Panel recommends FDA approval for telmisartan in patients resistant to ramipril

Panelists felt ramipril was superior for proposed indications in patients who could tolerate it.

Telmisartan, an angiotensin receptor blocker approved for the treatment of hypertension in 1998, was not recommended for approval for additional risk-reduction indications, except in patients resistant to ramipril.

The Cardiovascular and Renal Drugs Advisory Committee voted 7 to 0 not to recommend telmisartan (Micardis, Boehringer-Ingleheim) for FDA approval for reduction of the risk for MI, stroke, death from CV causes or hospitalization for congestive HF in high-risk patients aged 55 years or older. Telmisartan is already an FDA-approved hypertension medication. The panel did, however, vote 5-2 in favor of recommending approval of telmisartan for a narrower indication of the combined CV event risk-reduction in patients who were intolerant of the ACE inhibitor ramipril (Altace, King Pharmaceuticals). The narrower indication was added by the panel following lengthy discussions of the data from clinical trials evaluating telmisartan.

Three trials evaluating telmisartan

The panel reviewed results from three clinical trials evaluating telmisartan in several patient groups. The primary study was the ONTARGET trial, a randomized, double-blind trial that included 25,620 patients who were randomly assigned to receive either telmisartan (n=8,542), ramipril (n=8,576) or a combination of both (n=8,576). According to results cited in FDA documents, the combination of telmisartan and ramipril failed to achieve superiority over ramipril alone for the four-component efficacy endpoint of reduction in MI, stroke, CV death or hospitalization (HR=0.99; 95% CI, 0.92-1.07). In the TRANSCEND trial, which tested the superiority of telmisartan (n=2,954) vs. placebo (n=2,972) in patients resistant to an ACE inhibitor, the researchers reported an HR of 0.92 (95% CI, 0.81-1.05) for the four-component endpoint and an HR of 0.87 (95% CI, 0.76-1.00) when excluding hospitalization for congestive HF. In the Prevention PROFESS study evaluating telmisartan (n=10,146) vs. placebo (n=10,186) with background hypertensive therapy for prevention of second stroke, the researchers reported an HR of 0.94 (95% CI, 0.87-1.01) for the four-component endpoint and 0.94 (95% CI, 0.87-1.02) for the three-component endpoint.

Five of the panel members who voted not to recommend approval for the wider indications voted to recommend approval for the narrower indication.

“This was a difficult discussion today in terms of how certain one can be that the drug is as good as ramipril,” said Robert Harrington, MD, the panel chair and a professor of medicine at Duke University Medical School in Durham, N.C., said during the panel vote. “On the other hand, they did meet the standard, especially on the triple endpoint, that it is better than nothing and a reasonable choice in that group of patients for whom would otherwise be on nothing.”

Only two panel members voted not to recommend approval for the primary proposed indications or the narrower indication.

“I voted no on the second indication partly because of the marginal positive effects in the TRANSCEND trial, but also because when looking at concomitant medicines in these people, it is not just a matter of somebody who is intolerant of ACE inhibitors having nothing or [telmisartan],” Sidney M. Wolfe, MD, the acting consumer representative and director of the Health Research Group of Public Citizen in Washington, explained regarding his vote against recommending approval for both indications. “A number of them have not been adequately treated with other drugs known to reduce CV risk, so the campaign to add some of these other drugs with proven CV risk-lowering abilities would be preferable to something with marginally-proven drugs.” – by Eric Raible