Ximelagatran as Effective as Warfarin for Prevention of Stroke, Embolic Events

Peggy Peck

November 12, 2003

Nov. 12, 2003 (Orlando) -- In a double-blind, randomized trial, the oral direct thrombin inhibitor ximelagatran was as effective as well-controlled warfarin for preventing strokes and reducing embolic events in high-risk patients with nonvalvular atrial fibrillation (AF).

Principal investigator Jonathan L. Halperin, MD, professor of medicine at Mount Sinai School of Medicine in New York City, presented results from the Stroke Prevention using an Oral Direct Thrombin Inhibitor in Patients with Atrial Fibrillation (SPORTIF V) trial at a late-breaking clinical trials session at the American Heart Association (AHA) Scientific Sessions.

Although patients in the warfarin group were tightly controlled, with 68% of them maintained at standard international normalized ratio (INR) of 2.0 to 3.0, there were no significant differences in the primary embolic event rates observed at one year for ximelagatran (1.6%) and warfarin (1.2%), said Dr. Halperin. A pooled analysis of the results from SPORTIF V and SPORTIF III found similar equivalency, reporting a total of 91 events in the ximelagatran group vs. 93 events in the warfarin group.

But there was a significant decrease in the rate for all bleeding events (minor and/or major), with 37% of ximelagatran-treated patients experiencing bleeding events during an average 20 months of treatment compared with 47% of warfarin-treated patients ( P < .0001).

Dr. Halperin said that SPORTIF V confirms the results of SPORTIF III, which was a similar, nonblinded trial.

The study was a noninferiority trial designed to determine whether oral ximelagatran was as effective as dose-adjusted warfarin. SPORTIF V enrolled 3,922 patients who had nonvalvular AF as well as at least one more risk factor -- age 75 years or older, prior stroke or blood clot, congestive heart failure, hypertension, or a combination of advanced age and diabetes or coronary artery disease. Patients were randomized to ximelagatran 36 mg twice daily (n=1,960) or warfarin (n=1,962). Patients in the ximelagatran group underwent sham testing and dose variations of dummy warfarin to mimic INR management.

While the outcomes in the two treatment groups were comparable, ximelagatran has the advantage of ease of treatment, said Dr. Halperin. "We know from meta-analyses that warfarin can reduce stroke risk by 62% in this population, but warfarin is difficult to manage for both the patient and physician. It interacts with other drugs and with food, and it requires frequent anticoagulation screening. As a result, more than 50% of patients who need anticoagulation cannot sustain therapy."

Ximelagatran, on the other hand, is administered at a fixed oral dose and does not require anticoagulation monitoring, he said.

But ximelagatran is associated with an increased risk for elevated liver enzymes and 6% of the patients in SPORTIF V had serum ALT levels three times above the upper limit of normal, Dr. Halperin said. In addition, nine patients treated with ximelagatran had elevated bilirubin levels compared with one patient in the warfarin group. Dr. Halperin noted that "these elevations appear to be transient and occur within the first two to six months." Asked about the need for monitoring, he said, "I recommend monitoring liver function once a month for the first six months."

At an AHA press conference Dr. Halperin said that monitoring liver function for six months is much easier than "a lifetime of anticoagulation monitoring."

Larry B. Goldstein, MD, professor of medicine and director of the Duke Center for Cerebrovascular Disease in Durham, North Carolina, agreed that liver function monitoring is not as cumbersome as traditional anticoagulation monitoring. But Dr. Goldsmith, who was not involved in the study, told Medscape that "INR monitoring is now frequently turned over to anticoagulation clinics that are run by nurses, so that frees up physician time and makes it more convenient for patients. Also, there are some home monitoring devices that are now coming to market," thus anticoagulation monitoring is becoming easier, he said.

Nonetheless, Dr. Goldsmith, who is a spokesperson for the American Heart Association and the American Stroke Association, said that if the Food and Drug Administration approves ximelagatran for the prevention of stroke in patients with AF, it could be a good therapeutic option for many patients. "Ease of use could increase compliance. Only about 50% of patients who need anticoagulation are now receiving warfarin and only about 40% are well controlled," he said.

"But, of course, the other issue is cost," Dr. Goldsmith continued. "Right now, the INR monitoring costs are not direct-to-patient costs but are usually covered by third party payers. Those costs might be factored into the cost of a new drug." He said that the direct patient costs for warfarin are $20 a month.

The study was funded by AstraZeneca.

AHA 2003 Scientific Sessions: Late-Breaking Clinical Trials. Presented Nov. 11, 2003.

Reviewed by Gary D. Vogin, MD

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