Antihypertensive Outcomes Labeling Emphasized By FDA After ALLHAT

FDA is planning to include clinical outcomes data in antihypertensive labeling in light of findings from the ALLHAT and LIFE studies.

"We have been thinking about this in a somewhat desultory way for at least six years. We will eventually bring proposed language to the [cardio-renal advisory] committee on how to do just that," Office of Medical Policy Director Robert Temple, MD, told the Cardiovascular & Renal Drugs Advisory Committee Jan. 6.

The committee met to review the supplemental application for Merck's angiotensin II blocker Cozaar (losartan for reduction of cardiovascular morbidity/ mortality (see ¹ (Also see "Merck Cozaar Will Get Stroke Risk Reduction Claim – FDA’s Temple" - Pink Sheet, 13 Jan, 2003.) ).

The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study showed that Cozaar patients had a 13% risk reduction on the composite primary endpoint compared to the beta-blocker atenolol, with comparable blood pressure control.

"What Merck is doing here, I don't know if they intended it, but they are performing a very valuable service," Temple said. "They are provoking the question of whether it is time to start putting outcomes data into antihypertensive labeling."

"Current labeling for antihypertensives uniformly fails to include any outcomes data...and we're not particularly close to doing it," he said.

"From a regulator's narrow point of view, it is sort of forcing the issue of outcome data in labeling for clinical trials, which we don't have. Some people think that we do in the form of ramipril. We didn't think that was a hypertension claim," Temple said.

King's ACE inhibitor Altace (ramipril) was shown to reduce adverse outcomes in high-risk patients in the HOPE trial. Altace received supplemental approval Oct. 5, 2000 for reduction in risk of myocardial infarction, stroke and death from cardiovascular causes (² (Also see "King Altace Label Highlights Data Supporting Efficacy In Diabetic Patients" - Pink Sheet, 9 Oct, 2000.), p. 15).

Several committee members suggested that the LIFE study should be interpreted carefully in light of the recent findings of the NIH ALLHAT trial.

The ALLHAT trial concluded that the diuretic chlorthalidone is superior to the calcium channel blocker amlodipine (Pfizer's Norvasc ) and the ACE inhibitor lisinopril (AstraZeneca's Zestril ) (³ , p. 11).

"I recognize that we as a committee have not had a chance to review ALLHAT, but there is a signal there that makes me terribly nervous," committee member Steven Nissen, MD, Ohio State University, said.

"It appears from ALLHAT that drugs that work through the renin-angiotensin system are not particularly effective at stroke reduction," he said. Cozaar "works by the same mechanism, extremely similar."

ALLHAT used beta-blockers as add-on therapy to control blood pressure while LIFE used diuretics as add-on therapy.

"I think it is reasonable to look at blood pressure lowering data, with the knowledge that lowering blood pressure is beneficial, from all of these outcomes trials showing adding a diuretic to a beta-blocker or a beta-blocker to a diuretic," Merck Senior Director-Clinical Development Jonathan Edelmann, MD, said.

It is likely that ALLHAT and LIFE will influence future reviews by the cardio-renal advisory committee regarding the benefit of antihypertensive therapy. ALLHAT is bringing calls for more comparative trials and a greater focus on costs (⁴ (Also see "ALLHAT Study Brings Calls For Comparative Trials, Greater Focus On Costs" - Pink Sheet, 23 Dec, 2002.), p. 13).

"I really want to compliment [Merck] for doing this study," Nissen said. "What you see here is that basically it does seem to matter how you lower blood pressure. ALLHAT seemed to show the same thing....What we have to ask ourselves is, given this body of evidence, what will it take to convince us that you are the first folks in history to prove beyond a shadow of a doubt that a specific regimen for a comparable degree of lowering is better than another regimen."

The committee found that the LIFE data support a cardiovascular morbidity/mortality risk reduction claim for Cozaar, but not a claim for superiority to atenolol.