared with patients with lower adherence,” they concluded. “These data support continued efforts toward improving adherence to sacubitril/valsartan as an important strategy for improving clinical outcomes in routine practice.”


Carnicelli AP, Li Z, Greiner MA, et al. Sacubitril/valsartan adherence and postdischarge outcomes among patients hospitalized for heart failure with reduced ejection fraction. JACC Heart Fail. Published online September 1, 2021. doi:10.1016/j.jchf.2021.06.018

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