Aliskiren Plus ARB Boosts Antihypertensive Effects

March 27, 2007

March 27, 2007 (New Orleans, LA) - The combination of a new direct renin inhibitor, aliskiren (Tekturna, Novartis), and an angiotensin receptor blocker (ARB), valsartan (Diovan, Novartis), was more effective at lowering blood pressure (BP) than either drug alone in a population of difficult-to-treat hypertensive patients, according to a study presented here today in the late-breaking session. Dr Suzanne Oparil (University of Alabama at Birmingham School of Medicine), who reported the findings, said: "The results suggest a synergistic effect of this combination on renin-angiotensin-system blockade, which is particularly impressive given the patient population. Clearly [aliskiren] is an innovative drug that is going to be used."

Aliskiren has just been approved by the US FDA, the first in a new class of antihypertensives and the first new agent for reducing BP in 10 years. It is expected to be available in pharmacies soon.

Oparil said that it is still early in terms of doctors deciding how they will use the drug. "We don't know exactly how it will fit in, but it does give the physician another choice." It is licensed for use as monotherapy and in combination with other antihypertensive agents. She told heart wire that she foresees using it initially in people who can't tolerate or won't take diuretics, in stage 2 antihypertensives, and possibly in diabetics and the morbidly obese.

Combination employs maximum doses of both drugs

In the study, 1800 patients were randomized to one of four arms: aliskiren alone, valsartan alone, a combination of the two, or placebo. Importantly, Oparil noted the severity of the hypertensive patient population--JNC-7 type 2 patients, 50% of whom were obese and 15% of whom were African American.

For the first four weeks, patients took aliskiren 150 mg once daily, valsartan 160 mg once daily, a combination of the two, or placebo. They were then titrated to double the initial dose for four weeks. The fact that the combination consisted of the maximum therapeutic dose of both drugs is important, Oparil said.

The primary end point was a reduction in mean sitting diastolic BP. Secondary end points included reduction in mean sitting systolic BP, the proportion of responders, the proportion of patients achieving BP control, and the change in 24-hour BP profile as assessed by ambulatory BP monitoring (ABPM). In addition, change in plasma renin activity was assessed in a subgroup.

The combination lowered diastolic and systolic BP more than either aliskiren or valsartan alone, BP control rates were significantly greater with the two drugs together than either drug alone, and 24-hour ABPM showed superior reductions with the combination.

Results for end points at week 4

Week 4 end point Aliskiren/valsartan 150/160 mg, n=438 Aliskiren 150 mg, n=430 Valsartan 160 mg, n=453 Placebo, n=455
Change in DBP (mm Hg) -10.5* -7.5*† -8.7*† -4.8
Change in SBP (mm Hg) -15.3* -10.7*† -10.9*† -5.2

DBP=diastolic blood pressure; SBP=systolic blood pressure
*p<0.0001 vs placebo
†p<0.001 vs aliskiren/valsartan

Results for end points at week 8

Week 8 end point Aliskiren/valsartan 300/320 mg, n=438 Aliskiren 300 mg, n=430 Valsartan 320 mg, n=453 Placebo, n=455
Change in DBP (mm Hg) -12.2* -9.0*† -9.7*† -4.1
Change in SBP (mm Hg) -17.2* -13.0*† -12.8*† -4.6
BP control rate % 49.3* 37.4*† 33.8*† 16.5

DBP=diastolic blood pressure; SBP=systolic blood pressure
*p<0.0001 vs placebo
†p<0.001 vs aliskiren/valsartan

The two agents used together also reduced plasma renin activity in the subgroup more than ninefold, compared with a fourfold reduction seen with aliskiren alone, Oparil said.

In terms of adverse events, there were two that were more common in the combination group, she said; these were hyperkalemia and increased creatinine, but these were only small effects that did not affect tolerability.

Could a diuretic be just as good?

One of the panel members, Dr James Stein (University of Wisconsin School of Medicine and Public Health, Madison) asked Oparil whether aliskiren combined with a diuretic would not give just as good BP control as aliskiren with an ARB. She replied that although trial results have demonstrated good BP reduction with the renin inhibitor and a diuretic, the patient population was different so it was difficult to make a direct comparison.

"In that study [with the diuretic] the blood-pressure reduction was in the order of 6 mm Hg, whereas in the present study it was 4 mm Hg. However, it's my view that the blood-pressure lowering of the two different types of combinations is probably about the same," she noted.

Oparil added that work is ongoing into whether there will be improved organ protection with aliskiren, alone and in combination. "There are all kinds of target-organ situations where this drug will be tested and where it may be efficacious over other drugs. But this theoretical benefit does need to be demonstrated in humans."

She noted that Novartis is currently conducting studies with the drug in diabetes, obesity, metabolic syndrome, left ventricular hypertrophy, and other indications to determine whether there is any organ protection.

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