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9 December 2009,
A phase III randomised controlled trial demonstrated that darusentan reduced systolic/diastolic blood pressure by about 10/5mmHg compared with placebo in patients with treatment-resistant hypertension, but was associated with a significant increased risk of adverse effects, the most common of which was oedema and/or fluid retention (NNH 8).
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Action
Darusentan is not scheduled currently for a NICE appraisal. Hence, if the drug should reach the market local decision-making bodies will need to consider its place in therapy. Although it may offer an option for the management of patients with treatment-resistant hypertension, its place relative to other alternative add-on treatments is unclear presently. Further efficacy and safety studies are ongoing.
Although current data is limited, darusentan appears to reduce blood pressure by a statistically significant amount in patients who are unable to meet blood pressure targets by use of at least three other antihypertensive drugs (one of which is a diuretic). However, its use is associated with a significantly increased risk of side effects, notably fluid retention and/or oedema, and it is not suitable for use in people with a history of heart failure. There is no evidence at present to demonstrate that the reduction in blood pressure achieved with darusentan offers any meaningful advantages over placebo or other alternative treatment options with regard to important patient-oriented outcomes (e.g. cardiovascular events, cardiovascular mortality or total mortality).
What is the background to this?
Treatment-resistant hypertension is defined as occurring when patients with hypertension are unable to reach guideline blood pressure lowering targets despite adherence to a regimen of at least three other antihypertensive drugs, at their maximum tolerated doses. Patients whose hypertension is uncontrolled are more likely to have target-organ damage and a higher long-term cardiovascular risk than are patients whose blood pressure is controlled. The exact prevalence of treatment-resistant hypertension is unknown, but has been estimated in the US as in the region of 2% to 5% of patients with hypertension.
According to the NICE hypertension guideline add-on drug options for patients who fail to meet targets by use of three antihypertensive drugs include use of further diuretic therapy (with careful monitoring), beta-blockers or selective alpha-blockers.
Darusentan is a selective endothelin type A antagonist and, through its ability to block the vasoconstrictor effect of endothelin, offers an additional pharmacological approach to reducing blood pressure. The other endothelin receptor antagonists already on the market (e.g. bosentan▼) are not licensed for resistant hypertension.
According to a Gilead press release, the study reported here is one of two phase III trials evaluating darusentan as an add-on treatment for resistant hypertension. The second study (DAR-312) is fully enrolled and is expected to be completed with data available by the end of 2009. Both studies are considering the changes from baseline in systolic and diastolic blood pressure compared with placebo; DAR-312 includes an active comparator, guanfacine, which is not licensed in the UK. Longer term safety studies are planned including patients who complete the 14-week assessment periods of these two studies.
More information on the management of hypertension can be found on the cardiovascular section of NPC.
What does this study claim?
This double-blind, randomised controlled trial (RCT) evaluated the effect of various doses of darusentan in 379 patients with systolic blood pressure of 140mmHg or more (or at least 130mmHg in patients with diabetes or chronic kidney disease) who were receiving at least three antihypertensives, including a diuretic, at full or maximum tolerated doses. It found that darusentan (50mg, 100mg and 300mg daily) significantly reduced sitting systolic/diastolic blood pressure compared with placebo over a 14 week period by 8/5mmHg, 11/5mmHg, and 11/6mmHg, respectively (all P<0.0001 vs. placebo). Adverse events were more common in each of the darusentan arms of the study (72%, 78%, 77%, respectively) compared with placebo (49%). The most common adverse effect was oedema and/or fluid retention (darusentan: 25%, 32%, 25%, respectively; overall 27% [NNH 8] vs. 14% placebo).
Five patients receiving darusentan (any dose) had a cardiac-related serious adverse event. One patient on placebo died (sudden cardiac death).
How does this relate to other studies?
There is a lack of data from other well-designed RCTs on add-on treatments for resistant hypertension. Further research is required in this area, as recognised by NICE in its guideline on hypertension. A previous phase II dose-ranging study of 115 patients with resistant hypertension compared darusentan (10, 50, 100, 150, and 300 mg daily) with placebo or 10 weeks, and identified a dose-dependant decrease in mean systolic/diastolic blood pressure. This study is the first phase III study of darusentan for resistant hypertension to be published.
So what?
This study indicates that when patients fail to achieve NICE blood pressure lowering targets using at least three antihypertensive drugs, addition of darusentan to existing drug treatments can reduce blood pressure by about 10mm/5mmHg on average. The effect seems to be independent of dose in the range of 50 to 300mg daily. About half of the patients given darusentan achieved the systolic blood pressure goals of 140mmHg (130mmHg in patients with diabetes or chronic kidney disease) compared with about a quarter on placebo. However, as has been pointed out in a recent MeReC Rapid Review, drug treatment to lower a patient’s blood pressure is worthwhile even if the blood pressure does not fall below target on treatment with several drugs (or if the addition of more drugs is inappropriate or declined). Nevertheless, it is important to consider any benefit gained by aggressive blood pressure lowering to achieve target in the context of possible harms that may be caused. Clinicians need to carefully consider whether a fourth, fifth or even sixth drug is really going to have a significantly worthwhile benefit compared to the risks, side effects and the inconvenience to the patient in taking it.
This trial identified that a high proportion of patients given darusentan experience oedema and/or fluid retention. Other side effects more frequent than placebo were fatigue and flushing.
As pointed out in the accompanying commentary, darusentan is not suitable for patients with heart failure and might induce clinically significant fluid retention, oedema or both, which would prompt the need for further diuretic therapy. Fluid retention was most seen within six weeks of starting treatment. The potential teratogenicity of endothelin-receptor antagonists also precludes use of darusentan in women of child-bearing age.
This study is limited by its short duration. Appropriately powered, long-term studies are required to identify whether the blood pressure benefits are sustained, and, importantly, whether or not any blood pressure lowering reduction translates into meaningful patient-oriented outcomes (e.g. cardiovascular events, death, quality of life). It is not known if such studies are to be carried out, although follow-up safety studies are planned for the existing phase III studies. Further studies are also required to compare the benefits of darusentan alongside existing add-on drug options for treatment-resistant hypertension.
Design: Randomised, multicentre, double-blind, placebo-controlled, phase III trial. Allocation was concealed.
Patients: Of 718 patients screened for inclusion, 379 with systolic blood pressure of 140mmHg or more (> 130mmHg if patients had diabetes or chronic kidney disease) who were receiving at least three antihypertensives, including a diuretic, at full or maximum tolerated doses, were eligible. Patients were stratified by co-morbidity (diabetes or chronic kidney disease) and race. Exclusions included a heart failure, poorly controlled diabetes, anaemia, liver dysfunction, and those with coronary, arrhythmic, or stroke events in the last six months.
Intervention and comparison: eligible patients were randomly assigned to 14 weeks of darusentan 50mg (n=81), 100mg (n=81), 300mg (n=85) or placebo (n=132) orally every morning. Patients assigned to higher doses of darusentan were titrated to their final doses in 2-week intervals. In the event of intolerance to study drug, one blinded dose reduction was allowed. Changes to background antihypertensive therapy were not allowed during the study, but investigators could increase the use of diuretics to manage fluid-related side effects.
Outcomes and results: the primary outcomes were changes from baseline to week 14 in sitting systolic and diastolic blood pressures. Mean blood pressure at baseline was 151/86mmHg and 58% of patients were receiving four or more antihypertensives. Intention to treat analysis was used for all results. At 14 weeks, mean blood pressure fell in all four groups, with little difference between the three darusentan doses: placebo group 9/5 mmHg (standard deviation [SD] 14/8), darusentan 50mg 17/10mmHg (SD 15/9), 100mg 18/10mmHg (SD 16/9) and 300mg 18/11mmHg (SD 18/10); P<0.0001 for all doses compared to placebo. Responses were similar in all the pre-defined patient subgroups. About half the patients in the treatment groups achieved the goal systolic blood pressure of 140 or 130mmHg (53% in the 50mg and 100mg groups, 48% in the 300mg group vs. 27% in the placebo group).
Adverse events were more common in each of the darusentan arms of the study (72%, 78%, 77%, respectively) compared with placebo (49%). The most common adverse effect was oedema and/or fluid retention (darusentan: 25%, 32%, and 25%, respectively vs. 14% placebo). Eleven percent of patients in the darusentan groups with adverse events of fluid retention or oedema required increased diuretic therapy (5% in the placebo group). Other adverse events occurring more frequently in each of the darusentan arms of the study compared with placebo were fatigue (4–7% vs. 2%), flushing (1–5% vs. 0%). Five patients receiving darusentan (any dose) had a cardiac-related serious adverse event (none on placebo). One patient on placebo died due to sudden cardiac death (none on darusentan).
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