Systematic Review Article: New Drug Strategies for Treating Resistant Hypertension-the Importance of a Mechanistic, Personalized Approach

Abstract

Resistant hypertension (RHT) is characterized by persistently high blood pressure (BP) levels above the widely recommended therapeutic targets of less than 140/90 mmHg office BP, despite life-style measures and optimal medical therapies, including at least three antihypertensive drug classes at maximum tolerated dose (one should be a diuretic). This condition is strongly related to hypertension-mediated organ damage and, mostly, high risk of hospitalization due to hypertension emergencies or acute cardiovascular events. Hypertension guidelines proposed a triple combination therapy based on renin angiotensin system blocking agent, a thiazide or thiazide-like diuretic, and a dihydropyridinic calcium-channel blocker, to almost all patients with RHT, who should also receive either a beta-blocker or a mineralocorticoid receptor antagonist, or both, depending on concomitant conditions and contraindications. Several other drugs may be attempted, when elevated BP levels persist in these RHT patients, although their added efficacy in lowering BP levels on top of optimal medical therapy is uncertain. Also, renal denervation has demonstrated to be a valid therapeutic alternative in RHT patients. More recently, novel drug classes and molecules have been tested in phase 2 randomised controlled clinical trials in patients with RHT on top of optimal medical therapy with at least 2-3 antihypertensive drugs. These novel drugs, which are orally administered and are able to antagonize different pathophysiological pathways, are represented by non-steroid mineralocorticorticoid receptor antagonists, selective aldosterone synthase inhibitors, and dual endothelin receptor antagonists, all of which have proven to reduce seated office and 24-h ambulatory systolic/diastolic BP levels. The main findings of randomized clinical trials performed with these drugs as well as their potential indications for the clinical management of RHT patients are summarised in this systematic review article.

Keywords: Aldosterone synthase inhibitors; Aprocitentan; Baxdrostat; Endothelin receptor antagonists; Finerenone; Lorundrostat; Renin-angiotensin system; Resistant hypertension.

Fig. 1

Schematic representation of key molecular pathways involved in the pathogenesis of high blood pressure and sites of therapeutic interactions with different classes of antihypertensive agents. In figure: ERA, endothelin receptor antagonists; ET-1, endothelin-1; NO, nitric oxide; DRI, direct renin inhibitors; ACE, angiotensin-converting enzyme; ACE-I, ACE inhibitors; ARB, angiotensin receptor blockers; ASI, aldosterone synthase inhibitors; MRA, mineralocorticoid receptor antagonists. Created with BioRender.com (agreement number: QS26EZQUTU).

Fig. 2

PRISMA 2020 flow diagram for updated systematic reviews, which included searches of databases and registers only.