The European Society of Cardiology
General discussion
Antman: Before proceeding to the general discussion and the questions from the audience, it is worth remembering that it is some 50 years since the last oral anticoagulant, warfarin, was developed. However, at this symposium we have heard exciting information on what could be considered a breakthrough in our therapeutic armamentarium, ximelagatran, the first oral agent in the new class of direct thrombin inhibitors.
Verheugt: The first question from our audience is directed to Dr Antman. You described the phenomenon of rebound activation of the coagulation system when unfractionated heparin or low-molecular-weight heparin (LMWH) therapy is stopped. Could ximelagatran be a good drug to use to provide anticoagulation cover when heparin or LMWHs are stopped?
Antman: Rebound activation after initially successful anticoagulation is a persistent problem in the management of patients with acute coronary syndromes. Many clinicians have come up with a variety of hypotheses to explain this phenomenon, as well as some suggested treatment regimens to overcome the problem. Of all the treatments we have seen so far, ximelagatran may be the most promising because we now have an oral anticoagulant that is predictable and which we can rely on, and so potentially could be used to prevent the early rebound. Do any of my fellow panellists have any comments on this?
Wallentin: We have proposed for a number of years that the length of anticoagulation needs to be extended when treating patients with acute coronary syndromes. Now for the first time in a very long time, we have, with ximelagatran, a tool that allows us to accomplish this goal.
Verheugt: Turning to the ESTEEM trial, there are several questions from the audience on the increase in liver enzymes seen during the study. Many of the patients in ESTEEM were on concomitant statin therapy. As is well documented, the statins can also cause increases in liver enzymes. In ESTEEM, were any of the liver function abnormalities due to interactions between ximelagatran and statins?
Wallentin: A very extensive multivariate analysis was performed on the data from ESTEEM, which looked at all possible drug interactions with ximelagatran. To our surprise, it appeared that patients on statins had less elevation of liver enzymes rather than more. Why this should be is unclear presently. Perhaps exposure to agents that have a sensitizing effect on the liver leaves some kind of a ‘message’ there. Consequently, the next time the patient is exposed to another drug that also might affect the liver in a similar way, the second drug’s effect on the liver is diminished. Certainly, with ximelagatran some kind of tolerance to the drug seems to develop in the liver with continued use. Exactly what is happening in the liver with ximelagatran is actively being addressed by AstraZeneca. The company has about 17,000 patients exposed to ximelagatran in its database and currently is analyzing this database for a possible explanation.
Olsson: To comment further on the increase in liver alanine transaminase (ALAT) levels seen with ximelagatran, there does seems to be a dose–response relation between ximelagatran and ALAT increases. Therefore, could we reduce the rise in ALAT levels if the dose of ximelagatran was slowly increased in a step-wise manner? This is a challenging idea, and I look forward to seeing the results of such a ximelagatran dosing regime in the future.
Wallentin: To put ximelagatran’s effect on liver enzymes in a broader context, we could compare it with the statins and their effects on liver enzymes. Thus, statins also cause transient liver enzyme elevations (
3 times upper limit of normal), which are usually seen within the first 3–12 months of treatment. Additionally, statins were considered to require liver function testing before and at 6 or 12 weeks after drug initiation or dose increase, and periodically thereafter. Furthermore, when we compare the effects of the 24-mg dose of ximelagatran versus the statins on ALAT levels, the elevations of ALAT levels seem to be of comparable magnitudes.
Antman: Moving on to the doses of ximelagatran used in the SPORTIF and ESTEEM trials, we see that in SPORTIF essentially one dose was used, 36 mg twice daily, whereas in ESTEEM, which was a dose-finding study, a range of doses were used, from 24 mg twice daily to 60 mg twice daily. Could the panel give their thoughts on what would be their recommended dose, and would the dose vary depending on the patient’s condition, e.g., with atrial fibrillation or coronary arterial disease?
Wallentin: If we start with the ESTEEM study and the rationale for the ximelagatran doses used, when this trial was planned we had no experience with this new oral direct thrombin inhibitor in arterial disease. However, based on previous clinical experience with other anticoagulants, it appeared that higher doses, especially of unfractionated heparin and LMWHs, were required in arterial disease relative to the doses needed to prevent venous thrombosis. Therefore, in ESTEEM it was felt that two-fold higher doses of ximelagatran than that used to prevent thrombotic events in orthopaedic surgery should be used. It should also be remembered that when the ESTEEM protocol was being developed, the ximelagatran data from the SPORTIF trials were not available. Consequently, ESTEEM used doses of ximelagatran from 24 mg twice daily to 60 mg twice daily, the maximum dose being more than double the ximelagatran dose (24 mg twice daily) used in the long-term prophylaxis trial for venous thromboembolism (THRIVE lll). ESTEEM, however, demonstrated that the 24-mg dose was as efficacious as higher ximelagatran doses in arterial disease. Based on these results, no one really is arguing for doses higher than 24 or 36 mg ximelagatran twice daily in arterial disease.
Verheugt: Switching to the problems of atrial fibrillation and stroke prevention, this is a big problem in modern cardiology. A question to Professor Bode on the role of clopidogrel in stroke prevention in atrial fibrillation: is there any evidence to support its use?
Bode: Clopidogrel is effective, though it is probably only a little more effective than aspirin in the treatment of acute coronary syndrome. There is a recently started study examining the effect of the combination of aspirin plus clopidogrel in preventing stroke in patients with atrial fibrillation, but the results of this study are, of course, not yet known. Therefore, there is no evidence supporting superiority of currently available therapies over warfarin in stroke prevention in atrial fibrillation. The exception, however, could be ximelagatran based on the results of the SPORTIF study, as reported by Dr. Olsson today. So direct thrombin inhibition with an oral agent such as ximelagatran is potentially a new avenue to explore in this indication.
Verheugt: Returning to the ESTEEM trial, we have the question of whether differences in outcome were seen in the trial between patients who experienced a major myocardial infarction (Q-wave MI) and those who suffered a minor MI or had unstable angina?
Wallentin: As part of ESTEEM we performed several pre-specified subgroup analyses, and what we observed was that ximelagatran tended to have a larger effect on ST-elevation MI than on non ST-elevation MI. This observation makes sense given the larger thrombotic burden in patients with ST-elevation MI who have total occlusion of a coronary artery. However, while these results are interesting, please remember that this was a subgroup analysis performed on a phase ll trial population using four different ximelagatran doses. We need data from larger phase III ximelagatran trials to get really meaningful subgroup analyses.
Antman: A final personal question to my fellow panellists. In both ESTEEM and SPORTIF lll, and also in the venous thrombosis trials of ximelagatran, we see transient elevations in liver enzymes that appear relatively well tolerated. Ximelagatran is bioconverted to melagatran in the gut and is excreted renally. So where does the liver come into play here and why would there be transient liver enzyme elevations?
Wallentin: AstraZeneca is investigating the possible underlying mechanisms for the raised liver enzymes and is seeking advice on this issue from a world-wide group of liver experts. For a cardiologist like me, this is a difficult question to answer. No evidence of liver toxicity was seen with melagatran in the animal toxicology studies. It should, though, be remembered that the effects of ximelagatran on the liver in clinical trials appear transient. It should also be remembered that we have a number of drugs that cause similar elevations in liver enzymes as ximelagatran, and where the underlying mechanism for this effect is not known. We still use these drugs because the liver effects do not change the long-term clinical outcome.
Verheugt: With that final question we have to conclude this symposium On behalf of my co-chair, Dr Antman, I would like to thank our expert faculty for their presentations. These presentations have raised several important questions about current anticoagulant treatments for cardiac disease and also highlighted how oral direct thrombin inhibitors such as ximelagatran may address these issues, as evidenced by the ximelagatran data from the SPORTIF trial in stroke prevention in atrial fibrillation and the ESTEEM trial in post-acute coronary syndrome. Thank you.
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