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What Happened to Ximelagatran?

Jack Ansell, M.D.
March, 2005

Disclosure: Dr. Ansell has research support from AstraZeneca and Aventis-Sanofi. He serves as a consultant to AstraZeneca and speaks on behalf of AstraZeneca, Aventis- Sanofi, Bristol Myers Squibb.

The vitamin K antagonists (VKA) (e.g., warfarin, phenprocoumon, acenocoumarol) are excellent anticoagulants, but to achieve the desired outcomes, exquisite dose management is required. Such management is not the rule in the United States or worldwide. An entire industry (i.e., anticoagulation clinics) has evolved to provide the systematic management needed to achieve the outcomes reported in well designed and well managed prospective trials. Health care providers have been hopeful about the prospect of new oral anticoagulants with improvements similar to those achieved with the parenteral anticoagulants (e.g., low molecular weight heparin and fondaparinux). New agents, such as factor Xa and IIa inhibitors, offer target specificity compared to the broad affect of the VKAs, oral availability, limited (if any) interaction with other drugs or with diet, predictable pharmacokinetics such that monitoring is not required, and metabolic half-lives that make once or twice daily dosing possible. The landscape looked quite promising for these new agents, with ximelagatran being the most clinically advanced and many others in development; that is, until the FDA reviewed the submission for ximelagatran and rejected it for the indications sought. What happened to ximelagatran?

The FDA did not approve ximelagatran primarily for safety reasons related to the drug's effect on liver function in 6% - 12% of patients taking ximelagatran for at least 3 to 6 months. However, the FDA made a number of other statements that are troublesome, indicating an inconsistency in their procedures, a lack of understanding of the risks and benefits of current oral anticoagulation therapy, and a flawed interpretation of relevant studies. The following quotes from the FDA report (http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4069b1.htm) illustrate some of these problems.

In reference to the atrial fibrillation trials (SPORTIF III AND SPORTIF V)...

"Since SPORTIF V was double-blind, it could be considered as the pivotal efficacy study and the other study (SPORTIF III) serves as a supportive study that provides additional safety information."

Since when did the FDA not accept open label trials as support for efficacy? Both SPORTIF III AND SPORTIF V were almost identical studies except that the former was open label (conducted primarily in Europe) and the latter was double-blind (in North America). These studies were the largest studies in AF conducted to date and showed a dramatic consistency in the efficacy of ximelagatran, but differences in the benefit of warfarin (no surprise!). The FDA had trouble understanding why one would not obtain the exact same benefit with warfarin in the two studies.

Another comment about the AF trials...

"Based on one double-blind study of Exanta [ximelagatran] versus the active control warfarin, there is very little evidence that Exanta is effective at reducing the risk of the combined incidence of stroke or systemic embolic events."

And further...

"On the primary endpoint, both studies failed to show a difference between Exanta and warfarin."

Taking these two statements together, one would conclude that ximelagatran is ineffective in reducing the risk of stroke or systemic embolism in AF and that it is no different than warfarin. In fact, the FDA criticized the earlier landmark warfarin/AF trials (early 1990s) and raised questions about whether warfarin is really protective against stroke and systemic embolism in patients with AF.

"Here, we have a scenario where the magnitude of the effect of warfarin versus placebo is not precisely known for this patient population." and

"There is some uncertainty about the magnitude of the effect of warfarin relative to placebo because of the variability between the six historical trials in terms of their design and the observed results. Consequently, there is a great deal of uncertainty about whether Exanta retains a significant portion of the benefit of warfarin, and even if Exanta is better than placebo"

If this is the case, perhaps warfarin should not have FDA approval for stroke prevention in AF? For a clear understanding of the efficacy of ximelagatran, one is referred to the following references (1-3).

The FDA also had several interesting comments and analyses of ximelagatran's efficacy and safety in the orthopedic studies. Ximelagatran has been shown to be significantly better than warfarin in the prevention of venous thromboembolism in patients undergoing elective total knee replacement (4,5), but the FDA commented...

"However, the benefit was mainly due to a reduction in asymptomatic distal DVT diagnosed by venography which is not clinically meaningful."

Perhaps the FDA should re-review the outcome measures in the studies submitted for approval of fondaparinux and the low molecular weight heparins before they totally disregard venogram documented asymptomatic DVT.

Another comment...

"There are several major problems with using warfarin as an active comparator in these two studies. Warfarin is not approved for this short-term indication. The comparison is unfair, because warfarin will take about 3-5 days to reach therapeutic level, while Exanta reaches therapeutic levels within hours."

First, warfarin is approved for the "prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism." (6). It is used by at least half of the orthopedic surgeons in this country and many others world-wide. It has been studied extensively in major joint replacement and is recommended by expert consensus groups (7). Second, one reason orthopedic surgeons like warfarin is because it takes several days to have an effect (thus, less risk of bleeding at the surgical site), but also offers less protection early on. An advantage of ximelagatran as an oral anticoagulant is its rapid onset of action, and thus, protection. Because of this difference in pharmacokinetics the ximelagatran patients did experience a slight increase in bleeding, which was criticized by the FDA, but there was no significant difference in major bleeding.

The other major concern raised by the FDA, and correctly so, was a signal indicating the possibility of increased cardiovascular events in patients on ximelagatran. Such events were only considered as an outcome measure, and thus adjudicated, in the AF trials (SPORTIF trials) and in the acute coronary syndrome trial (ESTEEM trial) (8). Adjudicated coronary events were actually fewer in the ximelagatran group in the ESTEEM trial, and was not different from the warfarin group in the SPORTIF trials. However, unadjudicated coronary events were greater in the ximelagatran groups in the venous thromboembolism trials (THRIVE III (9) and THRIVE treatment trial (10)). This requires further evaluation, perhaps in a well managed post-marketing surveillance study.

Although there are many other aspects of the FDA review that deserve comment, space is limited and I am unable to address them here. My final thoughts about the proceedings are that the FDA may have arrived at the right conclusion, but for many of the wrong reasons. Their analysis lacked expertise; it failed to recognize the efficacy of ximelagatran which is supported by the literature and uniformly recognized by experts in the field; and it erected almost insurmountable hurdles for new drug development in this field. I am gravely concerned that the FDAs review will stifle or retard such development. The FDA has lately been under duress related to the approval of other drugs with unrecognized adverse events. Although it is charged with protecting the American public from dangerous drugs, the FDA may have done a disservice in the process by setting back the potential development of new drugs in a field that is ripe for improvement?

References

1. SPORTIF Executive Steering Committee. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non valvular atrial fibrillation: a randomized trial. Lancet 2003;362:1691.

2. SPORTIF Executive Steering Committee. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. JAMA 2005;293:690.

3. Gurewich V. Ximelagatran-promises and concerns. JAMA 2005;293:736.

4. Francis CW, Berkowitz SC, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349:1703.

5. Colwell CW, Berkowitz SD, Comp PC, et al. Randomized double-blind comparison of ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism after total knee replacement. EXULT B. Blood 2003;102:14A.

6. Physician Desk Reference, Edition 58, 2004, page 1048-1052.

7. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism. Chest 2004;126:338.

8. Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomized controlled trial. Lancet 2003;362:789.

9. Schulman S, Wahlander K, Lundstrom T, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713.

10. Fiessinger JN, Huisman MV, Davidson BL, et al. Ximelagatran vs low molecular weight heparin and warfarin for the treatment of deep vein thrombosis. JAMA 2005;293:681.

***This article has been posted with the permission of the Anticoagulation Forum.***

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Sunday, November 23, 2014