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dabigatran (Pradaxa)

Indications: 1) anticoagulation for non-valvular atrial fibrillation a) stroke prevention [6,7,10,12] b) prevents 5 more strokes per 1000 patients than warfarinm[22] c) lower risk of stroke & death than warfarin [31] d) annual risk of death lower than with warfarin (2.7% vs 8.5%) [41] e) superior to warfarin in Asians [42]; - reduced risks for ischemic stroke/systemic embolism, intracranial hemorrhage, & all-cause mortality at 1 year [42] 2) venous thromboembolism/deep vein thrombosis [5,25,28] - non-inferior to warfarin [26] - FDA-approved for DVT & pulmonary embolism [28] 3) prophylaxis for venous thromboembolism/deep vein thrombosis a) after total knee replacement [2] (off-label) b) after total hip replacement [3] (off-label) [17] 4) *prophylaxis for recurrent acute coronary syndromes? - probably not; associated with higher risk of acute coronary syndrome than warfarin (0.9% vs 0.2%) [25] 5) lowers risk of major vascular complications in patients with myocardial injury after non-cardiac surgery [47] * safe & effective in elderly [33] Contraindications: - not for use in anticoagulant 'bridge' therapy in the perioperative period [14] - mechanical heart valve [24] - ESRD [27] - pregnancy - valvular heart disease - severe obesity - high-risk antiphospholipid antibody syndrome [27] Dosage: - 110 or 150 mg PO BID - switch from warfarin when INR is < 2.0 - stop dabatrigan at least one day prior to surgery (or 3 days in patients with renal insufficiency) - restart dabigatran 24 hours after surgery or longer if high risk of postoperative bleeding [14] - 110 mg dose associated with lower risk of bleeding but higher risk of stroke [16] Storage: - moisture-sensivitive - keep in the original bottle WITH desiccant in the bottle cap - do not put in pill organizer [12,34] - good for <60 days after bottle open [15]; within 4 months [34] Dosage adjustment in renal failure: - 110 mg BID may be more appropriate for patients with renal insufficiency - 75 mg BID for creatinine clearance of 15-30 ml/min - potential benefit of monitoring anticoagulant activity & adjusting dose to minimize risk/benefit ratio [36] - contraindicated in patients with ESRD - do not use with creatinine clearance < 15 ml/min (AF) or < 30 ml/min (VTE) [27] Pharmacokinetics: - renal clearance: 80% - time to maximum concentration: 2 hours - 1/2life: 12-17 hours - protein_binding: 35% [27] Adverse effects: - higher risk of any bleeding than warfarin (33% vs 27%) [37] - lower annual risk of bleeding vs warfarin (2.4% vs 5.0%) [41] - major bleeding (conflicting reports) - reports of serious bleeding [23] - higher risk of major bleeding than warfarin (9% vs 6%) [37], especially in blacks & patients with renal failure [37] - similar to enoxaparin, warfarin [19,23] - safer than warfarin [26] - lower risk of intracranial hemorrhage in the elderly (> 75 years of age) than warfarin (0.6% vs 1.8%) [37] - fewer intracranial bleeds than warfarin (0.39 vs. 0.77/100 person-years) [45,48] - higher risk of GI bleed than warfarin [31,37] - similar risk of GI bleed compared with warfarin [38] - 150 mg q12h associated with higher risk of GI bleed than warfarin [30] - higher risk of extracranial bleeding than warfarin in patients > 75 years of age [30] - lower risk of hospitalization for GI bleed & for intracranial hemorrhage than with rivaroxaban [42,43] - similar risks for ischemic stroke & bleeding as warfarin but lower risk for death in nursing home residents (RR=0.7-0.8) [50] - elevated serum transaminases (similar to enoxaparin) (3-4%), returning to baseline afer cessation [2] - GI: dyspepsia, nausea, heartburn, bloating - increased risks for acute coronary syndrome & myocardial infarction (HR=1.33; absolute risk 0.27%) [21,35]; - 2 more myocardial infactions per 1000 patients than warfarin vs 5 fewer strokes per 1000 patients than warfarin [22] - increased risk or myocardial infarction with dabigatran vs warfarin (0.77 vs. 0.43/100 person-years) [45] - discontinuation due to adverse effects may be more common with dabigatran than warfarin [35] - less risk of osteoporotic fracture than with warfarin (0.7 vs 1.1 per 100 person-years) [44] Overdose or dabigatran-associated hemorrhage - idarucizumab (Praxbind) for dabigatran overdose [39,40] - idarucizumab reverses dabigatran across spectrum of renal failure [49] - prior to idarucizumab (Praxbind), no known antidote - stop dabigatran - administer fresh frozen plasma until bleeding stops - activated prothrombin concentrate complex 50-100 units/kg IV - 4-factor prothrombin complex concentrate [46] - prothombin complex concentrate does NOT reverse the anticoagulant effect of dabigatran [20] - activated charcoal within 2 hours of dabigatran dose - hemodialysis [27] Laboratory: - dabigatran in serum/plasma Mechanism of action: - direct thrombin inhibitor - dabigatran caps contain tartaric acid to improve absorption (this may result in dyspepsia) Notes: - recall 75 mg & 150 mg tablets March 2023 due to the presence of a nitrosamine [51] - cost 2010, $240/month [9]

Interactions

drug adverse effects of direct oral anticoagulants

General

thrombin inhibitor direct oral anticoagulant; novel oral anticoagulant (DOAC, NOAC)

Database Correlations

PUBCHEM correlations

References

  1. Veterans Administration
  2. Eriksson BL et al, Oral dabigatran etexilate vs subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: The RE-MODEL randomized trial. J Thromb Haemost 2007, 5:2178 PMID: 17764540 - Bauer KA Targeted inhibition of coagulation: Oral agents show promise in phase III trials. J Thromb Haemost 2007, 5:2175 PMID: 17764539
  3. Prescriber's Letter 15(8): 2008 New Drugs on the Horizon: Pradaxa (Dabigatran) and Xarelto (Rivaroxaban) Detail-Document#: 240805 (subscription needed) http://www.prescribersletter.com
  4. Connolly SJ et al, Dabigatran versus Warfarin in Patients with Atrial Fibrillation N Engl J Med 2009 Sep 17; 361:1139 PMID: 19717844 http://content.nejm.org/cgi/content/full/NEJMoa0905561
  5. Schulman S et al Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism N Engl J Med 2009 December 6 PMID: 19966341 http://content.nejm.org/cgi/content/full/NEJMoa0906598
  6. Boehringer Ingelheim Pharmaceuticals, Inc. New Release FDA Advisory Committee Unanimously Recommends Approval of Dabigatran Etexilate for Stroke Prevention in Atrial Fibrillation http://www.prnewswire.com/news-releases/fda-advisory-committee-unanimously-recommends-approval-of-dabigatran-etexilate-for-stroke-prevention-in-atrial-fibrillation-103372294.html
  7. FDA News Release, Oct. 19, 2010 FDA approves Pradaxa to prevent stroke in people with atrial fibrillation http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm
  8. Prescriber's Letter 17(11): 2010 New Drug: Pradaxa (Dabigatran) Detail-Document#: 261101 (subscription needed) http://www.prescribersletter.com
  9. Freeman JV et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med 2010 Nov 1 PMID: 21041570 http://www.annals.org/content/early/2010/11/03/0003-4819-154-1-201101040-00289.long
  10. Diener HC et al Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: A subgroup analysis of the RE-LY trial. Lancet Neurol 2010 Dec; 9:1157 PMID: 21059484 - Lane DA and Lip GY. Dabigatran in atrial fibrillation: Balancing secondary stroke prevention against bleeding risk. Lancet Neurol 2010 Dec; 9:1140 PMID: 21059485
  11. Prescriber's Letter 18(1): 2011 COMMENTARY: New Drug: Pradaxa (Dabigatran) Detail-Document#: 270101 (subscription needed) http://www.prescribersletter.com
  12. Wann LS et al 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran) A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines Circulation Feb 15, 2011 PMID: 21321155 http://circ.ahajournals.org/cgi/reprint/CIR.0b013e31820f14c0v1
  13. Prescriber's Letter 18(3): 2011 Helping Patients Store and Use Dabigatran Appropriately Detail-Document#: 270318 (subscription needed) http://www.prescribersletter.com
  14. Prescriber's Letter 18(3): 2011 Should Dabigatran Be Used for Bridging? Detail-Document#: 270310 (subscription needed) http://www.prescribersletter.com
  15. FDA MedWatch Pradaxa (dabigatran etexilate mesylate) Capsules: Special Storage and Handling Requirements http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm249005.htm
  16. Beasley BN et al Anticoagulant Options - Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran N Engl J Med April 13, 2011 PMID: 21488759 http://healthpolicyandreform.nejm.org/?p=14213&query=home - Hylek EM. Therapeutic potential of oral factor Xa inhibitors. N Engl J Med 2010; 363:2559-2561. PMID: 21175319
  17. Prescriber's Letter 18(6): 2011 Detail-Document#: 270608 Off-Label Use of Dabigatran (subscription needed) http://www.prescribersletter.com
  18. Prescriber's Letter 18(9): 2011 Reversing Dabigatran and Rivaroxaban Detail-Document#: 270912 - Prescriber's Letter 19(1): 2012 Reversing Dabigatran and Rivaroxaban Detail-Document#: 280102 (subscription needed) http://www.prescribersletter.com (subscription needed) http://www.prescribersletter.com
  19. FDA MedWatch: 12/07/2011 Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication - Safety Review of Post-Market Reports of Serious Bleeding Events http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm282820.htm
  20. Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011 Oct 4; 124:1573. PMID: 21900088 - Battinelli EM. Reversal of new oral anticoagulants. Circulation 2011 Oct 4; 124:1508. PMID: 21969317
  21. Uchino K et al Dabigatran Association With Higher Risk of Acute Coronary Events Meta-analysis of Noninferiority Randomized Controlled Trials Arch Intern Med. Published online January 9, 2012 PMID: 22231617 http://archinte.ama-assn.org/cgi/content/full/archinternmed.2011.1666
  22. Prescriber's Letter 19(3): 2012 COMMENTARY: Dabigatran and Risk of Myocardial Infarction CHART: Comparison of Oral Antithrombotics Detail-Document#: 280321 (subscription needed) http://www.prescribersletter.com
  23. FDA MedWatch. Nov 2, 2012 Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication - Safety Review of Post-Market Reports of Serious Bleeding Events http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm282820.htm
  24. FDA MedWatch: Dec 19, 2012 Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication - Should Not Be Used in Patients with Mechanical Prosthetic Heart Valves. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm332949.htm - Eikelboom JW et al. for the RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013 Sep 1 PMID: 23991661 http://www.nejm.org/doi/full/10.1056/NEJMoa1300615 - Hylek EM. Dabigatran and mechanical heart valves - Not as easy as we hoped. N Engl J Med 2013 Sep 1 PMID: 23991659 http://www.nejm.org/doi/full/10.1056/NEJMe1310399
  25. Schulman S et al Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism N Engl J Med 2013; 368:709-718February 21, 2013 PMID: 23425163 http://www.nejm.org/doi/full/10.1056/NEJMoa1113697 - Connors JM Extended Treatment of Venous Thromboembolism. N Engl J Med 2013; 368:767-769February 21, 2013 PMID: 23425170 http://www.nejm.org/doi/full/10.1056/NEJMe1215678
  26. Southworth MR et al. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013 Apr 4; 368:1272. PMID: 23484796 - Berger R, Salhanick SD, Chase M, Ganetsky M. Hemorrhagic complications in emergency department patients who are receiving dabigatran compared with warfarin. Ann Emerg Med. 2013 Apr;61(4):475-9 PMID: 23522810
  27. Medical Knowledge Self Assessment Program (MKSAP) 16, 17, 19 American College of Physicians, Philadelphia 2012, 2015, 2022
  28. Boehringer Ingelheim Pharmaceuticals, Inc. Press Release April 7, 2014 FDA Approves Pradaxa (dabigatran etexilate mesylate) for Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism. http://www.prnewswire.com/news-releases/fda-approves-pradaxa-dabigatran-etexilate-mesylate-for-treatment-and-reduction-in-the-risk-of-recurrence-of-deep-venous-thrombosis-and-pulmonary-embolism-254175631.html
  29. Eikelboom JW, Wallentin L, Connolly SJ Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011 May 31;123(21):2363-72. PMID: 21576658
  30. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  31. FDA MedWatch May 13, 2014 Pradaxa (dabigatran): Drug Safety Communication - Lower Risk for Stroke and Death, but Higher Risk for GI Bleeding Compared to Warfarin. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm397179.htm
  32. Wood Shelly. Medscape May 13, 2014 FDA Review Finds No Increased Risk of MI With Dabigatran (Pradaxa) http://www.medscape.com/viewarticle/825080
  33. Sardar P et al. New oral anticoagulants in elderly adults: Evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014 May; 62:857 PMID: 24786913 http://onlinelibrary.wiley.com/doi/10.1111/jgs.12799/abstract
  34. Prescriber's Letter 21(6): 2014 Oral Meds to Keep in Original Containers Detail-Document#: 300622 (subscription needed) http://www.prescribersletter.com
  35. Cairns J. ACP Journal Club. Review: Dabigatran increases MI and reduces mortality compared with warfarin, enoxaparin, or placebo. Ann Intern Med. 2012;156(12):JC6-JC11. PMID: 22711112 - Adam SS, McDuffie JR, Ortel TL, Williams JW Jr. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med. 2012;157(11):796-807 PMID: 22928173
  36. Cohen D Dabigatran: how the drug company withheld important analyses. BMJ 2014;349:g4670 PMID: 25055829 http://www.bmj.com/content/349/bmj.g4670 - Charlton B, Redberg R The trouble with dabigatran. BMJ 2014;349:g4681 PMID: 25055830 http://www.bmj.com/content/349/bmj.g4681
  37. Hernandez I et al Risk of Bleeding With Dabigatran in Atrial Fibrillation. JAMA Intern Med. Published online November 03, 2014 PMID: 25365537 http://archinte.jamanetwork.com/article.aspx?articleid=1921753
  38. Chang H-Y et al. Risk of gastrointestinal bleeding associated with oral anticoagulants: Population based retrospective cohort study. BMJ 2015;350:h1585 PMID: 25911526 http://www.bmj.com/content/350/bmj.h1585 - Abraham NS et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: Population based cohort study. BMJ 2015;350:h1857 PMID: 25910928 http://www.bmj.com/content/350/bmj.h1857 - Vaughan Sarrazin MS and Rose A. Safety of new oral anticoagulants. BMJ 2015;350:h1679 PMID: 25911527 http://www.bmj.com/content/350/bmj.h1679
  39. Pollack CV et al Idarucizumab for Dabigatran Reversal N Engl J Med. June 22, 2015 PMID: 26095746 http://www.nejm.org/doi/full/10.1056/NEJMoa1502000 - Pollack CV, Jr. Reilly PA, van Ryn J et al Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med. July 11, 2017 PMID: 28693366 http://www.nejm.org/doi/full/10.1056/NEJMoa1707278
  40. FDA News Release. October 16, 2015 FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm
  41. Larsen TB et al Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2016;353:i3189 PMID: 27312796 Free full text http://www.bmj.com/content/353/bmj.i3189
  42. Chan YH, Kuo CT, Yeh YH et al. Thromboembolic, bleeding, and mortality risks of rivaroxaban and dabigatran in Asians with nonvalvular atrial fibrillation. J Am Coll Cardiol 2016 Sep 27; 68:1389. PMID: 27659460 Free Article - Ruff C. The reality of "real-world" data: More questions than answers. J Am Coll Cardiol 2016 Sep 27; 68:1402 PMID: 27659461
  43. Graham DJ, Reichman ME, Wernecke M et al Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. JAMA Intern Med. Published online October 03, 2016 PMID: 27695821 http://archinte.jamanetwork.com/article.aspx?articleid=2560376 - Parks AL, Redberg RF Comparing Non-Vitamin K Oral Anticoagulants. Where We Are Now. JAMA Intern Med. Published online October 03, 2016 PMID: 27695820 archinte.jamanetwork.com/article.aspx?articleid=2560371
  44. Lau WC, Chan EW, Cheung CL et al Fractures Among Patients With Nonvalvular Atrial Fibrillation. JAMA. 2017;317(11):1151-1158 PMID: 28324091 http://jamanetwork.com/journals/jama/article-abstract/2612616
  45. Go AS, Singer DE, Toh S et al. Outcomes of dabigatran and warfarin for atrial fibrillation in contemporary practice: A retrospective cohort study. Ann Intern Med 2017 Nov 14 PMID: 29132153
  46. Anderson I, Cifu AS. Management of Bleeding in Patients Taking Oral Anticoagulants. JAMA. 2018;319(19):2032-2033. May 15, 2018 PMID: 29800198 https://jamanetwork.com/journals/jama/fullarticle/2681178
  47. Devereaux PJ, Duceppe E, Guyatt G et al Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo- controlled trial. Lancet. 2018 Jun 9;391(10137):2325-2334. PMID: 29900874
  48. Vinogradova Y, Coupland C, Hill T, Hippisley-Cox J Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care. BMJ 2018;362:k2505 PMID: 29973392 https://www.bmj.com/content/362/bmj.k2505
  49. Eikelboom JW, van Ryn J, Reilly P et al. Dabigatran reversal with idarucizumab in patients with renal impairment. J Am Coll Cardiol 2019 Oct 8; 74:1760. PMID: 31582135 Free Article
  50. Alcusky M et al. Comparative safety and effectiveness of direct-acting oral anticoagulants versus warfarin: A national cohort study of nursing home residents. J Gen Intern Med 2020 Aug; 35:2329. PMID: 32291717 PMCID: PMC7403286 https://link.springer.com/article/10.1007/s11606-020-05777-3
  51. Food & Drug Admnistration Safety Alert. March 22, 2023 Ascend Laboratories LLC. Issues Voluntary Nationwide Recall of Dabigatran Etexilate Capsules, USP 75 mg and 150 mg, Due to the Detection of N-Nitroso- dabigatran (NDAB) Impurity. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/ascend-laboratories-llc-issues-voluntary-nationwide-recall-dabigatran-etexilate-capsules-usp-75-mg