Darusentan provides additional BP lowering in resistant hypertension
MedWire News: The selective endothelin receptor antagonist darusentan lowers blood pressure (BP) levels in patients with hypertension who are failing to reach treatment goals with established antihypertensive drugs, study findings published in The Lancet show.
Compared with placebo, the drug reduced systolic BP by almost 10 mmHg, “despite continued antihypertensive therapy with well-selected drugs at recommended full doses… in a study cohort typical of patients with treatment-resistant hypertension,” say the authors.
The randomized controlled trial conducted at 117 sites across North and South America, Europe, New Zealand, and Australia included 379 patients with treatment-resistant hypertension – that is, systolic BP of 140 mmHg or higher (or 130 mmHg or higher in those with diabetes or chronic kidney disease [CKD]), despite treatment with at least three BP lowering drugs (including a diuretic) at full or maximum tolerated doses.
Patients were randomly assigned to receive darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85), or placebo once daily for 14 weeks.
Michael Weber (State University of New York, USA) and co-investigators report that (based on clinic seated BP measurements) patients had mean BP reductions of 17/10 mmHg, 18/10 mmHg, and 18/11 mmHg with darusentan 50-mg, 100-mg, and 300-mg daily doses, respectively, versus a 9/5-mmHg reduction with placebo (p<0.0001 for all comparisons).
The target systolic BP level of below 140 mmHg (below 130 mmHg in diabetic or CKD patients) was reached by 53% of the darusentan 50-mg and 100-mg groups, and 48% of the darusentan 300-mg group, compared with 27% of placebo-treated patients (all significantly different at p<0.001).
Darusentan was generally well tolerated; the main adverse effects of treatment related to fluid accumulation, with edema or fluid retention occurring in 27% of patients compared with 14% of those given placebo.
Five cases of fluid-related cardiac events occurred, including both of two myocardial infarctions in the whole cohort, in patients receiving darusentan. One case was of recurrent heart failure, the patient having been included in the study erroneously, explain the authors.
Other cases were diagnosed as heart failure with preserved systolic function, which the authors say were probably provoked by fluid retention. “This type of failure in patients with hypertension has been documented previously with other vasodilating agents, and potentially could be prevented by early or prophylactic treatment of fluid retention,” they write.
Acknowledging that further studies are needed to clarify the place of darusentan in treatment-resistant hypertension, Weber and colleagues conclude: “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 commentary article, Bryan Williams (University of Leicester, UK) highlights that darusentan appears to exert its effects regardless of gender, age, and other concurrent treatments and diseases.
But, noting that darusentan is not suitable for people with a history of heart failure, 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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By Caroline Price