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

Abstract

Aims: Patients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on 'apparent resistant hypertension' in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril-valsartan with valsartan.

Methods and results: In this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). 'Apparent resistant hypertension' was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. 'Apparent mineralocorticoid receptor antagonist (MRA)-resistant' hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril-valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6-19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7-14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05-1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril-valsartan vs. valsartan in patients with apparent resistant hypertension [-4.8 (-7.0 to -2.5) and 3.9 (-6.6 to -1.3) mmHg] and apparent MRA-resistant hypertension [-8.8 (-14.0 to -3.5) and -6.3 (-12.5 to -0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril-valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30-2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18-5.89).

Conclusion: Sacubitril-valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA.

Clinical trial registration: PARAGON-HF: ClinicalTrials.gov Identifier NCT01920711.

Keywords: Blood pressure; Heart failure; Preserved ejection fraction; Sacubitril–valsartan.

Almost one in six patients with heart failure and preserved ejection fraction had apparent resistant hypertension in PARAGON-HF and this was associated with worse clinical outcomes; neprilysin inhibition reduced systolic blood pressure significantly in these patients.

Figure 1

Hazard and survival curves according to hypertension category. (A) Primary outcome. (B) Total heart failure hospitalizations. (C) Cardiovascular death, total heart failure hospitalizations, strokes, and myocardial infarctions. (D) Cardiovascular death. BP, blood pressure; CV, cardiovascular; HF, heart failure; MI, myocardial infarction.

Figure 2

Change in systolic blood pressure in patients with controlled blood pressure, ‘non-resistant’, ‘apparent resistant’, and ‘apparent mineralocorticoid receptor antagonist-resistant’ hypertension. Week −2 = end of the open run-in period of treatment with valsartan 80 mg twice daily and Week 0 = end of the open run-in period of treatment with sacubitril–valsartan 49/51 mg, Thereafter, patients randomized to double-blind treatment with valsartan 160 mg twice daily or sacubitril–valsartan 97/103 mg twice daily. Models include systolic blood pressure at the end of the valsartan run-in, age, sex, body mass index, cigarette smoking, and region, as well as systolic blood pressure at all other time points up to Week 16 and an interaction term between treatment and time. MRA, mineralocorticoid receptor antagonist.