FDA Advisors Recommend Losartan for Stroke Prevention

January 07, 2003

Jim Kling

Jan. 7, 2003 A U.S. Food and Drug Administration (FDA) advisory committee has recommended that losartan (Cozaar), an antihypertensive agent marketed by Merck, be approved for the prevention of stroke. The pharmaceutical giant had hoped the drug would also be recommended for approval to prevent heart attacks and overall cardiovascular mortality, but the committee did not agree that there was sufficient evidence to support all three claims.

Even so, the decision and the study that sparked it are landmark events, according to Jeffrey Borer, MD, chair of the FDA's cardiovascular and renal drugs advisory committee and the director of the Division of Pathophysiology at Weill Medical College at Cornell University. Antihypertensive drugs have long been presumed to lower the risk of strokes, heart attacks, and other cardiovascular problems, but most clinical trials measure only a drug's effect on blood pressure without attempting to directly measure these clinical endpoints. "This company is saying that you don't have to infer this drug does reduce (adverse) events," Dr. Borer told Medscape.

In a lengthy clinical trial sponsored by Merck, losartan was compared with atenolol, an antihypertensive drug marketed by AstraZeneca, which had previously been shown to do a better job of lowering blood pressure than losartan. The new trial showed that when combined with diuretics, losartan reduced the risk of stroke by about 25% compared with atenolol combined with diuretics.

The results also hint that reducing blood pressure may not be the only key to reducing strokes and other cardiovascular events. Atenolol and losartan work by different mechanisms, so losartan's improvement in preventing strokes suggest that how blood pressure is lowered may also be important. "There is a difference, and it matters," asserted William F. Keane, vice president of clinical development for Merck.

The trial results also suggested reduced heart attacks and overall death rates in patients receiving losartan, but the data were not as robust as for strokes, leading the advisory committee to reject these claims. There was also a surprise. African-American patients, who made up a little more than 5% of the clinical trial participants, actually did a little better with atenolol. The panel therefore recommended that losartan's label contain an insert indicating that losartan appears not to work as well for African-Americans.

The trial data were difficult to interpret because of the standard treatment procedure for hypertension. Physicians often combine diuretics with other types of medication in order to achieve maximum effect, and this occurred with both losartan and atenolol during the trial. Many on the advisory committee questioned whether the effects seen in the trial were due to losartan, or to the diuretic that it was most often combined with. In the end, "we approved not the drug, [but the] regimen containing the drug," said Dr. Borer.

The FDA is not required to follow the committee's recommendations, but it usually does.

Reviewed by Gary D. Vogin, MD

Jim Kling is a freelance writer for WebMD.