Is there really misuse and abuse of dabigatran?

Appropriate and optimal anticoagulation for the increasing number of Australians with non-valvular atrial fibrillation (AF) remains a challenge. If achieved, it would substantially reduce the burden of disabling and fatal AF-related stroke.

Four large randomised controlled trials (RCTs) have reported that the direct thrombin inhibitor, dabigatran etexilate, and the direct activated factor X (Xa) inhibitors, rivaroxaban and apixaban, are at least as efficacious and safe as warfarin, and apixaban is superior to aspirin, in a broad range of individuals with non-valvular AF.1-5 On the basis of these results, regulators have approved dabigatran in more than 75 countries, including Australia, and guidelines suggest that the new oral anticoagulants are preferable to warfarin for most patients with non-valvular AF.6-9

The RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial of dabigatran versus warfarin included patients with all degrees of risk of stroke and systemic embolism.9 If the trial had excluded participants with a low risk, ie, a CHADS2 score of 1 (congestive heart failure, hypertension, age ≥ 75 years, diabetes, 1 point each; prior stroke or transient ischaemic attack, 2 points), clinicians would not now know that these patients derive benefit from dabigatran compared with warfarin.

RE-LY trial participants who were assigned warfarin had a median time in therapeutic range (TTR) of 67%. This may have led to an underestimate of the benefits of dabigatran compared with warfarin in community practice, where the median TTR for patients taking warfarin is rarely this high.

Dabigatran (150 mg twice daily) compared with warfarin produced reductions in ischaemic stroke (one-third) and haemorrhagic stroke (one-half) that were statistically significant and clinically important. The reduction in stroke with dabigatran was also evident in the very elderly, participants with renal impairment, participants with previous myocardial infarction (MI) or stroke, and in the presence and absence of aspirin.

Both doses (110 mg or 150 mg twice a day) of dabigatran were associated with significantly lower life-threatening and fatal bleeding than warfarin. Among participants aged ≥ 75 years, extracranial bleeding risk was similar or higher with both doses of dabigatran compared with warfarin, whereas intracranial bleeding risk was lower with both doses of dabigatran.10 In participants aged < 75 years, both doses of dabigatran were associated with lower risks of both intracranial and extracranial bleeding than warfarin.

Participants who were taking dabigatran also had lower rates of bleeding if they required urgent or emergency surgery than those taking warfarin, despite access to vitamin K and clotting factors that could pharmacologically reverse the anticoagulant effect of warfarin.11 Although there is no specific antidote for dabigatran, the case-fatality rate of intracranial haemorrhage was not significantly different in participants assigned dabigatran or warfarin.12

The absolute increase in MI with dabigatran compared with warfarin was 0.14%–0.17% per year. This was outweighed by a 0.6% per year reduction in stroke and systemic embolism.13 Adding aspirin to dabigatran did not protect against any increased risk of MI, but increased bleeding.

Recent postmarketing surveillance by the European Medicines Agency and the United States Food and Drug Administration (FDA) found no evidence of excess serious bleeding with dabigatran compared with warfarin.14,15

We have a continued responsibility to ensure that the favourable effects of new anticoagulants compared with warfarin demonstrated in RCTs are translated into clinical practice. Ongoing Phase IV safety surveillance, economic analysis, and doctor and patient education are key to this process.

Meanwhile, optimal safety and effectiveness of the new oral anticoagulants in routine clinical practice demand appropriate selection of patients (eg, estimated glomerular filtration rate ≥ 30 mL/min) and dose, a high level of adherence, regular monitoring of renal function (which may deteriorate in at-risk patients) and appropriate periprocedural management of anticoagulation interruption for invasive procedures. As treatment with a new oral anticoagulant is not suitable for all patients, warfarin will retain an important role in the management of patients who can maintain excellent anticoagulant control, as well as those with severe renal impairment and other contraindications to the new oral anticoagulants.