Recommendations on Use of Dabigatran

Developed by the Sections of Hematology/Oncology and Cardiology, University of Manitoba 5 April 2011 [NOTE: As of this writing, dabigatran is licensed for use in Canada but is NOT currently on the Manitoba Pharmacare benefit list. At present, patients prescribed this drug will pay its full cost (approximately $3.20 per day plus pharmacy markup) unless they have private insurance that will cover it. This must be discussed with a patient before the prescription is written.] Introduction Dabigatran is the vanguard of a new era of anticoagulant therapy. New oral agents are anticipated to revolutionize the prevention and management of thromboembolic disorders. All health care professionals caring for patients on anticoagulation will need to be aware of these agents, as routine anticoagulation management and monitoring will be very different. These recommendations have been developed to aid health professionals in making appropriate use of this new agent, and to highlight potential problems. The intent is to maximize positive outcomes and ensure patient safety as this new drug enters practice.

Indication Dabigatran is indicated in Canada for prevention of stroke or systemic embolization in patients with atrial fibrillation for whom anticoagulation is appropriate (i.e. where use of warfarin would otherwise be considered). This includes: CHADS2 score 2 CHADS2 score of 1, if low risk of bleeding It should NOT be used in patients with atrial fibrillation and mechanical heart valves or significant valve disease, as those patients have not been studied. CHADS2 Score Congestive heart failure or LVEF < 35% = 1 point Hypertension = 1 point Age 75 years = 1 point Diabetes = 1 point Stroke or TIA in past = 2 points In a large randomized (but non-blinded) trial dabigatran 150mg b.i.d. demonstrated superior efficacy to warfarin in preventing stroke or systemic embolism (36% relative risk reduction). Dabigatran at the standard dose of 150mg b.i.d. demonstrated statistically

equivalent safety overall for major bleeding, (i.e. it is NOT safer overall) though there was significantly less intracranial hemorrhage. It is worth keeping in mind that the incremental absolute benefit of dabigatran over warfarin is much smaller than the absolute benefit of warfarin compared to no anticoagulation (or aspirin alone). For example in a population patients with CHADS2 score of 4, the risk of stroke in a year is about 9%. In a practice of 100 patients, warfarin would prevent 6 of the 9 events, while dabigatran would prevent one additional event (7 of 9). Dabigatran (at a lower dose) is also approved for use in Canada for venous thromboembolism prophylaxis following total hip or knee arthroplasty. It is currently not on the Manitoba formulary for this indication; instead rivaroxaban, a new oral factor Xa inhibitor with superior efficacy data in this application, is available. There are no head to head trials of any of the new oral agents. Advantages and Disadvantages of Dabigatran compared to Warfarin for Atrial Fibrillation: Advantages Disadvantages Moderately superior efficacy Twice daily dosing Few significant drug interactions Greater risk of GI intolerance No diet interaction Greater risk of GI bleeding More rapid onset of anticoagulant No validated assay available if action (and offset after stopping) monitoring desired (see below) Lower risk of intracranial No antidote in the event of bleeding hemorrhage Possibly less benefit in protecting against myocardial infarction Lack of long term ( > 2 yrs) safety data (though no signals of unexpected toxicity thus far) Higher cost Recommendation: Until federal and provincial drug plans formally review dabigatran, we recommend dabigatran be considered as a good alternative to warfarin for patients with atrial fibrillation who are comfortable to pay the cost, and in particular in cases: where INR has been difficult to stabilize for reasons OTHER than poor adherence to medication (see below), on the basis that dabigatrans advantage in terms of efficacy accrues to populations with poorer INR control who have higher stroke risk as defined by higher CHADS2 or CHADS-Vasc scores (on basis of greater absolute stroke risk, and therefore greater absolute benefit)

where INR monitoring is problematic (e.g. poor venous access, or patient travels frequently or lives in remote location). Note that use of finger-poke point-of-care INR test devices (e.g. Coaguchek XS) is an alternative solution to this problem who have had embolic events despite warfarin (on basis of superior efficacy overall with the 150mg b.i.d. dose) for elective cardioversion It is not clear whether dabigatran offers an advantage to patients with a propensity to miss doses. The anticoagulant effect of dabigatran is much shorter lived than that of warfarin, so missing one or two doses will leave them unprotected; at the same time these patients are likely to have unstable INR results and have poorer outcomes with warfarin as well. Dabigatran has not been studied at this time for management of patients with acute coronary syndromes, ventricular thrombus, or mechanical heart valves and is not recommended for those patients. In general, off label use is discouraged until evidence is available supporting the use of dabigatran in these contexts. This caution also extends to other new oral anticoagulants (e.g. rivaroxaban). One controlled trial has demonstrated equivalent efficacy and safety in comparison to warfarin for the treatment of venous thromboembolism, but dabigatran is not currently approved in Canada for this indication. Use in deep vein thrombosis or pulmonary embolism may be considered in patients for whom INR monitoring is problematic, as above. Subgroup analysis of the major atrial fibrillation trial provided evidence that dabigatran was successfully used around the time of cardioversion; hence this appears to be an appropriate off-label indication for the use of the dabigatran. Use of dabigatran as a bridge during interruption of warfarin therapy at time of surgery has not been formally evaluated; low molecular weight heparin has been better studied for this purpose and may be used when a bridge is felt to be appropriate. For patients at high risk of bleeding, the 110mg b.i.d. dose may be used on the basis of a lower bleeding risk than warfarin. This advantage is modest, and for some patients the risk of bleeding is too high to consider any anticoagulation.

Contraindications Dabigatran is CONTRAINDICATED in patients: with creatinine clearance <30ml/min with active bleeding with very high risk of bleeding (essentially the same consideration of bleeding risk should apply as with warfarin) during concomitant use of ketoconazole who are pregnant or breastfeeding, on basis of lack of safety data and presumed hemorrhagic risk for the fetus or infant Special Populations

Dabigatran is not recommended for use in children at this time Limited data are available for patients weighing < 50 kg Drug levels are higher in the elderly and therefore a lower dose is advised

Recommendation: Until more data are available, we recommend dabigatran NOT be preferred to warfarin in patients who have: renal insufficiency (estimated creatinine clearance 30-50 ml/min) or unstable renal function (on basis that drug accumulates in renal insufficiency) recent MI or unstable angina (on basis of possible higher risk of MI). Phase III trials in ACS are ongoing a history of untreated GI bleeding or symptomatic upper GI tract disorders weight less than 50kg a record of stable anticoagulation control on warfarin maintaining more than 70% of INR results within therapeutic range (on basis of analysis showing no advantage accrues to populations with high quality INR control on warfarin) difficulty to swallow whole capsules Additionally, we recommend patients > 80 yrs have special attention paid to their renal function. The Canadian product monograph recommends that they receive a lower dosage of 110 mg twice daily. This lower dose should also be considered in patients especially above 75 yrs with at least one other risk factor from bleeding.

Monitoring Dabigatran acts as a direct thrombin inhibitor. No monitoring has been validated for this agent and monitoring in general is not recommended. Dabigatran was given without monitoring or dose adjustment in the pivotal clinical trials. The INR increases somewhat but is NOT very sensitive to the effect of dabigatran and cannot be used to assess or adjust dosing. In healthy volunteers on standard doses of dabigatran the INR is typically mildly elevated (about 1.2 - 1.8). DABIGATRAN DOSE SHOULD NOT BE ADJUSTED TO ACHIEVE AN INR OF 2 TO 3 AS IS THE PRACTICE FOR WARFARIN. Because of the influence on INR values, warfarin cannot be monitored if co-administered with dabigatran. The aPTT is sensitive to dabigatran. A normal aPTT indicates that the patient has a minimal drug level; a normal aPTT may therefore be used to exclude therapeutic or supertherapeutic dabigatran levels in a bleeding patient for whom no history is available, or to determine that the drug effect has worn off in a patient previously taking it. However, beyond this, the aPTT does not reliably determine whether dabigatran levels are too high or too low.

Use of antiplatelet agents As is the case for warfarin, the use of antiplatelet agents greatly increases the risk of bleeding with dabigatran, approximately two-fold. Addition of an antiplatelet agent does not enhance the protective effect against stroke. Therefore antiplatelet agents should be given along with dabigatran only for a strong indication (coronary stent or recent acute coronary syndrome). Warfarin is the preferred anticoagulant in these settings.

Management of surgery or procedures in patients on dabigatran Dabigatran should be held for surgery or procedures with risk of bleeding. Because of its shorter duration of effect it does not need to be stopped as long before surgery as is the practice with warfarin. It should be stopped 2 days before surgery (4 days if renal function compromised). Since dabigatran works immediately, resumption of anticoagulation after surgery must wait until hemostasis is secure (usually a day or two post-op). As is the case with other anticoagulants, spinal or epidural catheters must not be used in patients receiving dabigatran.

Management of bleeding on dabigatran There is no specific antidote for the anticoagulant effect of dabigatran, and no good trials are available to guide recommendations for therapy of bleeding that occurs in a patient receiving dabigatran. Consultation with the Hematologist on-call is recommended. The following recommendations are based on general principles of hemostasis. As in any bleeding patient, any correctable cause for bleeding should be addressed (e.g. vitamin K deficiency, thrombocytopenia, coagulation factor deficiency). Topical measures (direct pressure, fibrin sealant, hygroscopic hemostatic powders) should be employed where possible. Local measures for hemostatic control should also be used where appropriate (e.g. vessel embolization or ligation). Unlike warfarin, Vitamin K will not reverse the effects of dabigatran. Likewise, protamine has no effect to correct hemostasis in patients on dabigatran. The half-life of dabigatran is 12 hours in the presence of normal renal function, so if the patient can be supported the bleeding effect should resolve in that time frame. For patients with severe or life-threatening bleeding, we recommend Factor VIIa (Niastase) 90mcg/kg and repeated once at 2 hours, with escalation of the dose to 270mcg/kg if ineffective (on the basis that Factor VIIa has hemostatic efficacy through a bypass mechanism in hemophilia, and that it corrects hemostasis in laboratory assays and several animal models.) Activated prothrombin complex concentrates (e.g. FEIBA,

Baxter) have also been used (50-100units/kg) but this product is not widely available; the non-activated prothrombin complex concentrate (Octaplex) cannot be assumed to be equivalent. Fresh frozen plasma 500-1000ml may be tried if bleeding is less severe or if factor VIIa is not available, and should be used in preference to colloid and crystalloid solutions in major hemorrhage that necessitates massive transfusion, so as to avoid a superimposed dilutional coagulopathy. Plasma however does not reverse the effect of dabigatran as it does the effect of warfarin. Other adjunctive measures that may be given to improve hemostasis non-specifically include DDAVP 20mcg by slow i.v. infusion, and tranexamic acid (1g i.v. or 1.5g p.o. TID).

Management of overdose In addition to the above measures, dabigatran can be removed by dialysis so this should be considered if bleeding occurs in the context of an overdose of dabigatran. Activated charcoal should be given orally to reduce absorption if the drug was ingested recently.

Drug Interactions Although drug interactions are a relatively minor issue with dabigatran, powerful inhibitors of the p-glycoprotein pump increase plasma levels of dabigatran. It is recommended not to use dabigatran with ketoconazole, and to take the dabigatran dose at least 2 hours before either quinidine or verapamil.

References: Connelly SJ, Ezekowitz MD Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation (RE-LY). N Engl J Med 2009, 361: 1139-51 Nagarakanti R, Ezekowitz MD, Oldgren J et al. Dabigatran Versus Warfarin in Patients With Atrial Fibrillation. An Analysis of Patients Undergoing Cardioversion. Circulation 2011; 123: 131-136 PradaxTM Product Monograph. Boehringer Ingelheim Canada Ltd. October 26, 2010 Van Ryn J, Stangier J, Haertter S et al. Dabigatran etexilate- a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemostat 2010; 103: 1116-1127 Wallentin L, Yusuf S Ezekowita MD et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376: 975-83