Articles www.thelancet.com Vol 374 October 24, 2009 1423 A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial Michael A Weber, Henry Black, George Bakris, Henry Krum, Stuart Linas, Robert Weiss, Jennifer V Linseman, Brian L Wiens, Marshelle S Warren, Lars H Lindholm 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, 4–6 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 Lancet 2009; 374: 1423–31 Published Online September 14, 2009 DOI:10.1016/S0140- 6736(09)61500-2 See Comment page 1396 State University of New York, Downstate College of Medicine, New York, NY, USA (Prof M A Weber MD); New York University, New York, NY, USA (Prof H Black MD); University of Chicago, Chicago, IL, USA (Prof G Bakris MD); Monash University, Clayton, VIC, Australia (Prof H Krum MBBS); Denver Health Medical Center, Denver, CO, USA (Prof S Linas MD); Maine Research Associates, Auburn, ME, USA (R Weiss MD); Gilead Sciences, Foster City, CA, USA (J V Linseman PhD, B L Wiens PhD, M S Warren MD); and Umea University Hospital, Umea, Sweden (Prof L H Lindholm MD) Correspondence to: Prof Michael A Weber, State University of New York, Downstate College of Medicine, 450 Clarkson Avenue, Box 97, Brooklyn, NY 11203, USA michaelwebermd@cs.com