New Antihypertensive with 2 Proven Mechanisms of Action

Internal Medicine World Report, September 2007, Volume 0, Issue 0

ARB plub CCB May Sustain BP Control

Despite the abundance of antihypertensive medications—monotherapies as well as combination agents—the rates of blood pressure (BP) control among hypertensive patientsare not very encouraging. "We need many more effective antihypertensive medications," says Bertram Pitt, MD, FAACP, Professor Emeritus of Internal Medicine, University of Michigan School of Medicine, Division of Cardiology, Ann Arbor. Thus, he applauds the recent approval of the new antihypertensive agent Exforge (Novartis), which combines 2 tried-and-true drugs, the angiotensin-receptor blocker (ARB) valsartan and the calcium channel blocker (CCB) amlodipine.

Bertram Pitt,MD,FAACP

"This is not a breakthrough in a new class of drugs; it's taking 2 old friends who we have lots of experience with and putting them together in a pretty powerful combination," Dr Pitt tells IMWR.

And although this is not a miracle drug, the new combination is a good addition to the primary care physician's drug armamentarium. "Because of the scares recently about drug safety, a lot of us are afraid of using new drugsuntil we have a long experience with their side effects," he acknowledges. "Exforge combines 2 old agents that people are familiar with, and we have fantastic experience with both components."

According to the American Heart Association, many of the 72 million American adults with elevated BP do not suspect they have it. Even among those who are being treated, achieving a BP goal of <140/90 mm Hg has proven elusive, with only about one third of hypertensives reaching their BP goal.

The CCB?ARB Advantage

Most hypertensives will require more than 1 agent to control their BP. Fixed-dosed combinations are usually also better tolerated than a single agent, because the doses of each component are lower than those used for monotherapy. Of the several combination agents available, Exforge's potential advantage is in its combining the most often prescribed CCB with the most often prescribed ARB.

The combination of valsartan and amlodipine gives physicians "a very powerful therapy and should control more people than we're currently controlling," he says.

As with most combination agents, the 2 components are complementary: valsartan blocks the renin-angiotensin system (RAS), and amlodipine blocks the calcium channel and affects vasomotor tone more strongly. The well-known combination of another RAS blocker, the angiotensin-converting-enzyme (ACE) inhibitor benazepril HCl, and amlodipine (Lotrel) has already been shown to be very effective antihypertensive therapy in real-world settings. Dr Pitt says that Exforge "is an improvement over Lotrel, because its ARB component is better toleratedthan the ACE inhibitor benazepril."

Another CCB/ARB combination agent (Azor; Daiichi Sankyo) is currently under FDA review.

A number of other combination agents include a diuretic (eg, Atacand, Inderide, Lotensin), "because a diuretic is thought to be the base of therapy," Dr Pitt says. But the side-effect profile of the diuretics is problematic, especially dyslipidemia and a risk for type 2 diabetes.

Safety and Efficacy

The approval of Exforge was based on placebo-controlled and active-controlled trials. One study randomized patients with stage 2 hypertension to (1) amlodipine (5-10 mg/d) plus valsartan (160 mg/d) or (2) the ACE inhibitor lisinopril

(10-20 mg/d) plus the diuretic hydrochlorothiazide for a period of 6 weeks (Clin Ther. 2007; 29:279-289), which showed similar results:

  • Reduction in mean sitting systolic BP (SBP) of 35.8 mm Hg with amlodipine/valsartan and 31.8 mm Hg with lisinopril/hydrochlorothiazide
  • Response rates of mean sitting diastolic BP (DBP) <90 mm Hg, or a ≥10-mm Hg reduction from baseline of 100% and 95.5%, respectively
  • DBP control rates of 79.7% and 77.3%, respectively
  • Both combination agents were well-tolerated.

Another report assessed the results of 2 multicenter, 8-week, placebo-controlled trials that evaluated amlodipine and valsartan, alone or in combination (Clin Ther. 2007;29: 563-580). Study 1 randomized 1911 patients to amlodipine (2.5 or 5.0 mg/d), valsartan (40-320 mg/d), the combination of both agents across the same dose ranges, or placebo.

Study 2 randomized 1250 patients to amlodipine (10 mg/d), valsartan (160 or 320 mg/d), the combination of both agents across the same dose ranges, or placebo. All participants in both studies had mild-to-moderate essential hypertension at baseline, and all underwent an initial 2-week washout period, during which any current antihypertensive medications were discontinued.

In both trials, the combination regimens&#8212;except for a few that included the lowest amlodipine dose of 2.5 mg&#8212;resulted in significantly greater reductions in mean sitting DBP and SBP compared with the individual components (Table).

Subgroup analyses of these 2 trials(J Clin Hypertens. 2007;9:355-364) showed similar results in patients with stage 1 hypertension (140-159/90-99 mm Hg) or stage 2 hypertension (≥160/100 mm Hg), the elderly, and African Americans.

The combination regimen was also well-tolerated. And combining valsartan with amlodipine has been shown to significantly decrease the dose-limiting side effect of peripheral edema with amlodipine monotherapy.

When to Prescribe

Exforge is available at daily dosages of 5 to 10 mg amlodipine and 160 to 320 mg valsartan. And although it is not currently indicated for initial therapy, Dr Pitt says, "If I had someone with a BP over 160 mm Hg, I wouldn't hesitate to use Exforge as initial therapy."

He describes patients with mild renal disease, but not severe renal disease, or those with diabetes as good candidates for Exforge therapy, in addition to patients with BP >160 mm Hg that is difficult to control. Aside from women who are pregnant and should not be prescribed this drug, "There aren't too many other contraindications" to the new agent, Dr Pitt says, making Exforge a good choice in most patients.

"The most important thing to remember about treating hypertension is that it is less important how you lower blood pressure than the fact that you lower it," Dr Pitt emphasizes.

Many antihypertensive drugs have side effects, and people stop taking them. And many patients have to take 2 or 3 or even 4 drugs, and they forget to take them all. When 2 effective drugs are packaged in a single tablet, it is easier for the patient, and has been shown to improve compliance. And since it is also very well tolerated, "More people will tend to keep taking it, and we should get better blood pressure control," he notes.

Admitting that "we'd love to have new classes of agents," Dr Pitt adds that "we also need to take some ofthe old ones we have and use them more effectively. Exforge is one way to do that."

Side Effects

In placebo-controlled trials, 1.8% of patients treated with Exforge discontinued therapy because of side effects, compared with 2.1% of patients treated with placebo.

The most frequently reported side effects with the new combination were: peripheral edema (5.4%), nasopharyngitis (4.3%), upper respiratory tract infection (2.9%), dizziness (2.1%).