ArticlesA selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial
Introduction
Contemporary guidelines for treatment of hypertension have recommended target blood pressures of less than 140/90 mm Hg (<130/80 mm Hg if the patient has diabetes or chronic kidney disease), with the aim of improving protection against cardiovascular and renal events.1, 2 Most patients with hypertension can achieve these targets when only one or two antihypertensive drugs are administered in addition to appropriate lifestyle changes; however, other patients do not meet these targets, even with regimens of three or four drugs. Sometimes this treatment failure can be resolved by rectifying underlying reasons for inadequate control, including poor treatment compliance by the patient, inexpertly selected treatment regimens, or the conflicting effects of concomitant drugs for other reasons. Despite these approaches, some patients with hypertension do not achieve satisfactory blood pressures.
Treatment-resistant hypertension has been defined as failure to reach blood-pressure targets despite the use of at least three drugs, one of which should be a diuretic, at the full doses recommended by hypertension guidelines, with approved drug labels, and tolerated by the patient.1 Patients with this disorder are most likely at increased cardiovascular risk resulting from a history of longstanding, severe hypertension, typically in association with other cardiovascular risks such as obesity, diabetes, and chronic kidney disease.3 Thus, for patients whose blood pressures cannot be controlled by three or more drugs, innovative agents that might provide additional efficacy need to be assessed. Few prospective clinical trials have assessed treatment strategies in patients with treatment-resistant hypertension, and most have been largely empirical.3
One new approach is the use of endothelin-receptor antagonists. Raised circulating concentrations of endothelin 1 have been reported in patients with hypertension and diabetes,4, 5, 6 indicating the potential value of the endothelin-receptor blockade. This approach might be of particular relevance in patients with treatment-resistant hypertension who are already receiving standard antihypertensive therapies, such as blockers of the renin-angiotensin system, diuretic drugs, and calcium-channel blockers, since there is no evidence that the vasoconstrictor effects of endothelin at its type A receptor are successfully inhibited by these agents.
Treatment with the non-selective, sulphonamide-type endothelin-receptor antagonist bosentan produced significant reductions in systolic and diastolic blood pressures, similar to those detected with an angiotensin-converting-enzyme (ACE) inhibitor during 4 weeks of treatment in patients with hypertension.7 Darusentan is a propanoic acid-based endothelin type A selective-receptor antagonist of the propanoic acid class. When used as a single agent in patients with stage 1 or 2 hypertension, darusentan at a dose of 100 mg once daily decreased blood pressure by about 11/8 mm Hg, corrected for the placebo response, after 6 weeks of treatment.8 However, because of the potential risks associated with the use of endothelin-receptor antagonists, including the potential for teratogenicity, these agents should be used in specific patients, such as those with treatment-resistant hypertension. In a previous study of such patients, sequentially increasing doses of darusentan from 10 mg to 300 mg once daily reduced blood pressure significantly more than did placebo.9
We undertook a randomised, double-blind trial comparing differing doses of darusentan with placebo in patients with treatment-resistant hypertension as previously defined.1 To reflect clinical practice, in which treatment-resistant hypertension is often associated with serious concomitant disorders, we included patients with diabetes, heart disease, and chronic kidney disease in this study.
Section snippets
Patients
Patients were recruited from 117 sites in North and South America, Europe, New Zealand, and Australia. Patients were eligible to participate if they had treatment-resistant hypertension defined as systolic blood pressures of 140 mm Hg or greater (≥130 mm Hg if they had diabetes or chronic kidney disease) despite treatment with three or more antihypertensive drugs, including a diuretic, at full doses. The doses of antihypertensive drugs that each patient was receiving were characterised at study
Results
Figure 1 shows the trial profile. 718 patients were screened for this study of treatment-resistant hypertension; 339 patients were ineligible (mainly for not meeting the blood-pressure criteria required for study entry) and 31 withdrew during the study (11 for adverse events). An additional 13 patients prematurely discontinued study drug treatment (two in placebo group, two in darusentan 50 mg group, four in darusentan 100 mg group, five in darusentan 300 mg group), but completed all study
Discussion
On the basis of conventional readings or ambulatory blood-pressure monitoring, findings from our study have shown that darusentan significantly reduced systolic and diastolic blood pressures in patients with treatment-resistant hypertension—a patient population believed to be at increased risk for cardiovascular events.3 Compared with placebo, this selective endothelin-receptor antagonist reduced systolic blood pressures in the clinical setting by almost an additional 10 mm Hg, despite
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2022, Chemico-Biological InteractionsCitation Excerpt :Under pathophysiological conditions, expression of ETA and ETB receptors are enhanced in VSMCs, leading to vasospasm, which is a key process in various cardiovascular disorders [8,30,31]. Accumulating studies have shown that the expressions of endothelin receptors are upregulated in the arteries of patients with hypertension, ischemic stroke, and myocardial infarction, as well as in spontaneously hypertensive rats [32–35]. The present study demonstrates that cigarette smoke enhanced mesenteric artery contractility and increased the expression of ETA and ETB receptors, indicating that cigarette smoke upregulates ETA and ETB receptors and subsequently elevates blood pressure.