Weber, M. A. et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet 374, 1423-1431

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


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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    • "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.
    Full-text · Article · Sep 2014 · Journal of Pharmacology and Experimental Therapeutics
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    • "Finally, the lack of any blood pressure decrease in the control group of Symplicity HTN-2 [2••] was a matter of concern [15]. As a comparison, in three contemporary randomised studies performed in patients with resistant hypertension [16–18], office systolic blood pressure in the control group decreased by 8, 9 and 14 mmHg, respectively. "
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    ABSTRACT: After three years of excessive confidence, overoptimistic expectations and performance of 15 to 20,000 renal denervation procedures in Europe, the failure of a single well-designed US trial-Symplicity HTN-3-to meet its primary efficacy endpoint has cast doubt on renal denervation as a whole. The use of a sound methodology, including randomisation and blinded endpoint assessment was enough to see the typical 25-30 mmHg systolic blood pressure decrease observed after renal denervation melt down to less than 3 mmHg, the rest being likely explained by Hawthorne and placebo effects, attenuation of white coat effect, regression to the mean and other physician and patient-related biases. The modest blood pressure benefit directly assignable to renal denervation should be balanced with unresolved safety issues, such as potentially increased risk of renal artery stenosis after the procedure (more than ten cases reported up to now, most of them in 2014), unclear long-term impact on renal function and lack of morbidity-mortality data. Accordingly, there is no doubt that renal denervation is not ready for clinical use. Still, renal denervation is supported by a strong rationale and is occasionally followed by major blood pressure responses in at-risk patients who may otherwise have remained uncontrolled. Upcoming research programmes should focus on identification of those few patients with truly resistant hypertension who may derive a substantial benefit from the technique, within the context of well-designed randomised trials and independent registries. While electrical stimulation of baroreceptors and other interventional treatments of hypertension are already "knocking at the door", the premature and uncontrolled dissemination of renal denervation should remain an example of what should not be done, and trigger radical changes in evaluation processes of new devices by national and European health authorities.
    Preview · Article · Aug 2014 · Current Hypertension Reports
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    • "Prior work has studied the anti-hypertensive effects of darusentan in refractory hypertension. Our observed mean decrease in blood pressure of 9/7 mm Hg (systolic/diastolic) after 2 weeks (P < .001 compared to baseline) mirrors observations with the same dose of darusentan after 14 weeks in 81 patients with refractory hypertension of 9/5 mm Hg when offset by the placebo group.13 However, our observed mean increase in resting heart rate of 4 ± 7 bpm (P = .021) was not seen in that study. "
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    ABSTRACT: Heterogeneity of resting perfusion may be due in part to up-regulation of coronary vasoconstriction via endothelin (ET) type A receptors, as homogeneity increases during subsequent vasodilatory hyperemia. Therefore, we conducted a mechanistic study using an ET receptor antagonist to determine if it could alter the homogeneity of myocardial perfusion. Included subjects demonstrated a low myocardial perfusion homogeneity index (HI) compared to normal volunteers. Four serial cardiac positron emission tomography Rb-82 scans were performed 2 weeks apart. Before the middle two scans, subjects were randomized to receive either darusentan first then placebo or visa versa. Absolute flow and coronary flow reserve were quantified for each study. Rest flow was adjusted for the pressure-rate product (PRP). We screened 37 subjects and randomized 20 who satisfied entry criteria. Rest HI increased significantly while taking darusentan (0.39 ± 0.10 vs 0.33 ± 0.04 on placebo, P = .030, compared to a normal range of 0.52 ± 0.10) without an increase in the PRP (6,859 ± 1,503 vs 6,976 ± 1,092, P = .79), leading to a higher adjusted flow at rest (0.69 ± 0.18 cc/minute/g at 7,000 PRP vs 0.59 ± 0.07 with placebo). Antagonism of the type A ET receptor increases homogeneity of resting myocardial perfusion. The mechanism appears to be increased absolute rest flow without an increase in either the PRP or myocardial perfusion during hyperemia. Our translational results are consistent with one mechanism for the observed heterogeneity of myocardial perfusion in humans.
    Preview · Article · Jul 2013 · Journal of Nuclear Cardiology
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