Endothelin Antagonists Research Articles

From Plan to Pivot: How Model-Informed Drug Development Shaped the Dose Strategy of the Zibotentan/Dapagliflozin ZENITH Trials.

Getting the dose right is a key challenge in drug development; model-informed drug development (MIDD) provides powerful tools to shape dose strategies and inform decision making. In this tutorial, the case study of the ZENITH trials showcases how a set of clinical pharmacology and MIDD approaches informed an impactful dose strategy. The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, has yielded a robust and significant albuminuria reduction in the Phase IIb trial ZENITH-CKD and is being investigated for reduction of kidney function decline in a high-risk chronic kidney disease population in the Phase III trial ZENITH High Proteinuria. Endothelin antagonist treatment has, until now, been limited by the class effect fluid retention. ZENITH-CKD investigated a wide range of zibotentan doses based on pharmacokinetics in renal impairment, competitor-data exposure-response modeling, and clinical trial simulations. Recruitment delays reduced interim analysis data availability; here, supportive dose-response modeling recovered decision-making confidence. At trial completion, the low-dose arm enabled Phase III dose selection between Phase IIb doses. Dose-response modeling of efficacy and Kaplan-Meier analyses of tolerability identified a kidney-function-based low-dose strategy of 0.25 or 0.75 mg zibotentan (with 10 mg dapagliflozin) to balance benefit/risk in ZENITH High Proteinuria. The applied clinical pharmacology and MIDD principles enabled successful Phase IIb dose finding, rationalized and built confidence in the innovative Phase III dosing strategy and identified a potential therapeutic window for zibotentan/dapagliflozin, providing the opportunity for a significant improvement in the treatment of chronic kidney disease with high proteinuria.

Abstract P442: Impact of arterial stiffness on the blood pressure lowering effect of the dual endothelin antagonist aprocitentan in patients with resistant hypertension

Background: The phase-3 PRECISION study demonstrated the efficacy of aprocitentan to lower both office and ambulatory blood pressure (BP) in patients with resistant hypertension. Increased arterial stiffness has been associated with less favorable responses to pharmacologic BP lowering therapies. In this post-hoc analysis, we investigated the impact of arterial stiffness, assessed by the ambulatory arterial stiffness index (AASI), on the BP lowering effect of aprocitentan. Methods: The study included a 4-week double blind period (aprocitentan 12.5 mg, 25 mg, or placebo) and a 32-week single blind period (aprocitentan 25 mg). A total of 730 patients with resistant hypertension were randomized and 633 had available ambulatory BP monitoring (ABPM) results at baseline. The AASI was calculated from ABPM data as 1 minus the regression slope of diastolic on systolic BP. The patient population was dichotomized into two groups according to the baseline median AASI. Results: Patients with higher baseline AASI (≥0.54) tended to be older (63±11 versus 60±10) and to have a higher 24-hour ambulatory systolic BP (140±14 versus 135±14 mmHg) than patients with lower AASI (<0.54). These patients with higher baseline AASI were also more likely to have chronic kidney disease stage 3-4 corresponding to an estimated glomerular filtration rate in the 15 to 60 mL/min/1.73 m 2 range (27% versus 18%). The BP lowering effect of aprocitentan at Week 4 was similar for both the patients with stiffer vasculature who have a higher baseline AASI (≥0.54) and for those with a lower AASI (<0.54) (Table 1). No relevant change in AASI was reported with aprocitentan treatment at Week 4 (end of the double-blind period) or Week 36 (end of the single-blind period). Conclusion: Aprocitentan is an effective BP lowering therapy across the arterial stiffness continuum observed in patients with resistant hypertension. Longer observation times are needed to fully assess the impact of treatment on this structural and functional parameter.

A review of novel endothelin antagonists and overview of non-steroidal mineralocorticoid antagonists for treating resistant hypertension: An update

Several agents are emerging from five different novel classes of antihypertensive medications. We will focus on endothelin antagonists and non-steroidal mineralocorticoid receptor antagonists. While several agents exist in this later class, only a couple have demonstrated superior efficacy in resistant hypertension management. Endothelin receptor antagonists are effective therapy for primary and resistant hypertension, but they are not widely used. This is due to side effects demonstrated in large clinical trials, specifically increased peripheral edema and worsening heart failure in some cases, as well as the availability of many alternative agents to manage blood pressure effectively. However, the relationship between endothelin and its close ties to hypertension is evolving. Recent pre-clinical work explores new applications of more selective endothelin receptor antagonists. They suggest that specific subtypes of hypertension may benefit more from endothelin receptor blockade than simply those with primary hypertension. We review this topic and other related data. Lastly, we also provide a brief overview of non-steroidal mineralocorticoid receptor antagonists as some in the class show promise as antihypertensive agents.

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 thecritical 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 therecent regulatory approval of aprocitentanby the FDA. Aprocitentan may be a particularly useful antihypertensive option for individuals with advanced age, chronic kidney disease, and albuminuria.

Targeting the endothelium by combining endothelin-1 antagonism and SGLT-2 inhibition: better together?

Endothelin A and B receptors, together with sodium-glucose cotransporter-2 (SGLT-2) channels are important targets in improving endothelial function and intervention with inhibitors has been the subject of multiple mechanistic and clinical outcome trials over recent years. Notable successes include the treatment of pulmonary hypertension with endothelin receptor antagonists, and the treatment of heart failure and chronic kidney disease with SGLT-2 inhibitors. With distinct and complementary mechanisms, in this review, we explore the logic of combination therapy for a number of diseases which have endothelial dysfunction at their heart.

Is endothelin targeting finally ready for prime time?

The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.

#362 Dosing low, winning high: unlocking the promise of endothelin antagonism for the treatment of CKD in the zibotentan/dapagliflozin ZENITH trials

Abstract Background and Aims The Phase 2b ZENITH-CKD trial demonstrated that combined treatment with the endothelin A receptor (ETAR) antagonist zibotentan and the sodium-glucose co-transporter-2 inhibitor (SGLT2i) dapagliflozin yields a robust and significant reduction in albuminuria in individuals with chronic kidney disease (CKD), compared to dapagliflozin treatment alone [1]. This is hypothesized to translate into a significant reduction of kidney function decline and may further confer cardiometabolic benefits including reducing blood pressure, LDL cholesterol and (in type 2 diabetes) HbA1c in the ongoing Phase 3 ZENITH High Proteinuria trial. The usage of ETAR antagonists has until now been limited by the class effect of fluid retention, which is associated with an increased risk of heart failure in the at-risk CKD population. Zibotentan has previously been investigated at 10 mg per day in Phase 3 for the treatment of prostate cancer. Method Model-Informed Drug Development (MIDD) was integrated with clinical pharmacology data to develop the dose strategy for both ZENITH trials. A low-dose strategy was selected considering the increased plasma exposure of zibotentan in kidney impairment. The Phase 2b dose steps were selected based on an exposure response model for the efficacy marker urinary albumin to creatinine ratio (uACR) and were supported using clinical trial simulations. The dose strategy for Phase 3 was defined based on a combined analysis of ZENITH-CKD results for both efficacy and tolerability: efficacy (uACR reduction on top of dapagliflozin) was analysed with a Dose-Response Mixed Model for Repeated Measures, and tolerability (fluid retention events, defined as a combination of specified body weight and BNP increase) was evaluated with Kaplan Meier analyses. Results Zibotentan doses of 0.25 mg and 1.5 mg (in a first, discontinued study part also 5 mg), in combination with dapagliflozin 10 mg, were selected for ZENITH-CKD. Clinical trial simulations indicated that inclusion of the low dose of 0.25 mg was crucial to characterise the dose-response relationship. Dose-uACR response modelling of ZENITH-CKD data predicted a zibotentan dose of 0.75 mg to result in a mean uACR reduction of around 25% in addition to the reduction with dapagliflozin. A post-hoc regression analysis of uACR mean changes from baseline, stratified by dose, showed a trend towards lower uACR reduction with higher eGFR levels. Kaplan-Meier analyses of the fluid retention risk in different eGFR subgroups indicated that the fluid retention risk increased with increasing zibotentan dose for eGFR levels <45 mL/min/1.73 m2, while for higher eGFR levels, no differences were observed between treatments with dapagliflozin alone and added zibotentan 0.25 mg or 1.5 mg. Therefore, a kidney-function based zibotentan dose strategy was selected for the ZENITH High Proteinuria trial: Combined zibotentan/dapagliflozin is being compared against dapagliflozin alone; within the combination treatment arm, 0.25 mg zibotentan is selected for participants with baseline eGFR levels <45 mL/min/1.73 m2, and 0.75 mg is selected for higher eGFR level, with a tolerance eGFR window for participants whose eGFR declines below this cut-off, and with the possibility to reduce the dose to 0.25 mg in case of tolerability findings. Conclusion The favourable benefit/risk profile that was demonstrated for combined zibotentan/dapagliflozin in ZENITH-CKD was enabled by the zibotentan low-dose strategy. The wide dose ranging and MIDD further enabled selection of a kidney-function based zibotentan dosing strategy for ZENITH High Proteinuria which is designed to further balance benefit/risk. The low-dose zibotentan strategy and the combination with dapagliflozin opened for the first time a therapeutic window for ETAR antagonists, with the potential to redefine their value for the treatment of CKD. This work was sponsored by AstraZeneca.

Endothelin-1, Extracellular Volume Overload, and Hemodynamics in Hemodialysis Patients.

Extracellular volume (ECV) overload and endothelial cell dysfunction are mortality risk factors in hemodialysis (HD) patients. Endothelin-1 (ET-1), an endothelium-derived vasoconstrictive peptide, is associated with poor outcomes in HD patients. We hypothesized there would be associations between ET-1 and ECV overload in hypertensive HD patients. We obtained pre-HD ET-1, ECV/weight (bioimpedance spectroscopy), pre-HD hemodynamics, and ambulatory blood pressure (BP) in an HD cohort. Following appropriate transformations, we conducted correlation and linear regression analyses idendifying associations between ET-1, ECV overload, total peripheral resistance index (TPRI), cardiac index (CI), and ambulatory BP. Among 66 patients, median ET-1 was 1.93 (1.49-2.56) pg/ml. Median pre-HD ECV/weight, median TPRI, mean CI, and mean systolic ambulatory BP were 0.25 (0.22-0.30) l/kg, 3,161 (2,711-3,642) dynes × s/cm-5/m2, 2.92 (0.6) l/min/m2, and 143 (14) mm Hg, respectively. After reciprocal-transformation, ET-1 correlated with reciprocal-transformed ECV/weight (r = 0.3, P = 0.01), log-transformed TPRI (r = -0.3, P = 0.006), CI (r = 0.3, P = 0.009), and ambulatory BP (r = -0.3, P = 0.02). These associations persisted in linear regression analysis (β = 0.15, P = 0.002; β = -0.8, P = 0.002; β = 0.2, P = 0.002; β = -19, P = 0.03). In hypertensive HD patients, ET-1 associates with ECV overload higher TPRI and ambulatory BP, and lower CI. Further research is necessary to determine if ECV reduction lowers ET-1 or if pharmacologic ET-1 antagonism can improve outcomes in HD patients with refractory ECV overload.

Endothelin-1 Receptor Antagonism Attenuates Increased Uncoupling Protein-1 in Brown Adipose Tissue of Obese Mice

Endothelin-1 (ET-1) is increased in patients and rodent models with obesity and promotes metabolic syndrome by causing inflammation and adipocyte dysfunction. Recently, our laboratory demonstrated that treatment of obese mice with Atrasentan (Atr) and Bosentan (Bos) significantly improved fasting blood glucose, insulin, and glucose and insulin tolerance; however, the mechanisms are not completely understood. Brown adipocytes express all components of the ET-1 system and are important in limiting adiposity though an increase in uncoupling protein-1 (UCP-1) leading to increased metabolism via thermogenesis. We hypothesized that ET-1 antagonism may improve metabolism in obese mice by regulating UCP-1 in brown adipose. Mice were fed either normal (NMD) or high fat diet (HFD) for 10 week and treated with either vehicle, Atr, or Bos for the final two weeks. HFD significantly increased ET-1 and tumor necrosis factor alpha expression in brown adipose tissue compared to NMD controls with no significant effect of either ET-1 receptor antagonists. Interestingly, brown adipose expression of UCP-1 was significantly increased in HFD fed mice compared to NMD, an effect that was significantly attenuated in mice treated with atrasentan and bosentan. These data suggest that ET-1 modulates brown adipose tissue function in obesity, a potential contributor to obesity induced cardio metabolic risk. This work was supported by National Institutes of Health grant 5T32HL105324-14. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan.

Introduction: Pulmonary arterial hypertension (PAH) is characterised by endothelial dysfunction and pathological vascular remodelling, resulting in the occlusion of pulmonary arteries and arterioles, right ventricular hypertrophy, and eventually fatal heart failure. Targeting the apelin receptor with the novel, G protein-biased peptide agonist, MM07, is hypothesised to reverse the developed symptoms of elevated right ventricular systolic pressure and right ventricular hypertrophy. Here, the effects of MM07 were compared with the clinical standard-of-care endothelin receptor antagonist macitentan. Methods: Male Sprague-Dawley rats were randomised and treated with either normoxia/saline, or Sugen/hypoxia (SuHx) to induce an established model of PAH, before subsequent treatment with either saline, macitentan (30mg/kg), or MM07 (10mg/kg). Rats were then anaesthetised and catheterised for haemodynamic measurements, and tissues collected for histopathological assessment. Results: The SuHx/saline group presented with significant increases in right ventricular hypertrophy, right ventricular systolic pressure, and muscularization of pulmonary arteries compared to normoxic/saline controls. Critically, MM07 was as at least as effective as macitentan in significantly reversing detrimental structural and haemodynamic changes after 4weeks of treatment. Discussion: These results support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

Endothelial Dysfunction and Heart Failure with Preserved Ejection Fraction-An Updated Review of the Literature.

Heart failure (HF) is a clinical syndrome consisting of typical symptoms and signs due to structural and/or functional abnormalities of the heart, resulting in elevated intracardiac pressures and/or inadequate cardiac output. The vascular system plays a crucial role in the development and progression of HF regardless of ejection fraction, with endothelial dysfunction (ED) as one of the principal features of HF. The main ED manifestations (i.e., impaired endothelium-dependent vasodilation, increased oxidative stress, chronic inflammation, leukocyte adhesion, and endothelial cell senescence) affect the systemic and pulmonary haemodynamic and the renal and coronary circulation. The present review is aimed to discuss the contribution of ED to HF pathophysiology-in particular, HF with preserved ejection fraction-ED role in HF patients, and the possible effects of pharmacological and non-pharmacological approaches. For this purpose, relevant data from a literature search (PubMed, Scopus, EMBASE, and Medline) were reviewed. As a result, ED, assessed via venous occlusion plethysmography or flow-mediated dilation, was shown to be independently associated with poor outcomes in HF patients (e.g., mortality, cardiovascular events, and hospitalization due to worsening HF). In addition, SGLT2 inhibitors, endothelin antagonists, endothelial nitric oxide synthase cofactors, antioxidants, and exercise training were shown to positively modulate ED in HF. Despite the need for future research to better clarify the role of the vascular endothelium in HF, ED represents an interesting and promising potential therapeutic target.

Endothelin System in Hypertension and Chronic Kidney Disease.

ET (endothelin) is a powerful vasoconstrictor 21-amino acid peptide present in many tissues, which exerts many physiological functions across the body and participates as a mediator in many pathological conditions. ETs exert their effects through ETA and ETB receptors, which can be blocked by selective receptor antagonists. ETs were shown to play important roles among others, in systemic hypertension, particularly when resistant or difficult to control, and in pulmonary hypertension, atherosclerosis, cardiac hypertrophy, subarachnoid hemorrhage, chronic kidney disease, diabetic cardiovascular disease, scleroderma, some cancers, etc. To date, ET antagonists are only approved for the treatment of primary pulmonary hypertension and recently for IgA nephropathy and used in the treatment of digital ulcers in scleroderma. However, they may soon be approved for the treatment of patients with resistant hypertension and different types of nephropathy. Here, the role of ETs is reviewed with a special emphasis on participation in and treatment of hypertension and chronic kidney disease.

Expanding options of supportive care in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with a potentially serious prognosis. At present, management of IgAN is primarily based on therapeutic lifestyle changes, and excellent blood pressure control and maximized supportive treatment with the combination of inhibition of the renin-angiotensin-aldosterone system with either inhibitors of angiotensin-converting enzyme or angiotensin II receptor blockers and inhibitors of sodium-glucose cotransporter-2, and possibly in the future also with endothelin antagonists. Supportive care currently represents the cornerstone of treatment of IgAN. Targeted-release formulation of budesonide should replace systemic corticosteroids in patients with higher proteinuria and active histological lesions. New treatment options are aimed at immunopathogenesis of IgAN including depletion or modulation of Galactose-deficient-Immunoglobulin A1-producing B cells, plasma cells, and the alternate and/or lectin pathway of complement. The exact place of monoclonal antibodies and complement inhibitors will need to be determined. This article reviews potential supportive therapies currently available for patients with IgAN.

Treatment and practical considerations of diabetic kidney disease.

Diabetic kidney disease (DKD) is a complication of diabetes that can lead to kidney failure. Over the years, several drugs have been developed to combat this disease. In the early 90s, angiotensin blockade (ACEi and ARBs) was introduced, which revolutionized the treatment of DKD. In recent years, newer drugs such as sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, endothelin antagonists, and mineralocorticoid receptor antagonists (MRA) have shown great promise in reducing albuminuria and protecting the kidneys. These drugs are being used in combination with lifestyle modifications, patient education, and risk factor modification to effectively manage DKD. In this review, we will explore the latest pharmacological options, their efficacy, and their potential to revolutionize the management of this debilitating disease.

Endothelin antagonism: stepping into the spotlight

Endothelin antagonism: stepping into the spotlight

New trials in resistant hypertension: mixed blessing stories.

Resistant hypertension (RH) is linked to an increased risk of cardiovascular and renal complications. Treatment options include non-pharmacological interventions, such as lifestyle modifications, and the use of specific antihypertensive drug combinations, including diuretics. Renal denervation is another option for treatment-resistant hypertension. New compounds targeting different pathways involved in RH-including inhibitors of aminopeptidase A, endothelin antagonists and selective aldosterone synthase inhibitors-have been tested in clinical trials in this condition. The centrally acting drug firibastat, targeting the brain renin-angiotensin system, failed to demonstrate significant effectiveness in reducing blood pressure (BP) in patients with difficult-to-treat and RH in the Firibistat in Resistant Hypertension (FRESH) trial. Aprocitentan, a dual endothelin A and B receptor antagonist, showed a moderate but statistically significant decrease in BP in patients with RH in the Parallel-Group, Phase 3 Study with Aprocitentan in Subjects with Resistant Hypertension (PRECISION) trial. However, concerns remain about potential adverse events, such as fluid retention. The use of baxdrostat, a selective aldosterone synthase inhibitor, showed promising results in reducing BP in patients with treatment-resistant hypertension in the Baxdrostat in Resistant Hypertension (BrigHTN) trial. However, a subsequent trial, HALO, failed to meet its primary endpoint. The unexpected results may be influenced by factors such as patient adherence and white-coat hypertension. Despite the disappointing results from HALO, the potential benefits of inhibiting aldosterone synthesis remain to be fully understood. In conclusion, managing RH remains challenging, and new compounds like firibastat, aprocitentan and baxdrostat have shown varied effectiveness. Further research is needed to improve our understanding and treatment of this condition.

Pharmacological Prevention of Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage.

Causes of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH) include early brain injury and delayed neurologic deterioration, which may result from delayed cerebral ischemia (DCI). Complex pathophysiological mechanisms underlie DCI, which often includes angiographic vasospasm (aVSP) of cerebral arteries. Despite the study of many pharmacological therapies for the prevention of DCI in aSAH, nimodipine-a dihydropyridine calcium channel blocker-remains the only drug recommended universally in this patient population. A common theme in the research of preventative therapies is the use of promising drugs that have been shown to reduce the occurrence of aVSP but ultimately did not improve functional outcomes in large, randomized studies. An example of this is the endothelin antagonist clazosentan, although this agent was recently approved in Japan. The use of the only approved drug, nimodipine, is limited in practice by hypotension. The administration of nimodipine and its counterpart nicardipine by alternative routes, such as intrathecally or formulated as prolonged release implants, continues to be a rational area of study. Additional agents approved in other parts of the world include fasudil and tirilazad. We provide a brief overview of agents currently being studied for prevention of aVSP and DCI after aSAH. Future studies may need to identify subpopulations of patients who can benefit from these drugs and perhaps redefine acceptable outcomes to demonstrate impact.

The Anti-Anginal Efficacy of Bosentan in the Coronary Slow Flow Phenomenon

Background: The Coronary Slow Flow Phenomenon (CSFP) is a coronary microvascular disorder that presents with recurrent angina for which there is no available effective therapy. The vasoconstrictor Endothelin-1 (ET-1) has been implicated in the pathophysiology of the CSFP. This study aimed to determine whether the ET-1 antagonist (Bosentan) is effective in ameliorating angina symptoms in CSFP patients. Methods: Using a randomised, double-blind, placebo-controlled, cross-over trial methodology, the anti-anginal efficacy of Bosentan 125mg bd was assessed in 23 patients with symptomatic CSFP. Study endpoints were measured following 4 weeks of therapy with the primary endpoint being angina frequency. Secondary endpoints included (1) clinical measures of angina and health status, (2) endothelial function parameters, and (3) inflammatory and oxidative stress markers. Results: There was no statistically significant reduction in angina frequency with Bosentan therapy compared to placebo (median angina episodes/4weeks [25-75% IQ]: Bosentan 14[5,36] vs Placebo 25[9,55]) although a trend for improvement in symptoms during the Bosentan phase was observed. Furthermore, Bosentan did not impact on any of the secondary endpoints compared with placebo. Conclusion: Bosentan did not have a major impact on angina frequency in patients with the CSFP. A small anti-anginal effect cannot be excluded and requires a larger trial.

The Anti-Anginal Efficacy of Bosentan in the Coronary Slow Flow Phenomenon

Background: The Coronary Slow Flow Phenomenon (CSFP) is a coronary microvascular disorder that presents with recurrent angina for which there is no available effective therapy. The vasoconstrictor Endothelin-1 (ET-1) has been implicated in the pathophysiology of the CSFP. This study aimed to determine whether the ET-1 antagonist (Bosentan) is effective in ameliorating angina symptoms in CSFP patients. Methods: Using a randomised, double-blind, placebo-controlled, cross-over trial methodology, the anti-anginal efficacy of Bosentan 125mg bd was assessed in 23 patients with symptomatic CSFP. Study endpoints were measured following 4 weeks of therapy with the primary endpoint being angina frequency. Secondary endpoints included (1) clinical measures of angina and health status, (2) endothelial function parameters, and (3) inflammatory and oxidative stress markers. Results: There was no statistically significant reduction in angina frequency with Bosentan therapy compared to placebo (median angina episodes/4weeks [25-75% IQ]: Bosentan 14[5,36] vs Placebo 25[9,55]) although a trend for improvement in symptoms during the Bosentan phase was observed. Furthermore, Bosentan did not impact on any of the secondary endpoints compared with placebo. Conclusion: Bosentan did not have a major impact on angina frequency in patients with the CSFP. A small anti-anginal effect cannot be excluded and requires a larger trial.

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

PURPOSEOF 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.