A target-specific oral anti-coagulant, dabigatran/Pradaxa™ proves that Warfarin isn’t the only game in town.
Dabigatran/Pradaxa™ is one of the New Oral Anti-Coagulants (NOACs), or Target-Specific Oral Anti-Coagulants (TSOACs) that have rapidly infiltrated the niche of oral anti-coagulants formerly occupied entirely by warfarin.
How It Works:
Dabigatran is a reversible direct thrombin (Factor II) inhibitor. Thrombin is one of the final enzymes in the clotting cascade. Among other things, it catalyzes the conversion of fibrinogen to fibrin.
Major Indications:
The main uses for dabigatran are for the secondary prevention and treatment of patients with DVT/PE, and for stroke prevention in patients with atrial fibrillation. As with warfarin, in patients with a DVT or PE, a “bridging” period of 5-10 days with heparin or low molecular weight heparin is required before transitioning to dabigatran monotherapy.
Notable History:
Dabigatran was first approved for use in Europe in 2008. In the United States, it was approved by the FDA for use in atrial fibrillation in 2010 and for DVT/PE in 2014. The RE-LY trial, reported in the New England Journal of Medicine in 2009, enrolled more than 18,000 patients with non-valvular atrial fibrillation and randomized them to receive either dabigatran or warfarin. Patients on dabigatran were found to have lower rates of stroke and systemic embolic events, and similar rates of major bleeding complications compared with those on warfarin [1].
Recently In the News For:
In May 2014, the FDA released a Drug Safety Communication reporting that Medicare patients on dabigatran for atrial fibrillation had a lower risk of ischemic stroke, intra-cranial hemorrhage, and death compared with patients taking warfarin [2]. There was no difference in the risk of myocardial infarction, and patients on dabigatran had a higher risk of major GI bleed.
Adverse Events:
The most significant adverse event is bleeding. Life-threatening bleeding usually occurs in the form of intra-cranial hemorrhage, or GI bleeding. The RE-LY trial reported rates of life-threatening bleeding with 150mg PO BID dabigatran of 1.45%/year compared with 1.8%/year with warfarin (p value 0.11). Rates of all major bleeding were 3.75%/year and 3.36%/year for dabigatran and warfarin respectively (p value 0.052) [1].
Cautions:
Dabigatran should not be used in patients with mechanical heart valves because of an increased risk of major bleeding and thromboembolic events [3]. It also carries black box warnings for an increased risk of thromboembolic events if dabigatran is discontinued, as well as for the risk of spinal or epidural hematomas and neurologic impairment when lumbar punctures or spinal anesthesia are performed [4].
Dosing and Adjustments:
For treatment or secondary prevention of DVT/PE, and for stroke prevention in atrial fibrillation, the dose is 150mg PO twice daily. The dose for atrial fibrillation is reduced to 75mg twice daily in patients with CrCl 15-30mL/min.
Dosing levels are not defined for atrial fibrillation patients with a CrCl < 15mL/min or who are on hemodialysis, or for venous thromboembolism treatment in patients with a CrCL < 30mL/min [4].
Care should be taken when using dabigatran in patients more than 75 years of age [per the drug monograph], particularly those with renal impairment as there is an increased bleeding risk.
Dabigatran is excreted through the P-glycoprotein pump. Inducers of the pump (such as rifampin) will lead to decreased effect of dabigatran, while pump inhibitors (such as verapamil, clarithromycin, amiodarone, and others) will lead to an increased concentration of dabigatran, and both should be avoided [5], or the dose of dabigatran reduced if a pump inhibitor is started [4].
Special Considerations:
A major advantage of the TSOACs over warfarin is that TSOACs do not require frequent monitoring with INR testing. However, a disadvantage is that the level of anti-coagulation cannot be reliably determined using readily available coagulation studies such as the PT (INR) and aPTT.
Other tests such as thrombin time and ecarin clotting time are prolonged with dabigatran. However, these tests are not as readily available, and further work is needed to establish their utility in clinical settings.
In addition, there is no currently available reversal agent for dabigatran. Pro-thrombin complex concentrate, Fresh Frozen Plasma (FFP), and dialysis can be considered in patients with life-threatening hemorrhage depending on renal function and institutional availability of factor concentrations [6].
Cost:
60 tablets of 150mg dabigatran costs around $350, which is considerably more than warfarin (100 tablets of 5mg warfarin costs around $210) [5], although the costs of monitoring frequent INRs are absent for patients taking dabigatran.
REFERENCES
1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.
2. Food and Drug Administration. FDA drug safety communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with pradaxa (dabigatran) compared to warfarin. http://www.fda.gov/Drugs/DrugSafety/. Published 05/13/2014. Updated 2014. Accessed 12/3/2014.
3. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214.
4. Boehringer Ingelheim. Pradaxa – prescribing information. http://www.pradaxapro.com/. Published 2014. Updated 2014. Accessed 12/04, 2014.
5. UptoDate.com. Dabigatran: Drug information. Uptodate com. 2014. Accessed 12/3/2014
6. Babilonia K, Trujillo T. The role of prothrombin complex concentrates in reversal of target specific anticoagulants. Thromb J. 2014;12:8-9560-12-8. 2014.
1 Comment
Dr. Shenvi’s article on dabigatran is a welcome addition to our knowledge base.
There may be a point or 2 of clarification, however.
Dr. Shenvi notes that monitoring clotting time by PT testing is not required.
This is a bit of misapplied logic.
Dabigatran activity is not accurately measured by PT or any routinely available test.
“Testing not available” is not the same thing as “testing not required.” One is medical, the other is marketing. Testing may be be required but we can’t do it. “Can’t” is not the same concept as “don’t need to.”
Cost needs clarification: 90 tabs warfarin 5 mg. is $10, not $210. A difference of 21X is significant.
Additionally, with the development of POC/home PT testing, PT monitoring is likely to become less onerous. (Remember when diabetics had to come to the hospital to get a glucose run? We’ve come a long way.)