News from the American Society of Hypertension's 21st Annual Scientific Meeting 2006

New York City—Two new agents, 1 from a new class of antihypertensive drugs, should soon be available to add to the arsenal used to augment blood pressure (BP) control. These agents were the focus of investigations presented at the 21st Annual Scientific Meeting of the American Society of Hypertension. Other data presented here examined the utility of a combination antihypertensive/lipid-lowering pill in achieving BP and lipid goals in high-risk black patients.

A novel, highly selective beta blocker that appears to increase the bioavailability of nitric oxide reduces systolic and diastolic BP in a dose-dependent manner, said Joel M. Neutel, MD. The agent, nebivolol, is in phase 3 development.

Cardioselective beta blocker is a well-tolerated and potent antihypertensive

Nebivolol is a beta₁-selective beta blocker that exhibits vasodilating properties mediated by the endothelial L-arginine/nitric oxide pathway, said Dr Neutel, associate professor of medicine, University of California, Irvine. “Its impact on arterial compliance and endothelial function differentiates it from other beta blockers,” he said. “In this regard, it acts much like an ACE [angiotensin-converting enzyme] inhibitor.”

Data from a pooled analysis of 2 randomized, multicenter, double-blind trials were presented here. In the studies, nebivolol was compared with placebo in a total of 1716 adults with mild-to-moderate hypertension.

Patients were randomized to 12 weeks of treatment with placebo or nebivolol at 1.25, 2.5, 5.0, 10.0, 20.0, or 40.0 mg in 1 study; and placebo or nebivolol at 5.0, 10.0, or 20.0 mg in the other study.

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Trough—sitting systolic BP was reduced by 2.4 mm Hg with the 1.25-mg dose of nebivolol, and the reduction was as great as 7.6 mm Hg with the 40-mg dose. By comparison, patients assigned to placebo experienced a 0.7-mm Hg increase in sitting systolic BP ( = .005 for 2.5 mg vs placebo; < .001 for all higher doses vs placebo).

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Trough—sitting diastolic BP was reduced by 6.9 mm Hg (1.25 mg) to 10.1 mm Hg (40 mg) in nebivolol-treated patients, compared with a reduction of 3.8 mm Hg in the placebo recipients ( = .005 for 2.5 mg vs placebo; < .001 for all higher doses vs placebo).

“The dose response is unusual for beta blockers,” said Dr Neutel. “Most have a flat dose-response curve.”

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Some 45.8% of patients assigned to the 1.25-mg dose of nebivolol were considered treatment responders, defined as achievement of sitting diastolic BP less than 90 mm Hg or a reduction of at least 10 mm Hg from baseline. The treatment response increased to 65.1% of patients randomized to the 20-mg dose of nebivolol ( < .001 vs placebo).

Nebivolol seems to lower BP equally well regardless of gender or ethnicity, said Dr Neutel. Its efficacy in African Americans is unique among the beta blockers, he said.

“I expect that it will be an alternative as a first-line agent for the treatment of hypertension,” he said. “It works in all races and subgroups, including diabetics.”

A pooled analysis of 3 large trials in 2016 patients with mild-to-moderate hypertension showed that nebivolol was well tolerated at all doses studied, said Jan N. Basile, MD, professor of medicine at the Medical University of South Carolina in Charleston.

In the study, the most common ad&shy;verse events were headache, fatigue, dizziness, diarrhea, and nausea, and these were equally common among the placebo- and nebivolol-treated patients.

The rates of dyspnea, depression, bradycardia, and erectile dysfunction, all commonly associated with beta blocker use, were low with nebivolol, said Dr Basile. Fatigue, for example, occurred in 2.6% to 5.5% of nebivolol recipients, depending on the dose.

The first agent in a new class of orally active renin inhibitors for the treatment of hypertension is effective as monotherapy and in combination with hydrochlorothiazide, according to phase 3 data.

New renin inhibitor effectively controls BP, both as monotherapy and with a diuretic

The renin inhibitor aliskiren represents the first new class of antihypertensive agents in more than a decade, said Jerry Mitchell, MD, PhD, chairman and CEO of the Texas Center for Drug Development, Houston.

Aliskiren inhibits the angiotensin cascade at its point of activation, the top of the renin-angiotensin system (RAS), he explained, whereas ACE inhibitors and angiotensin receptor blockers interrupt the RAS further downstream. The result with aliskiren is a decline in plasma renin activity, and potentially superior end-organ protection, although this remains to be proved in clinical trials.

Because it has a half-life approaching 40 hours, the agent is well suited for once-daily dosing.

Dr Mitchell presented data from 216 patients with mild-to-moderate hypertension who had 24-hour ambulatory BP monitored over 8 weeks. As part of a larger study, they had been randomized to placebo or 1 of 3 doses of aliskiren (150, 300, or 600 mg daily).

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“All 3 treatment groups were highly statistically effective at lowering BP,” he said. Reductions in mean ambulatory systolic BP were superior to placebo by 11.4 mm Hg (150 mg), 10.5 mm Hg (30 mg), and 11.7 mm Hg (600 mg) (all < .001). Reductions in 24-hour ambulatory diastolic BP were also significantly better with all doses of aliskiren compared with placebo ( < .001).

“There was no morning surge in BP [with aliskiren],” said Dr Mitchell. “The drug works throughout the 24-hour cycle.” Variability in BP and early morning surges correlate with increased risk of cardiovascular events, he noted.

In a second trial presented here, this one a single-blinded study, aliskiren in combination with hydrochlorothiazide achieved the greatest reduction in sitting BP when compared with either monotherapy. This study included 2776 patients who were randomized to placebo, aliskiren (75, 150, or 300 mg), hydro&shy;chlorothiazide (6.25, 12.5, or 25 mg), or combinations of the 2 drugs for 8 weeks.

Aliskiren produced a dose-dependent reduction in BP, said lead investigator Alberto Vilamil, MD, from Fundapres, Las-Heras, Buenos Aires, Argentina.

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A mean reduction of 21.2/14.3 mm Hg in sitting BP was achieved with the aliskiren 300 mg/hydrochlorothiazide 25 mg combination ( < .001 vs placebo).

Combination therapy increased the proportion of responders compared with either monotherapy. The responder rate, defined as a final achieved sitting diastolic BP < 90 mm Hg or at least a 10-mm Hg reduction in sitting diastolic BP, was significantly higher with aliskiren 300 mg (64%) and all combinations (55%-81%) than with placebo (46%).

The incidence of adverse events was similar between the aliskiren and placebo groups. Headache and nasopharyngitis were the most common adverse events in both the placebo and treatment groups, said Dr Vilamil.

Discontinuation due to adverse events occurred in 0% to 4.4% of the aliskiren groups compared with 3.6% of the placebo group.

Single-pill dual therapy with amlodipine/atorvastatin is associated with a high rate of achievement of lipid and BP goals in black patients with concomitant hypertension and dyslipidemia, according to the results of a trial known as CAPABLE (Clinical Utility of Caduet in Simultaneously Achieving Blood Pressure and Lipid Endpoints in a Specific Patient Population).

Single blood pressure/lipid pill permits achievement of treatment goals in high-risk black patients

Other data from a real-world study show better adherence with the dual pill compared with their separate components.

In CAPABLE, 499 black patients with concomitant hypertension and dyslipidemia (treated or untreated) were entered into a 20-week, open-label study in which they were treated with amlodipine/atorvastatin single pill. A flexible titration using 8 dosage strengths (amlodipine 5 or 10 mg; atorvastatin 10, 20, 40, or 80 mg) was employed.

Lead investigator John Flack, MD, MPH, explained that the impetus of CAPABLE was the low levels of both treatment and control of hypertension and dyslipidemia in blacks compared with whites, and the high overall mortality rate from coronary heart disease (CHD) in this ethnic group.

Patients were divided into 3 risk groups: Group 1 consisted of those with hypertension and dyslipidemia without other cardiovascular risk factors; Group 2 had at least 1 other cardiovascular risk factor; and Group 3 had established CHD or a CHD risk equivalent (diabetes or any other atherosclerotic disease).

Among the entire cohort, 73.7% achieved their National Cholesterol Education Program (NCEP) goal for low-density lipoprotein (LDL) cholesterol and 56.8% achieved their BP goal at 20 weeks. (The LDL cholesterol goal was either <160, <130, or <100 mg/dL depending on risk factors; BP goals, as established by the Seventh Report of the Joint National Committee [JNC 7] were <140/90 mm Hg, or <130/80 mm Hg for patients with diabetes.)

Importantly, nearly half (48.3%) achieved both their NCEP lipid goal and JNC 7 BP goal.

Both goals were achieved by 69.7% of Group 1, 66.7% of Group 2, and 28.2% of Group 3. The LDL cholesterol goal alone was achieved by 88.9%, 87.4%, and 58.7% in Groups 1, 2, and 3, respectively; and the BP goal alone was achieved by 71.9%, 72.7%, and 40.7% in Groups 1, 2, and 3, respectively.

Among the patients who had uncontrolled LDL cholesterol at baseline, 68.5% achieved control by study’s end (88.0% in Group 1, 84.4% in Group 2, and 53.8% in Group 3).

According to Dr Flack, associate chairman for clinical research and urban health outcomes at Wayne State Uni&shy;versity in Detroit, the single-pill therapy “can target effectively the most important, modifiable cardiovascular risk factors in African American patients who are at particular risk of the disease.”

Adherence with the single pill therapy was 2 to 3 times greater than adherence with calcium antagonists and statins given as separate therapies in a retrospective analysis of 4703 insured patients who were taking both therapies at baseline, according to Michael B. Nichol, PhD, associate professor of pharmaceutical economics and policy, University of Southern California, Los Angeles.

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At 180 days, patients taking amlodipine/atorvastatin were nearly twice as likely to be adherent than patients taking amlodipine and atorvastatin as separate pills ( < .001), 3 times as likely to be adherent than patients taking amlodipine plus another statin ( < .001), twice as likely to be adherent than patients taking another calcium antagonist and atorvastatin ( < .001), and almost 3 times as likely to be adherent than patients taking another calcium antagonist and another statin ( < .001).