WHAT HAPPENED. Tryvio (aprocitentan) is a new drug indicated for the treatment of high blood pressure in adults.

Tryvio, prescribed in combination with other antihypertensive medications, is used when high blood pressure cannot be adequately controlled with standard drugs.

Aprocitentan is the first new oral antihypertensive drug in four decades that works quite differently from all existing antihypertensives.

Tryvio, developed by Switzerland’s Idorsia Pharmaceuticals, is approved by the U.S. Food and Drug Administration (FDA) in mid-March 2024 [1].

The prescribing information for Tryvio is labeled with boxed warnings about embryo–fetal toxicity: Aprocitentan should not be administered to pregnant women [2].

 

WHY IT MATTERS. High blood pressure affects approximately 1.4 billion people worldwide [1]. Of these, 10% are characterized by treatment resistance, when it is impossible to achieve proper control of blood pressure levels even with the simultaneous use of three antihypertensive drugs of different classes [2]. Persistently elevated blood pressure (≥ 140/90 mmHg) as a consequence of resistant arterial hypertension dramatically increases the risk of adverse cardiovascular and renal events such as peripheral arterial disease (PAD), coronary heart disease (CHD), stroke, heart failure, end-stage renal disease, and all-cause mortality [3] [4] [5] [6].

 

WHAT IT FOUND OUT. The PRECISION (NCT03541174) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial invited adult patients (n=730) with systolic blood pressure (SBP) ≥ 140 mmHg despite taking at least three antihypertensive drugs of different classes (including diuretics), i.e., resistant hypertension.

Before the start of the study, participants who received daily oral administration of 12.5 mg aprocitentan or placebo were standardized by switching to background antihypertensive therapy combining a calcium channel blocker (amlodipine), an angiotensin receptor blocker (valsartan), and a diuretic (hydrochlorothiazide). If a beta blocker was previously used, continued use was allowed.

After 4 weeks of treatment, the aprocitentan group demonstrated an average reduction in SBP and diastolic blood pressure (DBP) of 15.4 mmHg and 10.4 mmHg — versus a reduction of 11.6 mmHg and 6.4 mmHg in the placebo group [1].

The most frequently reported adverse events (AEs) to aprocitentan were edema or fluid retention (in 9% of patients) and anemia (4%).

 

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THE CONTEXT. It should be understood that a decrease in SBP, even by a seemingly insignificant 5 mmHg, leads to a 10% reduction in the relative risk of major adverse cardiovascular events (MACE). Thus, the risks for stroke, heart failure, coronary heart disease (CHD), and death from cardiovascular disease are reduced by 13%, 13%, 8% and 5% [1].

 

HOW IT WORKS. Aprocitentan (ACT-132577, JNJ-2820) is an oral small-molecule dual endothelin receptor antagonist that inhibits the binding of endothelin-1 (ET-1) to endothelin A and B receptors (ETA and ETB) [1]. Endothelin-1 mediates various deleterious effects such as vasoconstriction, fibrosis, cell proliferation, and inflammation. In hypertension, it causes endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic system activation, and increased aldosterone synthesis [2] [3]. Aprocitentan is the active metabolite of macitentan used in the treatment of pulmonary arterial hypertension (PAH) [4].

 

BETWEEN THE LINES. Before the advent of aprocitentan, none of the existing systemic antihypertensive drugs targeted the endothelin signaling pathway [1]. The available armamentarium of blood pressure medications targets salt and water regulation, antagonism of the renin–angiotensin–aldosterone system (RAAS), reduction of extracellular calcium influx into the cell, sympatholytic activity, and non-selective vasodilatory effects [2] [3].

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FOR REFERENCE. There are quite a few endothelin receptor antagonists (ERAs) on the world market. Thus, Letairis / Volibris (ambrisentan), Opsumit (macitentan), and Tracleer / Stayveer (bosentan) are used in the treatment of pulmonary arterial hypertension (PAH). Filspari (sparsentan) is indicated for the treatment of IgA nephropathy. Pivlaz (clazosentan) is utilized for the prevention of three conditions: cerebral vasospasm, vasospasm-related cerebral infarction, and cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage.

 

MEANWHILE. AstraZeneca is developing baxdrostat, an oral small-molecule aldosteron synthase inhibitor focused on the treatment of resistant hypertension./

heart
Baxdrostat: New Treatment for Resistant Hypertension

A selective aldosterone synthase inhibitor for significantly lowering blood pressure.

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