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

State University of New York, Downstate College of Medicine, New York, NY 11203, USA.
The Lancet (Impact Factor: 45.22). 09/2009; 374(9699):1423-31. DOI: 10.1016/S0140-6736(09)61500-2
Source: PubMed

ABSTRACT 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.
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, number NCT00330369.
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.
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.
Gilead Sciences.

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Available from: George Bakris, Apr 25, 2015
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    • "In recent years, considerable attention has been paid to the possibility of using this class of drugs for the treatment of resistant hypertension and diabetic nephropathy. The ET A -selective antagonist, darusentan, has been studied in a series of phase 2 and phase 3 clinical trials for blood pressure lowering in patients with resistant hypertension (Weber et al., 2009; Bakris et al., 2010). Ambrisentan significantly reduced ambulatory blood pressure in subjects already being treated with an average of five distinct antihypertensive medications. "
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    ABSTRACT: Experiments determined whether the combination of ETA receptor antagonist (ABT-627, atrasentan) and a thiazide diuretic (chlorthalidone) would be more effective at lowering blood pressure and reducing renal injury in a rodent model of metabolic syndrome (metS) compared to either treatment alone. Male Dahl salt sensitive rats were fed a high fat (36% fat) high salt (4% NaCl) (HF/HS) diet for four weeks. Separate groups of rats were then treated with vehicle (control), ABT-627 (ABT; 5 mg/kg/day, in drinking water), chlorthalidone (CLTD; 5 mg/kg/day, in drinking water), or both ABT plus CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 4 weeks, both ABT and CLTD severely attenuated the development of hypertension, while the combination further reduced MAP compared to ABT alone. All treatments prevented the proteinuria. CLTD and ABT+CLTD significantly reduced nephrin (a podocyte injury marker) and KIM-1 (a tubulointerstitial injury marker) excretion. ABT with or without CLTD, significantly reduced plasma 8-oxo-2'-deoxyguanosine (8-OHdG), a measure of DNA oxidation, while CLTD alone had no effect. All treatments suppressed the number of ED1+ cells (macrophages) in the kidney. Plasma TNF receptor 1 and 2 were reduced only in the combined ABT and CLTD group. These results suggest that ABT and CLTD have antihypertensive and renal protective effects in a model of metabolic syndrome that are more effective when both drugs are administered together. The findings support the hypothesis that combined ETA antagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.
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    • "This has been clearly shown by elevated plasma levels of endothelin-1 (ET-1) [8] and plasma renin activity [9] in such subjects. More recently, endothelin receptor blockers have shown to be effective in resistant hypertensives [10]. It is now well established that increased ET-1 activity is one of the contributors for increased incidence of hypertension in diabetics with insulin resistance [11] [12] [13]. "
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    • "Angiotensin I-converting enzyme-neutral endopeptidase (ACE- I/NEP-I) inhibitors such as omapatrilat or samapatrilat delivered a 20/8mmHg (15%) reduction[24] but caused angioedema and were discontinued. The endothelin-I antagonist darusentan (LU-135252; HMR-4005) which remains in development reduced blood pressure by an added 18/11mmHg (11%) at a 300mg dose in patients with refractory hypertension in the DORADO study but was associated with high rates (30%) of peripheral oedema [25]. "
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