Endothelin blockade shows promise for resistant hypertension

A drug that blocks the vasoconstricting effects of endothelin could be an effective treatment for refractory hypertension, according to the results of a Phase III trial.

Patients with resistant hypertension have an increased risk of cardiovascular events such as stroke and myocardial infarction.
Patients with resistant hypertension have an increased risk of cardiovascular events such as stroke and myocardial infarction.

In the DAR-311 (DORADO) trial, darusentan significantly reduced both systolic and diastolic blood pressure in patients already receiving multiple antihypertensive therapy.1

The study investigators, who report their findings in The Lancet, recruited 379 patients worldwide to receive either darusentan – at daily oral doses of 50mg, 100mg or 300mg – or placebo for 14 weeks.

To be eligible for the study, participants had to have failed to reach their target systolic blood pressure – generally <140mmHg – on full or maximum tolerated doses of three or more antihypertensive agents, including a diuretic.

Systolic and diastolic blood pressures fell by an average of 17/10mmHg in patients who received 50mg darusentan per day, 18/10mmHg in those on the 100mg dose, and 18/11mmHg in the 300mg group. By contrast, placebo reduced blood pressure by only 9/5mmHg.

The main adverse events associated with darusentan were oedema or fluid retention, which developed in 27% of patients who received the drug compared with 14% of patients given placebo.

Darusentan, currently under development by Gilead Sciences, is a selective inhibitor of the type A endothelin receptor. Two other drugs of this class, ambrisentan and sitaxentan, are already available for the treatment of pulmonary arterial hypertension. However, no such agents have yet been approved for systemic hypertension.

"The size of the [antihypertensive] effect with this drug was really encouraging," says DAR-311 study leader Michael A. Weber, from the State University of New York. "For many people with treatment-resistant hypertension, adding this drug to the drugs they are taking would be all they would need to do to get their blood pressure down to where it needs to be."

Results from a larger trial of darusentan are due to be reported before the end of 2009.

NICE guidance on hypertension


  1. Weber MA et al. Lancet 2009, published online 14th September 2009.
Want news like this straight to your inbox?
Sign up for our bulletins

Have you registered with us yet?

Register now to enjoy more articles and free email bulletins

Already registered?
Sign in

MIMS app

Access the full drug database and quick-reference tables on the go

Find out more