Dabigatran 'Real Life' Results Suggest Caution Needed

May 15, 2013

New data from the real-life experience of dabigatran use for the prevention of stroke in patients with atrial fibrillation (AF) in Denmark after the drug was first introduced show that it was often being used outside prescribing recommendations, and that the risk for both thromboembolism and bleeding may be raised in patients being switched to dabigatran from warfarin.

The study, published in BMJ Open Access on May 4, was conducted by a team led by Rikke Sørensen, MD, Copenhagen University Hospital Gentofte, Denmark.

"It is great that we have an alternative to warfarin; and the large-scale trials with all the new oral anticoagulants suggest similar efficacy but with a lower risk of cerebral bleeding," Dr. Sørensen commented to Medscape Medical News. "But our results show we need to careful to follow the prescribing recommendations. And patients need to be followed up carefully to start with, especially if they have been switched from warfarin because of poor control."

For the study, the researchers looked at how dabigatran (Pradaxa, Boehringer Ingelheim) was being prescribed in the first 4 months after its approval for AF in Denmark. They used data from nationwide registries of patients with an AF diagnosis who had received a prescription for dabigatran during that 4-month period.

They found that dabigatran quickly became one of the first-line anticoagulants to be used in patients with AF, taking 5% of the market during the initial months after approval. The authors note that slightly higher numbers have been seen in the United States after approval, where the market share of dabigatran was 7%, 12%, and 28% during the first, second, and fifth quarters, respectively.

In the present study, about half the patients taking the 110-mg dose and two thirds of those receiving the 150-mg dose were vitamin K naive.

They also report that dabigatran was prescribed as recommended in more than 80% of patients taking the 110-mg dose but in only 55% of those taking the 150-mg dose.

"It is somewhat complicated because the European Society of Cardiology and the European Medicines Agency have issued slightly different recommendations on its use which may have caused some confusion," Dr. Sørenson told Medscape Medical News. "But doctors may have been a little too enthusiastic on the use of the 150-mg dose. We found that one quarter of patients prescribed this dose had a high bleeding risk, so in fact should have been on the lower dose."

The most surprising finding in the study, however, was a much greater risk for both thrombotic and bleeding events in patients receiving dabigatran compared with those receiving warfarin. But when looked at more closely, this increased risk was confined to patients who had been switched from warfarin, and there was no increased risk in patients who were new anticoagulant users.

Table. Risk for Thromboembolism and Bleeding With Dabigatran vs Warfarin

Group Thromboembolism Hazard Ratio Bleeding Hazard Ratio
All patients    
  Dabigatran 110 mg 2.92 2.29
  Dabigatran 150 mg 3.79 1.01
VKA experienced    
  Dabigatran 110 mg 3.52 3.30
  Dabigatran 150 mg 5.79 1.11
VKA naive    
  Dabigatran 110 mg 0.95 1.13
  Dabigatran 150 mg 1.14 0.79

VKA = vitamin K antagonist.

Dr. Sørensen suggested that vitamin K antagonist–experienced patients probably had an increased risk with dabigatran because they were high-risk patients in general.

"These are the patients who have been switched from warfarin to dabigatran as soon as the new drug had become available," she said. "So we would suspect that they were particularly badly controlled on warfarin. They may have been too ill to go the anticoagulation clinic or they may have had poor compliance.

"Although we have tried to adjust the results for baseline characteristics in the multivariate analysis, it is highly likely that there will be unmeasured confounders that haven't been taken into account, so I don't think we should be too worried by these results," she added.

I don't think you can just switch a badly controlled warfarin patient onto one of these drugs and leave them to it. Dr. Rikke Sørensen

But she noted that patients who have been switched from warfarin because of poor control need to be monitored carefully. "I don't think you can just switch a badly controlled warfarin patient onto one of these drugs and leave them to it. It needs to be clearly established that they are not at high bleeding risk, and if they are the lower dose should be used, and perhaps a proton-pump inhibitor could be given to prevent gastrointestinal bleeds."

In contrast, there was no increased risk in patients new to anticoagulation. Dr. Sørensen said it was "reassuring that we have seen this in a real-life study."

The study did not receive specific funding. Coauthor Gunnar Gislason is supported by an independent research scholarship from the Novo Nordisk Foundation. The authors have disclosed no relevant financial relationships.

BMJ Open. Published online May 4, 2013. Full text


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