A new drug—darusentan—provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. This is the conclusion of an Article published Online First and in an upcoming edition of the Lancet, written by Professor Michael A Weber, State University of New York, Brooklyn, NY, USA, and colleagues.
High blood pressure cannot always be controlled with conventional drugs. One new approach is the use of a class of drugs called endothelin-receptor antagonists. The molecular pathway involving endothelin type A is different to that targeted by conventional blood pressure medications, such as blockers of the renin-angiotensin system, diuretic drugs, and calcium-channel blockers. The authors therefore investigated blood-pressure-lowering effects of the new 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 (81), 100 mg (81), or 300 mg (85) taken once daily. Changes in sitting systolic and diastolic blood pressures were measured at baseline and at the end of treatment.
The mean reductions in systolic and diastolic blood pressures were 9/5 mm Hg with placebo, 17/10 mm Hg with darusentan 50 mg, 18/10 mm Hg with darusentan 100 mg, and 18/11 mm Hg with darusentan 300 mg. 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.
The authors conclude: "Darusentan provided meaningful lowering of systolic and diastolic blood pressures in patients with treatment-resistant hypertension already receiving many well chosen antihypertensive drugs. Generally, darusentan was well tolerated, the main adverse effects being related to fluid retention. The use of this drug accompanied by effective diuretic therapy seems to represent a new and effective strategy for dealing with treatment-resistant hypertension."
In an accompanying Comment, Dr Bryan Williams Department of Cardiovascular Sciences and NIHR Cardiovascular Biomedical Research Unit, University of Leicester, UK, says that Darusentan offers the potential for around a further 10mm Hg decrease in systolic blood pressure in people with resistant hypertension, and appears to exert its effects regardless of gender, age, and other concurrent treatments and diseases. But he adds: "These findings do not mean that darusentan would necessarily be the best treatment for every patient with resistant hypertension. This important question can only be addressed by further studies directly comparing various existing and newer treatments."
Prof Michael A Weber, State University of New York, Brooklyn, NY, USA. T) +1 212 584 9191 E) michaelwebermd@cs.com
Dr Bryan Williams Department of Cardiovascular Sciences and NIHR Cardiovascular Biomedical Research Unit, University of Leicester, UK. T) +44 (0) 7747 614288 E) bw17@le.ac.uk
For full Article and Comment, see: http://press.thelancet.com/hypertensionash.pdf
Notes to editors: *odema=an abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body
Journal
The Lancet