Published: September 2011

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Dabigatran - is there a bleeding problem?

Information on this subject has been updated. Read the most recent information.

Prescriber Update 32(3): 19-20
September 2011

Dabigatran etexilate (Pradaxa) is an anticoagulant that has been funded in both New Zealand (by PHARMAC) and Australia since 1 July 2011. Dabigatran is a direct thrombin inhibitor and is approved in New Zealand to:

• Prevent Venous Thromboembolism (VTE) in patients following major orthopaedic surgery.
• Prevent stroke, systemic embolism and reduce vascular mortality in patients with atrial fibrillation.

This anticoagulant represents an alternative treatment option to warfarin in patients who are unable to take it or may not have their INR well controlled. A recommendation to use dabigatran for stroke prevention in patients with atrial fibrillation has been incorporated into a number of clinical guidelines. Examples are guidelines produced by the European Society of Cardiology, the Canadian Cardiovascular Society,¹ and the American College of Cardiology.

Prescribers are reminded that the recommended dose of dabigatran differs between the two approved indications, as does the need for dose reductions in special patient groups. These are presented in Table 1.

Prescribers are advised to check the data sheet for full details.² Capsules must not be opened as this increases absorption and bleeding risk.

Switching patients from warfarin to dabigatran requires monitoring. Most notably, after stopping warfarin treatment the INR must fall below 2 before dabigatran is initiated. Full details are contained in the dabigatran data sheet.

As expected for any anticoagulant medicine the main side effect is bleeding.

Clinical studies suggest the risk of bleeding with dabigatran is equivalent to enoxaparin when used for VTE prophylaxis.³

Table 1: Overview of dabigatran dosing

	VTE prophylaxis	Prevention of stroke in atrial fibrillation
Adults	220mg once daily	150mg twice daily
Moderate renal impairment (30 - 50 mL/min CrCl)	150mg once daily	150mg twice daily
Severe renal impairment (<30mL/min CrCl)	Contraindicated	Contraindicated
Elderly over 80 years	220mg once daily	110 mg twice daily
Children up to 18 years	Not recommended	Not recommended
Weight	No adjustment necessary	No adjustment necessary
Use with ketoconazole	Contraindicated	Contraindicated
Use with potent P-glycoprotein inhibitors (amiodarone, quinidine, verapamil)	150mg once daily, initiation of verapamil should be avoided.	No adjustment necessary
Use with other P-glycoprotein inhibitors: clarithromycin	No adjustment necessary	No adjustment necessary
Use with P-glycoprotein inducers: rifampicin	No recommendations made; if dabigatran plasma concentrations are reduced by more than half there is a risk of lack of efficacy
Patients at risk of bleeding (including those taking other anticoagulants)	No adjustment recommended	Consider 110mg twice daily

In patients with atrial fibrillation the RE-LY study found the overall risk of bleeding was lower in patients taking dabigatran versus warfarin (16.4% vs 18.2%); however dabigatran had a higher incidence of gastrointestinal bleeds.^4,5

As for all anticoagulants, patients taking dabigatran should be monitored for signs of bleeding or anaemia. The Ecarin Clotting Time (ECT) provides the most sensitive prediction of bleeding risk and should be used when available.⁶ The aPTT test may also be useful in patients considered to be at high risk of bleeding, such as the elderly.⁶ INR measurement is not affected by dabigatran and should not be used to monitor its anticoagulant effect.

There is no specific reversal agent for dabigatran currently available. Supportive measures and maintenance of adequate diuresis is recommended in cases of bleeding or overdose.⁷

Although dabigatran is not metabolised by the cytochrome P450 enzymes, it is a substrate for P-glycoprotein. Strong P-glycoprotein inhibitors have the potential to increase dabigatran plasma levels and increase the risk of bleeding. P-glycoprotein inducers have the potential to decrease dabigatran plasma levels resulting in a lack of efficacy. Further information about P-glycoprotein and its effect on medicine pharmacokinetics is provided on page 21 of this bulletin.

As for all new medicines patients should be closely monitored for any suspected adverse reactions. All suspected adverse reactions associated with dabigatran should be reported to the Centre for Adverse Reactions Monitoring (CARM).

References

1. Cairns JA, Connolly S, McMurray S et al. 2011. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: Prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol. 27:27-30.
2. Boehringer Ingelheim (NZ) Ltd. 1 July 2011. Pradaxa data sheet www.medsafe.govt.nz/profs/Datasheet/p/Pradaxacap.pdf.
3. Friedman RJ, Dahl OE, Rosencher N et al .2010. ‘Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials’ Thromb Res; 126: 175-82
4. Connolly SJ, Ezekowitz MD, Yusuf S et al .2009. ‘Dabigatran versus warfarin in patients with atrial fibrillation’ N Engl J Med 361: 1139-51
5. Eikelboom JW, Wallentin L, Connolly SJ et al. 2011. An analysis of the randomised evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation; 123:2363237
6. PHARMAC. Guidelines for testing and perioperative management of dabigatran. August 2011. Wellington. Accessed online: http://www.pharmac.govt.nz/2011/06/13/Dabigatran%20testing%20and%20perioperative%20 management.pdf
7. PHARMAC. Guidelines for management of bleeding with dabigatran. August 2011. Wellington. Accessed online: http://www.pharmac.govt.nz/2011/06/13/Dabigatran%20 bleeding%20management.pdf