Closer Look at Cardiovascular Risk Of IBS Drug Tegaserod Reassuring
MUNICH — Results of a large case-control study suggest the irritable bowel syndrome drug tegaserod (Zelnorm) may have gotten a bum deal when the Food and Drug Administration suspended its marketing in March 2007 because of cardiovascular concerns.
“Our results suggest that a prior observation of a differential increase in cardiovascular events with tegaserod may be due to chance rather than causal,” Dr. Jeffrey L. Anderson said at the annual congress of the European Society of Cardiology.
The FDA approved tegaserod, a selective serotonin-4 receptor agonist, in 2002 for treatment of irritable bowel syndrome (IBS) of the constipation-predominant subtype, then later granted an added indication for chronic idiopathic constipation in patients under age 65.
Tegaserod sales were halted when a Novartis review of more than 18,000 patients in its database turned up 13 cardiac ischemic events in 11,614 treated patients, versus 1 case in 7,031 placebo-treated controls, said Dr. Anderson, associate chief of cardiology at LDS Hospital in Salt Lake City.
All cases occurred in individuals who had a history of cardiovascular disease or were at increased cardiovascular risk. When Dr. Anderson was asked to conduct a follow-up independent review of the Novartis data, he found that three reported events in the tegaserod group were false-positives and another five involved “soft” anginal episodes. That left five hard cardiovascular events in the tegaserod group and one in the placebo group, a nonsignificant difference.
Furthermore, no consistent relationship was seen between cardiovascular events and tegaserod dose or timing. And tegaserod had shown no ECG or other cardiovascular effects in the three randomized trials of nearly 2,500 women with IBS that led to the drug's approval.
IBS is a common and burdensome disorder in young women. On the basis of Dr. Anderson's largely reassuring review of the Novartis database along with the lack of a known vascular mechanism, he and his coinvestigators conducted a prospective study free of any industry support.
Using the Intermountain Healthcare database, which contains comprehensive hospital, outpatient, and prescription information on the Utah-based health plan's 1.2 million enrollees, they identified 2,603 tegaserod-treated patients and matched them by age and gender with 15,618 untreated controls. The tegaserod group averaged 38.6 years of age; 94% were women. Therapy duration was 2 months in IBS patients, in accordance with the product labeling, and up to 4 years in those with chronic idiopathic constipation.
The composite end point of cardiac death, acute MI, cerebrovascular event, or hospitalization for unstable angina occurred in 12 tegaserod-treated patients and 54 controls during a mean 2.3 years of follow-up, yielding similar event rates of 0.46% and 0.35%, respectively. The most common events were cerebrovascular accidents, occurring in 10 tegaserod patients and 36 controls. All six cardiovascular deaths occurred in the control group.
The cardiovascular event rates in this study—roughly 3 per 1,000 person-years in both groups—were lower than the expected rate of about 5 per 1,000 person-years in a population of mostly premenopausal women, Dr. Anderson noted.
Dr. Dan Atar, professor of cardiology at the University of Oslo, said platelet function could be a plausible mechanism of vascular effects for tegaserod.
Dr. Anderson agreed, although such an effect has not yet been found.
The Intermountain Healthcare study was funded by the Deseret Foundation.
The prior observation of an increase in cardiovascular events 'may be due to chance rather than causal.' DR. ANDERSON
