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Variation in Renal Function With Sacubitril/Valsartan in Heart Failure
Quick Takes
- Early, moderate declines in eGFR with initiation of sacubitril/valsartan for HF management are common (~10% of patients).
- These early declines in eGFR do not impact CV outcomes and patients still receive similar benefits from the medication when compared to patients without an eGFR decline.
Study Questions:
In patients with heart failure (HF) with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) starting on sacubitril/valsartan (SV), what is the association between a moderate decrease in estimated glomerular filtration rate (eGFR) (>15%) and cardiovascular (CV) outcomes?
Methods:
This is a post hoc analysis of the PARADIGM-HF (HFrEF, enalapril vs. SV) and PARAGON-HF (HFpEF, valsartan vs. SV) randomized control trials. In each trial, there were sequential control medication and SV run-in periods. Patients were excluded prior to randomization from the study for an eGFR declined to <30 mL/min/1.73 m2 in PARADIGM-HF or <25 mL/min/1.73 m2 in PARAGON-HF. Patients were also excluded if eGFR decreased >35%. The primary endpoints of the trials were a composite of CV death and first HF hospitalization in PARADIGM-HF and a composite of CV death and total HF hospitalizations in PARAGON-HF. For this study, an eGFR decline >15% during the run-in period was considered for the analysis. Predictors of eGFR decline were identified. Associations to subsequent CV outcomes were made.
Results:
After exclusion of patients for significant renal dysfunction during the run-in phase, the rates of eGFR decline >15% were noted in 919 of 8,096 patients (11%) in PARADIGM-HF and in 461 of 4,665 patients (10%) in PARAGON-HF when transitioning to SV. In PARADIGM-HF, no eGFR decline was seen in 52% of patients and an eGFR decline of ≤15% was seen in 37% of patients transitioning to SV. In PARAGON-HF, no eGFR decline was seen in 48% of patients and an eGFR decline of ≤15% was seen in 42% of patients transitioning to SV. Many patients had partial recovery of renal function at 16 weeks after randomization. After multivariable modeling, more severe HF (New York Heart Association [NYHA] class III or IV) was significantly associated with an eGFR decline in the trials. For PARAGON-HF, systolic blood pressure, history of hypertension, and female sex were associated with an eGFR decline.
There was no clear association between an eGFR decline with SV and development of the primary outcome (PARADIGM-HF: hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.87-1.16; p = 0.94) (PARAGON-HF: rate ratio [RR], 1.26; 95% CI, 0.98-1.61; p = 0.07). Also, there was no difference in the treatment benefit of SV between the eGFR decline versus no eGFR decline groups (PARADIGM-HF: HR, 0.69; 0.53-0.90 vs. HR, 0.80; 0.73-0.88; p for interaction = 0.32) (PARAGON-HF: RR, 0.84; 95% CI, 0.52-1.36 vs. RR, 0.87; 95% CI, 0.75-1.02; p for interaction = 0.92).
Conclusions:
An early eGFR decline >15% with initiation of SV is not associated with poor CV outcomes, with similar treatment benefit when compared to no eGFR decline.
Perspective:
Medications like SV are critical for the management of patients with HF. It is not uncommon to see worsening in renal function with the initiation of these medications, which in many cases represent altered hemodynamics and physiology rather than kidney injury. In fact, there are renal protective aspects to these medications. The work by these authors highlights that while an early decline in eGFR occurs in about 10% of patients that are started on SV (excluding those that have more significant renal dysfunction during the run-in phase), there is no associated worsening of CV outcomes. This provides health care providers reassurance that these initial changes in renal function in general are not a reason for discontinuation of the medication.
Clinical Topics: Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Hypertension
Keywords: Blood Pressure, Enalapril, Geriatrics, Glomerular Filtration Rate, Heart Failure, Hemodynamics, Hypertension, Kidney Diseases, Renal Insufficiency, Stroke Volume, Valsartan
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