The endothelin-receptor antagonist darusentan appears effective in lowering blood pressure in patients with resistant hypertension who have not been able to reach goal despite taking three or more antihypertensive drugs.
The results of the randomised, double-blind study have been published online in the Lancet. Michael Weber is the first author of the report.
379 patients with resistant hypertension were randomized to placebo or one of 3 daily doses (50, 100, and 300 mg) of darusentan for 14 weeks. The main side effect was edema or fluid retension, which occurred in 27% of darusentan patients versus 14% of placebo patients. Here are the reductions in blood pressure:
- placebo: 9/5 mm Hg
- darusentan 50 mg: 17/10 mm Hg
- darusentan 100 mg: 18/10 mm Hg
- darusentan 50 mg: 18/11 mm Hg
Bryan Williams, in an accompanying editorial, said that darusentan may have a legitimate role in the treatment of resistant hypertension. However, because of the high rate of edema, patients with heart failure should not receive darusentan. Williams also noted that spironolactone is often used to treat resistant hypertension and may have greater efficacy.
Franz Messerli sent the following comment to CardioBrief:
The study of Weber et al.shows that darusentan is an useful add on in so called “resistant” hypertension. We should remember though that the definition of this entity was created almost 2 decades ago and is in urgent need to be updated. No experienced clinician would today consider a patient not at goal on full dose of triple therapy, including a diuretic, as truly resistant. However, in the present study more than 50% of patients were on 4 or more antihypertensive drugs and therefore probably did have somewhat resistant hypertension. Of note, the dose response curve of darusentan was remarkably shallow. With 50 mg placebo corrected BP response was 8/5 mmHg and with a 6 fold dose escalation to 300 mg it was merely 9/6 mmHg. This brings up the question whether the most common AE of darusentan, i.e. fluid retention, also was dose dependent. If so, there seems to be little, if any, need to up titrate since with dose escalation no therapeutic benefits but only more AEs were observed. The darusentan associated edema seems to differ from the calcium antagonist induced vasodilatory edema in that it is due to true fluid volume expansion which makes it much more amenable to diuretic therapy. Clearly however, the ultimate place of darusentan in the antihypertensive armamentarium remains to be defined.
Here is the Lancet press release:
NEW DRUG LOWERS HIGH BLOOD PRESSURE IN PATIENTS RESISTANT TO CONVENTIONAL MEDICATION
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.”
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