ASH: Darusentan helpful in resistant hypertension


Two thousand hypertension experts traveled to San Francisco for the American Society of Hypertension (ASH) Annual Meeting, in May. Reviewed below are a session on an endothelin receptor antagonist in treatment-resistant hypertension, and several others on fixed-dose combinations. Two trials used the more concise measure of ambulatory blood pressure control monitoring (ABPM) to support their findings.

Fixed doses of darusentan
The systolic blood pressure goal of ≥140mmHg (or ≥130mmHg for patients with diabetes or chronic kidney disease) was met by about half of patients with treatment-resistant hypertension receiving the endothelin receptor antagonist darusentan, according to a presentation by Michael Weber, professor of medicine, State University of New York Downstate Medical Center, Brooklyn, New York. The Darusentan 311 Study, Weber said, included 379 patients (mean age 62 years), all with blood pressure above goal despite full or maximally tolerated doses of ≥3 antihypertensive medications. The co-primary endpoints were change from baseline to week 14 in trough sitting systolic (SBP) and diastolic blood pressure (DBP).

Patients were randomised to darusentan once-daily at 50, 100, or 300mg, or placebo. Nearly 40% were older than 65 years, ~40% had diabetes, more than a quarter had established heart disease and ~25% had chronic kidney disease. At baseline, 99.5% were taking diuretics, ~96% ACEIs and/or ARBs, 73.5% calcium channel blockers and 65.5% beta-blockers. Mean baseline blood pressure for the entire cohort was ~151/86mmHg.

Darusentan was clearly superior to placebo at week 14. Mean change from baseline sitting SBP was -8.6mmHg for placebo and -16.5/-18.1/-18.1mmHg for 50, 100 and 300mg darusentan, respectively (all p<0.001 compared to placebo). Mean diastolic BP changes were -5.3mmHg for placebo and -10.1/-9.9/-10.7mmHg (p< 0.001 for all). There were no significant changes in heart rate.

Weber explained that because ABPM eliminates both placebo and “white coat hypertension” effects, ABPM revealed smaller absolute differences, but a similar differential between placebo and active treatment. Placebo group reductions (mmHg) were -1.1 for SBP and -0.7 for DBP. Darusentan reductions (SBP/DBP) were -9.0/-7.8 for 50mg, -9.8/-7.7 for 100mg and -9.5/-7.4 for 300mg (all p<0.001). SBP goals were met by 27.3% of placebo patients, and by 53.1%/53.%/48.2% of the 50/100/300mg darusentan group patients (all p<0.001). “No argument. A really good blood pressure response,” said Weber.

Edema and fluid retention (10% for placebo, ~20% for darusentan), the most common adverse events, tended to resolve with increased doses of diuretics. Weber concluded, “Darusentan treatment produced robust decreases in office and ambulatory blood pressure in patients with treatment-resistant hypertension.”

A strategy of stepwise, olmesartan-based treatment led to attainment of the seated blood pressure goal of <140/90mmHg in 67% of elderly hypertension patients in the BENISILVER (Benicar Efficacy: New Investigation Shows olmesartan medoxomil treatment Increasingly Leads Various Elderly populations to safe BP Reductions) trial. Joel M Neutel, associate professor of medicine at the University of California, Irvine, US, noted that prior long-term clinical trials in the elderly with uncontrolled SBP/DBP or isolated systolic hypertension have shown greater benefit from treatment than in younger patients. Only half of elderly patients, however, achieve seated cuff blood pressure goals of <140/90mmHg. Importantly, age-related increases in systolic blood pressure independently predict cardiovascular mortality in the elderly. BENISILVER included 176 patients ≥65 years with newly diagnosed or uncontrolled hypertension (SBP/DBP ≥140/90mmHg on antihypertensive medication). After a placebo run-in, participants in the 12-week active treatment study were given 20mg olmesartan. Patients not achieving mean cuff BP of ≤120/70mmHg were then uptitrated from 20mg to 40mg olmesartan at week 3, with 12.5mg of hydrochlorothiazide added at week 6 and increased to 25mg at week 9. The primary endpoint of the open-label, blinded-endpoint study was change in SBP from baseline to week 12, as assessed by 24-hour ABPM.

In the mostly Caucasian population (83%), mean age was 71.9 years (52.3% male). Mean baseline sitting SBP was 165.5mmHg and mean sitting DBP was 87.7. Baseline ABPMs were 148.8 and 80.9mmHg, respectively.

Twenty-four hour ABPM change from baseline was -25.7mmHg for systolic BP and -12.3mmHg for diastolic (p<0.0001 vs. baseline). Sitting office cuff reductions were similar (25.4/10.5mmHg). The recommended seated cuff level of <140/90 was achieved by 67%. Neutel noted that adverse event rates were low, with drug-related dizziness and hypotension ≤3.4%, and 5.1% (9) patients discontinuing due to treatment-emergent adverse events.

In an interview, Neutel commented that diuretics address volume-dependent hypertension particularly well in the elderly, and that ARBs are thought to address age-related vessel stiffness by correcting the imbalance between angiotensin II and nitric oxide – allowing lower blood pressures to be achieved in the elderly without causing postural hypertension.

AZTEC study
AZTEC (AZOR Trial Evaluating Blood Pressure Reductions and Control), also presented by Joel Neutel, a further trial of olmesartan (OM), examined an uptitration strategy’s ability to lower SBP and to increase the proportion of patients meeting the goal of (<140/90mmHg or <130/80mmHg for those with diabetes. Typically about a third of patients meet goal with treatment, said Neutel. A further goal was to confirm that the vasodilating effects of the angiotensin receptor blocker would effectively combat the edema commonly caused by amlodipine (AML).

AZTEC included individuals with mean sitting SBP ≥140 and ≤199mmHg and sitting DBP ≥90 and ≤109mmHg. Patients with type 2 diabetes were included if stably treated (plasma glucose <160mg/dL). After a placebo run-in, patients (n=185) were titrated upwards from AML 5mg to AML 5mg/OM 20mg, to AML 5mg/OM 40mg, to AML 10mg/ OM 40mg if their sitting BP was ≥120/80mmHg.

Systolic and diastolic mean 24-hour ABPM blood pressures dropped 21.4mmHg and 12.7mmHg, respectively, after 12 weeks of treatment (p<0.0001 for both versus baseline). Baseline mean ABPM SBP of 144.8mmHg was reduced to 123.5mmHg. Blood pressures were reduced consistently across the 24-hour interval. The SBP goal of (<140/90mmHg) was achieved by 76.8% of patients receiving OM.

Treatment was well tolerated. Drug-related adverse events occurred in 7.6% of patients. Edema was reported in only four patients, with three (1.6%) withdrawing because of adverse events.
The stepwise AM/OM regimen, Neutel concluded, successfully reduced mean 24-hour blood pressure and was well tolerated. Neutel commented, “ABPM is a much more stringent way of looking at blood pressure. We wanted to see if by testing patients in their natural environment with ABPM to get rid of ‘white coat’ and placebo effects, we could still get very significant control. And that is what we found.”

ACCOMPLISH combination
Cardiovascular events were 20% lower with the amlodipine/benazepril (AML/BZ) combination than with the hydrochlorothiazide/benazepril (HCTZ/BZ) combination in the 11,500 patient ACCOMPLISH (24-hour Ambulatory Blood Pressure Control Results) trial. An investigation testing whether that event reduction was attributable simply to the degree of blood pressure-lowering or to differences in the agents evaluated points to the choice of drugs. Overall systolic blood pressure reductions in ACCOMPLISH, said Kenneth Jamerson, University of Michigan Health System, Ann Arbor, USA, were significantly greater with AML/BZ than with HCTZ/BZ, but the difference was small (0.9mmHg). Jamerson hypothesised that an analysis of the 573 ACCOMPLISH hypertensive patients evaluated through the far more accurate ABPM would reveal no significant differences in mean 24-hour blood pressure between treatment groups. Mean age was 68.5 years among the 371 males and 202 females enrolled. Mean baseline sitting SBP was 142.3mmHg in the AML/BZ group and 140.9mmHg in the HCTZ/BZ group.

After two years, mean ambulatory SBP over 24 hours was slightly lower in the HCTZ/BZ group (-1.6mmHg, p=0.128). No subgroups stood out, Jamerson said at an ASH press conference. Similar percentages in both treatment groups of patients achieved control (SBP ≤135mmHg, ~30%), had any hourly reading of SBP >160mmHg (~11%), had nocturnal hypertension >130mmHg (~19%), or had an early morning SBP surge (~3%). “The message,” Jamerson said, “is hugely important, especially taken together with the initial ACCOMPLISH findings. It says that if you put together agents with synergistic mechanisms you have better outcomes.”

­Moderator George Bakris, University of Chicago-Pritzker School of Medicine, Chicago, commented that while diuretics like HCTZ do nothing for the vessel, angiotensin converting enzyme inhibitor BZ and calcium antagonist AML benefit vessel walls by increasing nitric oxide levels.