By: Kevin Lin, PharmD Candidate c/o 2015
The FDA recently completed an observational cohort study that compared Pradaxa® (dabigatran) to warfarin for rates of ischemic stroke, intracranial hemorrhage, major gastrointestinal bleed, myocardial infarction, and death. The study enrolled more than 134,000 patients, with 64% over the age of 65 and found a lower risk of stroke (0.8 times), intracranial hemorrhage (0.34 times), and death (0.86) with dabigatran. The risk of major GI bleed, however, was 1.28 times higher for dabigatran compared to warfarin.1
Warfarin and dabigatran are common anticoagulants used to prevent stroke. Warfarin is indicated for prophylaxis and treatment of venous thrombosis, pulmonary embolism, complications associated with atrial fibrillation, cardiac valve replacement and reduction in risk of death, myocardial infarction and stroke. Warfarin works by inhibiting vitamin K epoxide reductase. This prevents activation of clotting factors II (thrombin), VII, IX, and X. Warfarin has no effect on fully activated factors in circulation, so the full anti-thrombotic effect of warfarin is not achieved until the activated clotting factors are cleared. This equates to about the fifth day of therapy. Due to the slow onset of action of warfarin, patients are temporarily anticoagulated with a fast-acting agent, typically heparin.2
Dabigatran is a reversible, competitive direct thrombin inhibitor. Thrombin is an enzyme which converts soluble fibrinogen to fibrin, the major component of blood clots. The onset of anticoagulation is within 0.5 – 2 hours after administration.3 This eliminates the need for heparin bridge therapy when initiating dabigatran or during a treatment hiatus due to surgery. Dabigatran also has the same indications as warfarin except for its contraindication in patients with mechanical heart valves.4
To maximize safety and efficacy, each anticoagulant has its own considerations. For warfarin, an international normalized ratio (INR) is used for monitoring. The INR is derived from prothrombin time— a test that measures the time it takes for blood to clot. Warfarin dose is individualized to a goal INR of 2-3 but can be higher in certain cases, such as in patients with a mechanical mitral heart valve.2 Once stabilized, patients still need to be monitored as frequently as every 12 weeks.5 Unlike warfarin, dabigatran dosing requires adjustment in renal dysfunction. Patients with a creatinine clearance >30mL/min take 150 mg twice daily, while those with a creatinine clearance between 15-30 mL/min take 75 mg twice daily.4 Although there are no dosage recommendations for a creatinine clearance <15 ml/min, the American College of Cardiology does not recommend dabigatran in these patients.6
In the event of a serious bleed, warfarin can be reversed with vitamin K administration. However, as vitamin K generally takes 12 to 14 hours to reverse anticoagulation, it is typically given with fresh frozen plasma which can fully reverse the effects of warfarin. 7 With this in mind, dietary vitamin K needs to be kept consistent for patients on warfarin therapy. Unlike warfarin, management of a dabigatran bleed is not as clear. It remains largely supportive with transfusions of red blood cells, dialysis and fluid replacement. A prothrombin complex concentrate can be considered in those with a life threatening bleed but clinical evidence is lacking.8 Therefore, a serious bleed with dabigatran becomes more problematic.
Although recent FDA observational trials show a greater risk of GI bleeding with dabigatran compared to warfarin in older patients, these findings are not surprising, as they are consistent with previous trials, such as the RE-LY trial. RE-LY is the original trial that resulted in the approval of dabigatran. Thus, the FDA’s recommendations on dabigatran’s place in therapy have not changed. The FDA recommends that “patients should not stop taking Pradaxa®… health care professionals who prescribe Pradaxa® should continue to follow the dosing recommendations in the drug label.”2 In consideration, patients with GI problems may be better candidates for warfarin therapy. There is not only a lower incidence of GI bleed but also a lower incidence of GI adverse reactions (0.69 times) such as dyspepsia and gastritis-like symptoms.8
- 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/ucm396470.htm
- Weitz JI. Chapter 30. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011.http://accesspharmacy.mhmedical.com.jerome.stjohns.edu:81/content.aspx?bookid=374&Sectionid=41266237. Accessed September 25, 2014.
- Baetz BE. Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. Pharmacotherapy.2008 Nov;28(11):1354-73. doi: 10.1592/phco.28.11.1354. http://www.ncbi.nlm.nih.gov/pubmed/18956996
- Blumenthal DK. Dabigatran Etexilate: The First Orally Active Direct Thrombin Inhibitor. In: Brunton LL. eds. Goodman & Gilman Online Updates. New York, NY: McGraw-Hill; 2011.http://accesspharmacy.mhmedical.com.jerome.stjohns.edu:81/updatesContent.aspx?bookid=537&Sectionid=41706917. Accessed September 25, 2014.
- Guyatt GH. Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2_suppl):7S-47S. doi:10.1378/chest.1412S3 http://journal.publications.chestnet.org/article.aspx?articleID=1159399
- January CT, Wann L, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;.
- Su M. Chapter 59. Anticoagulants. In: Nelson LS, Lewin NA, Howland M, Hoffman RS, Goldfrank LR, Flomenbaum NE. eds. Goldfrank’s Toxicologic Emergencies, 9e . New York, NY: McGraw-Hill; 2011.http://accesspharmacy.mhmedical.com.jerome.stjohns.edu:81/content.aspx?bookid=454&Sectionid=40199451. Accessed September 25, 2014.
- Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc. 2014.
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