Sacubitril–Valsartan for Resistant Hypertension in HFpEF Patients
- In a post hoc analysis of the PARAGON-HF trial, resistant hypertension was noted in 15% of patients.
- Patients with resistant hypertension and nonresistant hypertension had similar baseline systolic BP. However, composite of HF hospitalization, MI, stroke, and CV death was higher only in the resistant hypertension group compared to controlled BP.
- Sacubitril–valsartan was more effective than valsartan in lowering BP in the resistant hypertension group with a lower risk for hyperkalemia and elevated creatinine.
What is the effect of neprilysin inhibition on blood pressure (BP) in patients with heart failure with preserved ejection fraction (HFpEF) and resistant hypertension?
This was a post hoc analysis of the PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial that enrolled patients with New York Heart Association class II-IV HF symptoms with left ventricular EF ≥45%, elevated B-type natriuretic peptide, treated with diuretics, and evidence of structural heart disease. Patients were randomized to sacubitril–valsartan or valsartan alone. All patients received valsartan 80 mg twice daily in the initial run-in period. Resistant hypertension was defined as systolic blood pressure (SBP) ≥140 mm Hg (≥135 mm Hg with diabetes) despite treatment with an angiotensin-receptor blocker, calcium channel blocker, and diuretic.
Of the 4,795 patients, 731 (15.2%) had resistant hypertension, 1,268 (26.4%) had hypertension that was not resistant, and 2,796 (58.3%) had controlled BP. Patients with resistant hypertension had a similar baseline SBP compared to those with nonresistant hypertension, but higher than in patients with controlled hypertension. Patients with resistant hypertension were more likely to be White, less likely Asian, and had a higher body mass index and more likely to have diabetes compared to those with controlled hypertension. Over a median follow-up of 35 months, composite of HF hospitalization and cardiovascular (CV) mortality was higher in patients with resistant hypertension compared to those with controlled BP. This was driven by a higher risk for HF hospitalizations. The composite of CV death, HF hospitalizations, stroke, and myocardial infarction (MI) was higher in patients with resistant hypertension. Decline in estimated glomerular filtration rate was greater in patients with resistant hypertension compared to controlled BP. Event rates were similar between patients with controlled hypertension and nonresistant hypertension. The proportion of patients with resistant hypertension achieving a controlled SBP was greater in the proportion randomized to sacubitril–valsartan (47.9% vs. 34.3%). Hypotension was more common with sacubitril–valsartan, but elevated creatinine and hyperkalemia were less common with sacubitril–valsartan compared to valsartan.
In a large randomized trial of HFpEF patients, resistant hypertension was noted in 15% of patients. These patients were at a higher risk for composite of HF hospitalization, CV mortality, stroke, and MI compared to patients with controlled BP. Patients with resistant hypertension had better controlled BP with sacubitril–valsartan than valsartan alone.
Hypertensive phenotype is the most common subtype of HFpEF. In the PARAGON-HF trial, 15% of enrolled HFpEF patients had resistant hypertension. The most significant finding of this study is that while the baseline SBP was similar between resistant and nonresistant hypertension, risk for adverse events was higher only in the resistant hypertension group compared to the controlled BP group. Sacubitril–valsartan was more effective in lowering BP in the resistant hypertension group compared to valsartan alone (mean difference between groups of 4 mm Hg). Incidence of renal injury and hyperkalemia was lower in the sacubitril–valsartan group as well. Major limitations of this study include lack of standardized BP measurements at follow-up visits and lack of data on doses of other antihypertensives that challenge the fact that these patients had true versus pseudo-resistant hypertension.
Keywords: Antihypertensive Agents, Blood Pressure, Calcium Channel Blockers, Creatinine, Diabetes Mellitus, Diuretics, Glomerular Filtration Rate, Heart Failure, Hyperkalemia, Hypertension, Hypotension, Myocardial Infarction, Natriuretic Peptide, Brain, Neprilysin, Secondary Prevention, Stroke, Stroke Volume, Valsartan
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