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 concluded in presenting the study findings at the annual congress of the European Society of Cardiology.

The FDA approved tegaserod in 2002 for treatment of irritable bowel syndrome (IBS) of the constipation-predominant subtype, then later granted an added indication for treatment of chronic idiopathic constipation in patients under age 65.

Tegaserod, a selective serotonin-4 receptor agonist, was the only drug approved for treatment of IBS with constipation until it was yanked from the market. However, in April 2008, Takeda Pharmaceutical's chloride channel activator lubiprostone (Amitiza) received FDA approval for IBS with constipation and for chronic idiopathic constipation.

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, compared with just 1 case in 7,031 placebo-treated controls, explained Dr. Anderson, professor of medicine at the University of Utah and associate chief of cardiology at LDS Hospital, both in Salt Lake City.

All cases occurred in individuals who had a history of cardiovascular disease or were at increased cardiovascular risk. And when Dr. Anderson was asked to conduct a follow-up independent review of the Novartis data, he determined 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 minimal difference that did not approach statistical significance.

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 totaling 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 decided to conduct a prospective study free of any industry support. They turned to 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. In keeping with IBS demographics, the tegaserod group averaged 38.6 years of age, and 94% were women. Duration of therapy 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 comprising cardiac death, acute MI, cerebrovascular event, or hospitalization for unstable angina occurred in 12 tegaserod-treated individuals and 54 controls during an average 2.3 years of follow-up. This translated to very similar event rates of 0.46% and 0.35%, respectively. The most common events were cerebrovascular accidents, occurring in 10 tegaserod-treated patients and 36 control patients. 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 actually 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, commented that if one were searching for a plausible mechanism of vascular effects for tegaserod, platelet function would be the place to start. At least 14 different serotonin receptors have been identified to date, and while tegaserod is relatively selective for the type 4 receptors in the gut, the drug could, in theory, act on other serotonin receptors promoting platelet activation.

Dr. Anderson agreed, although such an effect has not been found to date. He added that cardiovascular event rates are so low in women under age 40—the typical IBS population—that a formal randomized trial of tegaserod with cardiovascular end points would have to be so huge as to be impractical.

“It raises the question of what should be required of a drug like this that treats relatively young women who are highly symptomatic with this disease, when if there is a cardiovascular risk it's very, very small,” the cardiologist observed.

The Intermountain Healthcare study was funded by the Deseret Foundation.

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The 'increase in cardiovascular events with tegaserod may be due to chance rather than causal.' DR. ANDERSON

Tegaserod's CV Risk May Have Been Exaggerated