The Global Burden of Resistant Hypertension and Potential Treatment Options.

Resistant hypertension (RH) is defined as systolic blood pressure (SBP) or diastolic blood pressure (DBP) that remains .140 mmHg or .90 mmHg, respectively, despite an appropriate lifestyle and the use of optimal or maximally tolerated doses of a three-drug combination, including a diuretic. This definition encompasses the category of controlled RH, defined as the presence of blood pressure (BP) effectively controlled by four or more antihypertensive agents, as well as refractory hypertension, referred to as uncontrolled BP despite five or more drugs of different classes, including a diuretic. To confirm RH presence, various causes of pseudo-resistant hypertension (such as improper BP measurement techniques and poor medication adherence) and secondary hypertension must be ruled out. Inadequate BP control should be confirmed by out-of-office BP measurement. RH affects about 5% of the hypertensive population and is associated with increased cardiovascular morbidity and mortality. Once RH presence is confirmed, patient evaluation includes identification of contributing factors such as lifestyle issues or interfering drugs/substances and assessment of hypertension-mediated organ damage. Management of RH comprises lifestyle interventions and optimisation of current medication therapy. Additional drugs should be introduced sequentially if BP remains uncontrolled and renal denervation can be considered as an additional treatment option. However, achieving optimal BP control remains challenging in this setting. This review aims to provide an overview of RH, including its epidemiology, pathophysiology, diagnostic work-up, as well as the latest therapeutic developments.

Recent developments in the management of resistant hypertension: focus on endothelin receptor antagonists.

Resistant hypertension is characterized by the inability of guideline-recommended triple combination therapy to control blood pressure (BP) to target. It is associated with a significantly increased risk of adverse outcomes. Despite abundant preclinical evidence supporting the critical role of the endothelin pathway in resistant hypertension (RH), clinical implementation of endothelin antagonists for the treatment of hypertension was hindered by various factors. Recently, the novel dual endothelin-receptor antagonist aprocitentan was tested in individuals with resistant hypertension in the PRECISION trial and provided compelling evidence supporting both short and longer-term safety and clinically meaningful and sustained BP lowering efficacy. These findings resulted in the recent regulatory approval of aprocitentan by the FDA. Aprocitentan may be a particularly useful antihypertensive option for individuals with advanced age, chronic kidney disease, and albuminuria.

What is this article about? Elevated blood pressure that remains uncontrolled despite recommended drug treatment with at least three established medications including a diuretic, also known as resistant hypertension, is a worldwide health concern and leaves many patients at high risk for adverse cardiovascular consequences such as heart attacks, strokes, and chronic kidney disease. While past research suggested the potential utility of endothelin receptor antagonists in managing hypertension, their efficacy remained unconfirmed until recently.What are the results of the PRECISION study? The PRECISION study examined the safety and efficacy of a novel dual endothelin receptor antagonist aprocitentan in individuals with resistant hypertension. The trial demonstrated that aprocitentan effectively lowered blood pressure both with short- and long-term administration and that it had a favorable safety profile.What do the results of the PRECISION study mean? As a direct consequence of the trial findings, aprocitentan is now approved by the US FDA for the treatment of uncontrolled blood pressure. This drug may prove particularly useful in individuals with clinical features known to render elevated blood pressure more difficult to control such as advanced age, chronic kidney disease, and increased levels of protein in their urine.

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

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.

Population pharmacokinetics of the dual endothelin receptor antagonist aprocitentan in subjects with or without essential or resistant hypertension.

Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors (covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates.PK data from 902 subjects in ten Phase 1, one Phase 2, and one Phase 3 study were pooled to develop a joint population PK model. The concentration-time course of aprocitentan was described by a two-compartment model with absorption lag time, first-order absorption and elimination, and reduced relative bioavailability following very high doses of 300 and 600 mg.The population PK model described the observed data well. Volume and clearance parameters were associated with body weight. Renal function as reflected by estimated glomerular filtration rate (eGFR), hepatic impairment, and sex were identified as relevant covariates on clearance.The subject-specific characteristics of body weight, eGFR, hepatic impairment, and sex were shown to influence exposure parameters area under the concentration-time curve and maximum concentration in steady state to a limited extent, i.e., not more than 25% different from a reference subject, and therefore do not warrant dose adjustments.

Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: Mechanism of action and therapeutic potential.

Hypertension is reaching epidemic proportions worldwide and is a significant public health concern. However, ∼15% of patients with hypertension continue to experience elevated blood pressure, even after taking antihypertensive medications [such as angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), dihydropyridine calcium channel blockers (CCBs) and thiazide diuretics], a condition referred to as resistant hypertension (RH). Within the complex realm of blood pressure regulation and vascular function, endothelin-1 (ET-1), a potent vasoconstrictor, plays a pivotal role. Recent research, particularly a Phase III clinical trial (NCT03541174), has shed light on the potential of aprocitentan, a dual ET-1 receptor antagonist, in significantly lowering blood pressure in individuals with RH. In this review, we summarize the mechanism of action and therapeutic potential of aprocitentan as an innovative approach for treating RH.

Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension.

PURPOSE OF REVIEW: Resistant hypertension (RH) defined as uncontrolled blood pressure despite the use of a combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic at maximally tolerated doses is associated with a substantially increased risk of cardiovascular and renal events. Despite targeting relevant pathophysiological pathways contributing to elevated blood pressure, approximately 10-15% of hypertensive patients remain above recommended blood pressure targets. Further optimization of blood pressure control is particularly challenging in patient populations who frequently present with RH such as elderly and patients with chronic kidney disease, due to the unfavorable safety profile of the recommended fourth-line therapy with mineralocorticoid receptor antagonists. This review explores the potential role of endothelin antagonists as an alternative fourth-line therapy. RECENT FINDINGS: Despite the well-described role of the endothelin pathway in the pathogenesis of hypertension, it is currently not targeted therapeutically. Recently however, main outcome data from the PRECISION study, a randomized placebo-controlled phase 3 trial, in patients with RH on guideline-recommended standardized single-pill background therapy convincingly demonstrated the safety and blood pressure-lowering efficacy of the dual endothelin antagonist Aprocitentan. Findings from the phase 3 PRECISION study could signify a turning point in the utilization of endothelin receptor antagonists as a standard treatment for patients with RH.

Aprocitentan: A new development of resistant hypertension.

As the blood pressure threshold for commencing antihypertensive treatment diminishes, the cohort suffering from resistant hypertension (RH) correspondingly expands. Notwithstanding the availability of known antihypertensive medications, there exists a conspicuous lacuna in therapeutic options specifically intended for the management of RH. Currently, aprocitentan is the sole endothelin receptor antagonist (ERA) under development for addressing this pressing clinical challenge. Aprocitentan (ACT-132577), deriving its active form as a metabolite of macitentan, demonstrates oral potency as a dual endothelin (ET) receptor antagonist. This compound effectively obstructs the binding of endothelin-1 (ET-1) to both ETA and ETB receptors, exhibiting an inhibitory potency ratio of 1:16. Clinical investigation of aprocitentan has advanced to phase 3 trials, yielding promising preliminary outcomes.

Novel Dual Endothelin Inhibitors in the Management of Resistant Hypertension.

Resistant hypertension (RH) is defined as the failure to achieve blood pressure control despite using triple combination therapy with a renin-angiotensin system inhibitor (RAS-i), a calcium antagonist, and a diuretic. The endothelin (ET) system is implicated in the regulation of vascular tone, primarily through vasoconstriction, intervenes in cardiac contractility with inotropic effects, and contributes to water and sodium renal reabsorption. ET inhibitors, currently approved for the treatment of pulmonary hypertension, seem to be also useful for essential hypertension and RH as well. Studies into the development of new dual ET inhibitors, which inhibit both type A and B ET (ETA and ETB) receptors, present initial results of managing RH. Aprocitentan (ACT-132577) is a novel, orally active and well tolerated dual ET receptor antagonist, which has been examined in several experimental studies and clinical trials with promising results for RH control. The recent publication of the large PRECISION study in The Lancet journal provides further reassurance regarding the efficacy and safety of aprocitentan for RH, with the aim of overcoming unmet needs in the management of this difficult group of patients.

New and developing pharmacotherapies for hypertension.

INTRODUCTION: Despite the significant contribution of hypertension to the global burden of disease, disease control remains poor worldwide. Considering this unmet clinical need, several new antihypertensive drugs with novel mechanisms of action are under development. AREAS COVERED: The present review summarizes the recent advances in the development of emerging pharmacological agents for the management of hypertension. The latest technological innovations in the design of optimized formulations of available antihypertensive drugs and the potential role of the modification of intestinal microbiota to improve blood pressure (BP) control are also covered. EXPERT OPINION: Significant efforts have been made to develop new antihypertensive agents with novel actions that target the main mechanisms involved in resistant hypertension. Sacubitril/valsartan may emerge as a potential first-line drug due to its superiority over renin angiotensin system inhibitors, and SGLT2 inhibitors can reduce BP in difficult-to-control hypertensive patients with type 2 diabetes. In addition, firibastat and aprocitentan may expand the therapeutic options for resistant hypertension by novel mechanism of actions. Since gut dysbiosis not only leads to hypertension but also causes direct target organ damage, prebiotics and probiotics could represent a potential strategy to prevent or reduce the development of hypertension and to contribute to BP control.

Identifying and treating resistant hypertension in PRECISION: A randomized long-term clinical trial with aprocitentan.

The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel-group Phase 3 study and its three-part design assesses the short-term and sustained long-term effects of aprocitentan on BP. Results are expected in 2022. Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single-tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single-blind placebo run-in period. The 4-week placebo run-in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4-week double-blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32-week single-blind part with aprocitentan 25 mg; and (3) a 12-week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3). Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT.

Aprocitentan and the endothelin system in resistant hypertension.

Endothelin has emerged as a target for therapeutic intervention in systemic hypertension. As a vasoconstrictor, comitogenic agent, linking pulse pressure and vascular remodeling, and mediator of aldosterone and catecholamine release, endothelin is a key player in hypertension and end-organ damage. In 10%-20% of the hypertensive population, the high blood pressure is resistant to administration of antihypertensive drugs of different classes in combination. Because endothelin is not targeted by the current antihypertensive drugs, this may suggest that this resistance is due, in part at least, to a dependence on endothelin. This hypothesis is supported by the observation that this form of hypertension is often salt-sensitive, and that the endothelin system is stimulated by salt. In addition, the endothelin system is activated in subjects at risk of developing resistant hypertension, such as African Americans or patients with obesity or obstructive sleep apnea. Aprocitentan is an investigational, novel, potent, dual endothelin receptor antagonist (ERA) currently in phase 3 development for the treatment of difficult-to-treat hypertension. This article discusses the research that underpinned the discovery of this ERA and the choice of its first clinical indication for patients with forms of hypertension that cannot be well controlled with classical antihypertensive drugs.

Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension.

Aprocitentan (ACT-132577) is an orally active, dual endothelin-1 (ET-1) receptor antagonist that prevents the binding of ET-1 to both ETA/ETB receptors. It is an active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. Aprocitentan is highly bound to plasma proteins and is eliminated in both urine and feces. It is well tolerated across all doses (up to 600 mg with single dose and 100 mg once a day at multiple doses). Its pharmacokinetic profile shows a half-life of 44 h, fitting a once-daily dosing regimen with plasma ET-1 concentrations (reflecting ET receptor antagonism), significantly increasing with doses ≥ 25 mg. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, fed and fasted conditions, and renal function have been observed. Aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III trial (ClinicalTrials identifier: NCT03541174). Nonetheless, results of pre-clinical data and studies in humans support the potential role of aprocitentan in this clinical setting. The absolute blood pressure (BP) reductions with aprocitentan are in the ranges established as a surrogate for reduction in cardiovascular morbidity in hypertension. Significant changes in BP with aprocitentan are observed within 14 days, and its BP-lowering effects have also been documented with ambulatory BP monitoring. Finally, aprocitentan enhances the BP-lowering effects of other antihypertensive drugs, including renin-angiotensin-system blockers. In conclusion, aprocitentan ameliorates the effects of ET-1 and could potentially reduce BP and provide broader cardiovascular protection in patients with resistant hypertension. Available data support the hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension, making aprocitentan an attractive candidate for further large-scale trials.

Absorption, Distribution, Metabolism, and Excretion of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Humans.

BACKGROUND: Aprocitentan is an orally active, dual endothelin receptor antagonist that may offer a new therapeutic option for the treatment of difficult-to-control hypertension. OBJECTIVE: To investigate safety, tolerability, mass balance, absorption, distribution, metabolism, and excretion of aprocitentan. METHODS: In this single-center, open-label study, a single oral dose of 25 mg containing 3.7 MBq of 14C-radiolabeled aprocitentan was administered to 6 healthy male subjects. Metabolites were identified using mass spectrometry and, where possible, confirmed and quantified with reference compounds. RESULTS: Aprocitentan was well tolerated and there were no clinically significant findings for any safety variable. The geometric mean cumulative recovery of radioactivity from urine and feces over 14 days was 77% of the administered radioactive dose, with 52.1% cumulative recovery from urine and 24.8% from feces. Concentrations of total radioactivity in whole blood were markedly lower compared to plasma. In plasma, 94.3% of total radioactivity was aprocitentan. In urine and feces, 5 and 2, respectively (in feces one being aprocitentan) main products were identified. Metabolism data of aprocitentan identified two main elimination pathways, glucosidation to M3 and hydrolysis to M1, representing approximately 25% and 32% of the radioactive dose, respectively. CONCLUSIONS: Based on these metabolism data, aprocitentan can be concomitantly administered without dose adjustment with drugs that are inhibitors or inducers of any metabolizing enzyme, specifically cytochrome P450 enzymes.

Multiple-Dose Pharmacokinetics, Safety, and Tolerability of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Healthy Japanese and Caucasian Subjects.

Aprocitentan is an orally active dual endothelin receptor antagonist currently in development for treatment of difficult-to-control (resistant) hypertension. In phase 1 and 2 studies, aprocitentan has been characterized predominantly in Caucasian subjects. In this bridging, double-blind study, 20 healthy Japanese and Caucasian male and female subjects received 25 mg of aprocitentan or placebo once daily for 10 days and were monitored until 216 hours after the last dosing. The pharmacokinetics of aprocitentan were similar between ethnicities. At steady state, maximum plasma concentration was reached at 4 and 3 hours, and elimination half-life was 49.1 and 48.8 hours for Japanese and Caucasian subjects, respectively. The accumulation index was around 3 for both populations. Geometric means ratios for maximum plasma concentration and area under the plasma concentration-time curve during 1 dosing interval were around 1, with 90% confidence interval ranging from 0.87 to 1.30. Aprocitentan was safe and well tolerated in both groups. As no clinically relevant differences were found between Japanese and Caucasian subjects, it is unlikely that the pharmacokinetics of aprocitentan would differ significantly between Caucasian subjects and other ethnicities. Aprocitentan can therefore be administered at a dose level of up to 25 mg in any ethnicity without dose adjustment.

Effects of Multiple-Dose Administration of Aprocitentan on the Pharmacokinetics of Rosuvastatin.

Aprocitentan is an investigational, orally active, dual, endothelin receptor antagonist that targets a novel pathway in the treatment of difficult-to-control (resistant) hypertension. The drug-drug interaction potential of aprocitentan on the breast cancer resistance protein (BCRP) transporter substrate rosuvastatin was investigated in this single-center, open-label, single-sequence study. Twenty healthy male subjects received a single dose of 10-mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours. From day 5 to day 17, subjects received 25 mg of aprocitentan once daily. Seventeen of 20 enrolled subjects completed the treatment. At steady state, aprocitentan did not affect the pharmacokinetics of rosuvastatin in a clinically relevant way. The maximum plasma concentration was increased by 40% with a 90% confidence interval of 1.19 to 1.65. However, the ratio of the geometric means for both area under the plasma concentration-time curve from time 0 to time t and area under the plasma concentration-time curve from time 0 to infinity was close to 1 with the 90% confidence interval within a reference interval of 0.80 to 1.25. Adverse events leading to study discontinuation were reported in 2 subjects. Overall, the combination of rosuvastatin and aprocitentan was well tolerated. Based on these data, aprocitentan does not affect BCRP and can be administered concomitantly with drugs dependent on BCRP transport.

Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension.

This study examined the dose-response characteristics of aprocitentan, a dual endothelin A/endothelin B receptor antagonist, in patients with essential hypertension. In a randomized, double-blind, parallel study design, eligible patients with a sitting diastolic blood pressure (BP) of 90-109 mm Hg received aprocitentan 5, 10, 25, or 50 mg, placebo, or lisinopril 20 mg as a positive control once daily for 8 weeks. Multiple automated office BP readings were obtained with patients resting unattended (unattended automated office BP) at baseline, weeks 2, 4, and 8. Ambulatory BP was monitored for 24 hours at baseline and week 8. After a single-blind placebo run-in period, 490 eligible patients were randomized to the double-blind phase, with 409 patients completing 8 weeks of therapy per protocol. Aprocitentan 10, 25, and 50 mg decreased sitting systolic/diastolic unattended automated office BP from baseline to week 8 (placebo-corrected decreases: 7.05/4.93, 9.90/6.99, and 7.58/4.95 mm Hg, respectively, P≤0.014 versus placebo), compared with an unattended automated office BP reduction of 4.84/3.81 mm Hg with lisinopril 20 mg. For patients with valid ambulatory BP, aprocitentan 10, 25, and 50 mg significantly decreased placebo-corrected 24-hour BP by 3.99/4.04, 4.83/5.89, and 3.67/4.45 mm Hg, respectively. Incidence of adverse events was similar in the aprocitentan groups (22.0%-40.2%) and the placebo group (36.6%). Aprocitentan produced dose-dependent decreases in hemoglobin, hematocrit, albumin, and uric acid, an increase in estimated plasma volume, but no change in weight versus placebo. These findings support further investigation of aprocitentan at doses of 10 to 25 mg in hypertension. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02603809.

Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects.

BACKGROUND: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. SUBJECTS AND METHODS: In this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd. RESULTS: Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration-time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ETB receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure-response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. CONCLUSION: Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.