Elsevier

The Lancet

Volume 374, Issue 9699, 24–30 October 2009, Pages 1423-1431
The Lancet

Articles
A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(09)61500-2Get rights and content

Summary

Background

Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, darusentan, in patients with treatment-resistant hypertension.

Methods

This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (≥130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369.

Findings

All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with darusentan 50 mg, 18/10 mm Hg (16/9) with darusentan 100 mg, and 18/11 mm Hg (18/10) with darusentan 300 mg (p<0·0001 for all effects). The main adverse effects were related to fluid accumulation. Oedema or fluid retention occurred in 67 (27%) patients given darusentan compared with 19 (14%) given placebo. One patient in the placebo group died (sudden cardiac death), and five patients in the three darusentan dose groups combined had cardiac-related serious adverse events.

Interpretation

Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed.

Funding

Gilead Sciences.

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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