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BARCELONA -- A high dose of dabigatran, an investigational oral direct thrombin inhibitor, was more effective in preventing strokes in high-risk patients than warfarin, researchers reported here.

The results led some here at the European Society of Cardiology Meeting to predict that dabigatran could replace warfarin as the standard treatment for atrial fibrillation.

In an 18,000-patient, phase III trial, those randomized to 150 mg of dabigatran twice a day had significantly lower rates of both hemorrhagic stroke and ischemic stroke than patients taking warfarin, according to Michael Ezekowitz, MB,ChB, DPhil, of the Lankenau Institute for Medical Research and Heart Center in Wynnewood, Pa., and colleagues.

But at the lower dose of 110 mg twice a day, the drug was comparable to warfarin, he reported.

The findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) were simultaneously published in the New England Journal of Medicine and presented at an ESC HotLine session by Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, lead author of the NEJM paper.

The rate of major bleeding was 2.71% per year among patients who received low dose dabigatran, versus 3.36% in the warfarin arm (P=0.003).

"From my perspective, it is an amazing result. The 150 mg dose was unequivocally superior to warfarin without compromising, without major bleeding," Ezekowitz said.

He said that if dabigatran were to be approved, "it will become the new standard against which every other [anticoagulant] will need to be compared."

Clyde W. Yancy, MD, president of the American Heart Association and medical director of the Baylor Heart and Vascular Institute in Dallas, called the results a "game-changer." But he also said that if the drug is approved, implementation should be "incremental."

Asked to explain the term "game-changer," Yancy, put it this way:

"If you are ever in the exam room initiating warfarin, trying to explain what is at risk and what is needed -- change in diet to the complete rearrangement of lifestyle -- when we tell patients that the active ingredient in warfarin is rat poison ... and the best adherence we get with warfarin is only about 40% to 60%, it's not surprising that patients are reluctant to do warfarin therapy. Now to have the possibility to offer an alternative, that's a game-changer."

He said it was not yet known if both doses would go forward for FDA approval, "but both doses are better than warfarin, so warfarin is out of the picture."

It was, however, not a clear victory: rates of myocardial infarction, dyspepsia, and gastrointestinal bleeding were higher among patients taking dabigatran.

Ezekowitz and colleagues concluded that the "net clinical benefit outcome, which is a measure of overall benefit and risk, was similar between the two doses of dabigatran, owing to the lower risk of ischemia with the 150-mg dose and the lower risk of hemorrhage with the 110-mg dose."

This suggested that the dose could be tailored to suit the individual patient risk profile.

Ischemic stroke occurred in 134 patients taking high dose dabigatran versus 199 patients receiving warfarin therapy (P<0.001), a 34% reduction in relative risk compared with warfarin. High dose dabigatran was associated with a hemorrhagic stroke rate of 0.10% per year versus 0.38% for warfarin (P<0.001).

"To prevent one nonhemorrhagic stroke, the number of patients who would need to be treated (NNT) with dabigatran at a dose of 150 mg twice daily, rather than warfarin, is approximately 357," Brian F. Gage, MD, of Washington University in St. Louis, wrote in an accompanying editorial.

"The high NNT tells us that this is an incremental benefit," said Yancy.

Ezekowitz agreed that dabigatran offered an incremental benefit, but said, "I cannot confirm an NNT of 357 ... I'm not sure how he [Gage] arrived at that number."

But proper managment of warfarin remains a challenge, because patients must undergo regular monitoring of international normalized ratio (INR) to be sure the drug is correctly dosed.

A 2001 Cochrane review by Segal et al found that the NNT to prevent stroke with warfarin was 18, but that was compared with placebo. This may explain why the NNT to prevent stroke with dabigatran versus warfarin was so high: warfarin, when properly managed is just that good.

A major plus for dabigatran is that it does not require INR monitoring, said Fausto Pinto, MD, PhD, of the University of Lisbon. Pinto, who chairs the ESC Congress program committee, was not involved in the RE-LY trial.

Yancy agreed, noting that warfarin is a labor intensive therapy, with the cost of the drug, INR testing, and close monitoring ranging from $50 to $500 a month, depending upon region and patient comorbidities.

Pinto said the search for a warfarin substitute has been long and frustrating but, based on RE-LY, "dabigatran will probably replace heparin."

He said the RE-LY findings were, not a "home run," but he characterized them as "very strong" and he suggested that the data were impressive enough to make approval likely in Europe.

But it may be harder in the U.S., especially since there was a small, but statistically significant increase in myocardial infarction in the high dose dabigatran group compared with warfarin (89 versus 63, P=0.048).

Connolly said the MI finding was unexpected and will require "additional analysis," but he theorized that it was more likely a reflection of the "benefit of warfarin in reducing MI" than a safety signal for dabigatran.

He also said that current plans are to seek approval for the drug at both the 110 mg and the 150 mg bid doses.

A potentially greater obstacle than MI risk, which was slight regardless of treatment, was the rate of dyspepsia with dabigatran, which was twice the rate as the rate in the warfarin group (11.3% versus 5.8%, P<0.001).

Dyspepsia was the main driver of a significantly higher second year dropout rate in the dabigatran arm (21% versus 16.6%, P<0.001).

Ezekowitz said the drug increases gastric acid, which causes the dyspepsia.

The trial, which was designed as a noninferiority study, enrolled 18,113 patients who had documented atrial fibrillation and at least one additional stroke risk factor -- history of stroke, left ventricular ejection fraction less than 40%, New York Heart Association Class II or higher within six months before screening, age 75 or older, or ages 65 to 74 plus diabetes, hypertension, or coronary artery disease.

Patients were randomized in a blinded fashion to 110 mg dabigatran (N=6,015) or 150 mg dabigatran (N=6,076) or unblinded, dose-adjusted warfarin (6,022). The median duration of follow-up was two years.

Among the findings:

• There were 80 disabling or fatal strokes in the dabigatran 150 mg arm, versus 118 in the warfarin arm (P=0.005).
• The were 274 deaths from vascular causes in the high dose dabigatran arm, versus 317 in the warfarin arm (P=0.04).
• The hospitalization rate was 20.2% with 150 mg dabigatran, versus 20.8% for warfarin (P=0.003).
• The overall mortality rate was 4.13% in the warfarin group, versus 3.75% in the high- dose dabigatran arm, which was not significant (P=0.051).

The authors noted that use of open-label warfarin "could have introduced a bias in the reporting or adjudication of events," but they said this potential for bias was reduced by the use of "blinded evaluation of outcome events."

As evidence they offered the "unexpectedly different rates of myocardial infarction and gastrointestinal bleeding among the three treatment groups."