• 31
    Mar
  • Multiple Sclerosis Symposium and American Society of Hypertension: AMERICAN SOCIETY OF HYPERTENSION

Aliskiren (Rasilez, Novartis), a direct renin inhibitor and the first in a new class of antihypertensive drugs to be introduced in a decade, has been submitted for approval by the Food and Drug Administration (FDA). In clinical trials presented at the American Society of Hypertension’s Annual Scientific Meeting and Exposition (ASH 2006), aliskiren provided uninterrupted blood pressure (BP) control over 24 hours in combination with hydrochlorothiazide (HCTZ), a diuretic. This year’s meeting took place from May 16 to May 20, 2006.

(Novartis) is an FDA-approved angio-tensin II receptor blocker (ARB) known to reduce high sensitivity C-reactive protein (hsCRP) levels. A combination of canadian valsartan and HCTZ also controlled BP but raised the specter of a possible inflammatory effect for HCTZ.

Aliskiren with HCTZ

Jerry Mitchell, MD, of the Texas Center for Drug Development in Houston, noted that variability in BP is associated with damage to the heart, kidney, brain, and other organs. The benefits of BP reduction are maximized if control is maintained continuously. Furthermore, he said, the continuity and smoothness of BP lowering with antihypertensive agents can be assessed via 24-hour ambulatory BP monitoring. Aliskiren’s half-life of about 40 hours allows for once-daily dosing.

In a substudy of the larger aliskiren trial, 833 patients were randomly assigned to receive one of three aliskiren doses (150 mg, 300 mg, 600 mg) or placebo. This substudy included 216 patients who had been evaluated before their first dose of aliskiren or placebo and at the end of eight weeks of treatment.

Results showed that BP was effectively reduced with aliskiren (Table 2). BP lowering was consistent at all doses at each hourly point, including the high-risk early morning period, when dangerous surges in BP often occur. With the 300-mg dose of aliskiren, the trough-to-peak ratio of 0.98 reflected a nearly complete preservation of BP-lowering effect just before the next dose.

Table 2 Ambulatory Blood Pressure Monitoring: Mean 24-Hour Change from Baseline Values at Eight Weeks

Aliskiren 150 mg

Aliskiren 300 mg

Aliskiren 600 mg

Placebo

once daily

Once Daily

Once Daily

Mean average diastolic (mm Hg)

+ 1.61

-6.55*

-5.96*

-7.43*

Mean average systolic (mm Hg)

+ 1.75*

-9.63*

-8.77*

-9.92*

* P < .001 versus placebo.

The trough-to-peak ratio was 0.64 with 150 mg of aliskiren and 0.86 with 600 mg. High smoothness indices for aliskiren, when compared with those for placebo, reflected a smaller degree of variability in 24-hour BP measurements.

The mean BP with placebo surged to hypertensive levels in the morning. Mean reductions in daytime and nighttime diastolic BP and systolic BP were similar in the aliskiren patients.

“The drug very effectively eliminates morning surges,” Dr. Mitchell said, adding that the incidence of stroke rises by 25% to 30% for every surge of 10 mm Hg in morning BP

He concluded, “Once-daily aliskiren has the potential to maximize end-organ protective benefits through continuous, smooth BP lowering.”

Placebo and Aliskiren Monotherapy

A further analysis by Alberto Villamil, MD, from Fundapres, Buenos Aires, Argentina, compared placebo and aliskiren alone (75-300 mg), HCTZ monotherapy (6.25-25 mg), and eight aliskiren/HCTZ dose combinations. In a trial of approximately 2,800 patients, both aliskiren and HCTZ produced significantly greater reductions in mean average diastolic and systolic BP compared with placebo.

Responder rates reached 80.6% with aliskiren 300 mg/HCTZ 12.25 mg and 45.8°% with placebo (P < .0001). The responder rate for aliskiren monotherapy 300 mg was 63.9%, and the rate for HCTZ 12.25 mg alone was 60.6%. Overall, the treatments were well tolerated, and the incidence of adverse dug events (ADEs) was unrelated to the dose.
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Dr. Villamil concluded that aliskiren monotherapy effectively lowered BP; in combination, it provided significant additional BP reductions and an increased proportion of responders.

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