Physicians' Academy for Cardiovascular Education

ARNI potential treatment for apparent resistant hypertension in HFpEF

Sacubitril–valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction

Literature - Jackson AM, Jhund PS, Anand IS et al. - Eur Heart J. 2021 Aug 15;ehab499. doi: 10.1093/eurheartj/ehab499.

Introduction and methods

The majority of patients with HFpEF have a history of hypertension [1-3]. Moreover, hypertension is often difficult to control in this patient population despite use of multiple antihypertensive medications [4,5]. Resistant hypertension is therefore common in patients with HFpEF. In the PARAGON-HF trial, more than 95% of patients had a history of hypertension [6,7]. This post-hoc analysis of the PARAGON-HF trial investigated the association between apparent resistant hypertension and outcomes in HFpEF and studied the effect of neprilysin inhibition on blood pressure in patients with HFpEF and apparent resistant hypertension.

PARAGON-HF was a phase III randomized trial which compared treatment with sacubitril/valsartan vs. valsartan on outcomes in patients with HFpEF. A total of 4795 patients were included in the current analysis. Included patients had NYHA functional class II-IV, LVEF ≥45%, elevated natriuretic peptide concentration, evidence of structural heart disease, and were treated with a diuretic. Patients with SBP >180 mmHg, SBP <110 mmHg, eGFR < 30 mL/min/1.73 m², and serum potassium >5.2 mmol/L were excluded. Patients with SBP>150-180 mmHg were excluded, unless they received three or more antihypertensive agents. Patients first entered two run-in periods consisting of valsartan 80 mg b.i.d. for 1-2 weeks, and sacubitril/valsartan 49/51 mg b.i.d. for 2-4 weeks. Patients were then randomized in a 1:1 ratio to receive either sacubitril/valsartan (target dose 97/103 mg b.i.d.) or valsartan (target dose 160 mg b.i.d.). Of note: plasma exposure of valsartan 103 mg in sacubitril/valsartan is equivalent to 160 mg of the standard valsartan formulation. 15.2% (n=731) had apparent resistant hypertension (defined as SBP ≥140 mmHg [≥135 mmHg if diabetes], despite treatment with valsartan, a calcium channel blocker, and a diuretic). 2.8% (n=135) of patients had apparent MRA-resistant hypertension (defined as SBP ≥140 mmHg [135 mmHg if diabetes], despite treatment with valsartan, a calcium channel blocker, a diuretic, and MRA). The primary composite outcome was first and recurrent HF hospitalizations and CV death. Median follow-up was 35 (IQR 30-41) months.

Main results


This post-hoc analysis of PARAGON-HF suggests that sacubitril/valsartan is an effective and safe treatment of apparent resistant hypertension and apparent MRA-resistant hypertension. These results warrant further investigation in a prospective hypertension trial in patients with resistant hypertension.


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