Sacubitril/Valsartan Shows Efficacy in Treatment of Resistant Hypertension

Investigators of a study with results published in Hellenic Journal of Cardiology found that angiotensin receptor neprilysin inhibitors (ARNIs) could be a promising alternative to angiotensin receptor blockers (ARBs) or angiotensin converting enzyme (ACE) inhibitors in the standard management of resistant hypertension. They found that the regimen offered superior reductions in blood pressure without increasing the risk of serious adverse events compared with the standard of care.¹

Angiotensin receptor neprilysin inhibitors (ARNI) could be a promising alterative to angiotensin receptor blockers (ARB) or angiotensin converting enzyme (ACE) inhibitors. | Image Credit: appledesign | stock.adobe.com

Resistant hypertension is defined by the American Heart Association as “the [blood pressure] of a hypertensive patient that remains elevated above goal despite the concurrent use of 3 antihypertensive agents of different classes,” which includes ACE inhibitors and ARBs. Apparent treatment-resistant hypertension is estimated to be approximately 12% to 15% of population-based reports and 15% to 18% of clinical-based reports. Currently, the management of resistant hypertension includes excluding other causes such as white-coat effect and medication nonadherence, optimizing lifestyle interventions (6 or more hours of sleep, weight loss, exercise, having a low sodium diet, etc.), and optimizing a 3-drug regimen.²

The addition of medications has failed to control resistant hypertension in real-world settings, according to investigators. ARNI therapies, such as sacubitril/valsartan, have shown efficacy for patients with heart failure, demonstrating reductions in cardiovascular mortality and heart failure hospitalizations. Furthermore, it has shown reductions in systolic blood pressure. Investigators aimed to provide a review that evaluates and compares the efficacy and safety of an ARNI with an ACE inhibitor and ARB for the management of resistant hypertension.¹

Investigators searched eligible studies from August 2013 to August 2023 using Cochrane, PubMed, Google Scholar, and ProQuest. Randomized controlled and observational studies published in English were included, using the search terms “sacubitril/valsartan,” “angiotensin receptor neprilysin inhibitors,” “neprilysin inhibitors,” “ARNI,” “refractory hypertension,” and “resistant hypertension.” Investigators found 6 studies, excluding 2 due to insufficient data. The overall risk of bias was low in 3 studies, with only 1 study being “of concern.”¹

Investigators found that ARNIs consistently demonstrated greater reductions in blood pressure for patients with resistant hypertension compared to valsartan alone or an ACE inhibitor. The results were consistent across all studies chosen, even if the method of blood monitoring differed. In one study by Rakugi et al., reductions in systolic blood pressure from baseline to 18.78 (200 mg) and 19.52 mmHg (400 mg) were compared with olmesartan (20 mg) at 11.51 mmHg.³ For another study, by Izzo et al., the systolic reductions were 14 mmHg for ARNI 400 mg, 9.6 mmHg for valsartan 320 mg, and 2.2 mmHg for the placebo.^1,4

In the PARAMETER study, the regimen showed superior efficacy in reducing aortic pressure and arterial stiffness, especially for patients with systolic hypertension, compared with olmesartan.⁵ Investigators noted that only 2 studies reported adverse events (AEs). The most commonly observed were hypotension and elevated serum potassium levels; however, there was no reported discontinuation of ARBU due to AEs. When compared to olmesartan, the AEs with ARNI were 23.4% compared with 21.9%, respectively, with headache and dizziness as the most common AEs.¹

Investigators state that future studies should compare the efficacy of ARNI with placebo and other antihypertensive drugs.¹

REFERENCES

1. Lim H, Agustian H, Febriana V, Supit AI. Sacubitril/Valsartan Role in Patients with Resistant Hypertension: A Systematic Review. Hellenic J Cardiol. Published online January 24, 2025. doi:10.1016/j.hjc.2025.01.004

2. Carey RM, Calhoun DA, Bakris GL, et al. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension. 2018;72(5):e53-e90. doi:10.1161/HYP.0000000000000084

3. Rakugi H, Kario K, Yamaguchi M, Sasajima T, Gotou H, Zhang J. Efficacy of sacubitril/valsartan versus olmesartan in Japanese patients with essential hypertension: a randomized, double-blind, multicenter study. Hypertens Res. 2022;45(5):824-833. doi:10.1038/s41440-021-00819-7

4. Izzo JL Jr, Zappe DH, Jia Y, Hafeez K, Zhang J. Efficacy and Safety of Crystalline Valsartan/Sacubitril (LCZ696) Compared With Placebo and Combinations of Free Valsartan and Sacubitril in Patients With Systolic Hypertension: The RATIO Study. J Cardiovasc Pharmacol. 2017;69(6):374-381. doi:10.1097/FJC.0000000000000485

5. Williams B, Cockcroft JR, Kario K, et al. Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study. Hypertension. 2017;69(3):411-420. doi:10.1161/HYPERTENSIONAHA.116.08556