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
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.
- The primary outcome of first and recurrent HF hospitalizations and CV death occurred more often in patients with apparent resistant hypertension compared to those with controlled blood pressure (17.3 [95%CI 15.6-19.1] vs. 13.4 [95%CI 12.7-14.3] per 100 person-years), with an adjusted rate ratio of 1.28 (95%CI 1.05-1.57). This was driven by a greater risk of HF hospitalization as risk of CV death was not different between treatment groups.
- In patients with apparent resistant hypertension, sacubitril/valsartan reduced SBP to a greater extent than valsartan. Differences between treatment groups were -4.8 (SE -7.0 to -2.5) mmHg at week 4 (change from end of valsartan run-in to week 4) and -3.9 (SE -6.6 to -1.3) mmHg at week 16. In patients with apparent MRA-resistant hypertension, the between group differences were -8.8 (SE -14.0 to -3.5) mmHg at week 4 and -6.3 (SE -12.5 to -0.1) mmHg at week 16.
- The proportion of patients with apparent resistant hypertension achieving a controlled SBP by week 16 was significantly greater in the sacubitril/valsartan group compared to the valsartan group (47.9% vs. 34.3%, adjusted OR 1.78, 95%CI 1.18-5.89). This was also observed in patients with apparent MRA-resistant hypertension (45.6% vs. 28.4%, adjusted OR 2.63, 95%CI 1.18-5.89).
- Elevation of serum creatinine and potassium was less common, while hypotension was more common, with sacubitril/valsartan compared with valsartan in patients with apparent resistant hypertension.
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.