Dabigatran: Difference between revisions

{{shortShort description|Anticoagulant medication}}

{{Use dmy dates|date=SeptemberNovember 20192023}}

| drug_name = Dabigatran etexilate

| INN =

| image = Dabigatran etexilate structure.svg

| width = 135275

| USAN = Dabigatran etexilate

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Dabigatran (Pradaxa) Use During Pregnancy | website=Drugs.com | date=27 December 2018 | url=https://www.drugs.com/pregnancy/dabigatran.html | access-date=16 May 2020 | archive-date=1 October 2020 | archive-url=https://web.archive.org/web/20201001223633/https://www.drugs.com/pregnancy/dabigatran.html | url-status=live }}</ref>

| class = [[Direct thrombin inhibitor]]

| legal_CA = Schedule VIRx-only

| CAS_number = 211915211914-0651-91

| PubChem = 135565674216210

| ChemSpiderIDDrugBank = 4948999DB14726

| ChEBIUNII = 70746I0VM4M70GC -->

| PDB_ligand = 4CC

| synonyms = BIBR-953, BIBR-1048

<!-- | IUPAC_nameIUPAC_name2 = Ethyl ''N''-[(2-<nowiki/>{[(4-<nowiki/>{''N''{{'}}-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1''H''-benzimidazol-5-yl)carbonyl]-''N''-2-pyridinyl-β-alaninate

-->| C=3425 | H=4125 | N=7 | O=53

| SMILES = CCCCCCOC(CN1C=O)N=C2C(C1=CC=(C(C=C1N(CCC(O)NCC2=NC3=C(N2CO)CC3=CC(=C3CC=N3)C(=O)N(CCC(=OCC2)OCC)C4N=CCC1CNC4=CC=N4C(C(=N)N)C=C4

'''Dabigatran''', sold under the brand name '''Pradaxa''' among others, is an [[anticoagulant]] used to treat and prevent [[venous thromboembolism|blood clots]] and to prevent [[stroke]] in people with [[atrial fibrillation]].<ref name=AHFS2019/><ref name=BNF76/> Specifically it is used to prevent blood clots following [[hip replacement|hip]] or [[knee replacement]] and in those with a history of prior clots.<ref name=AHFS2019/> It is used as an alternative to [[warfarin]] and does not require monitoring by blood tests.<ref name=AHFS2019/> In a meta analysis of 7 different studies, there was no benefit of dabigatran over warfarin in preventing [[Stroke#Ischemic|ischemic stroke]]; however, dabigatran were associated with a lower hazard for intracranial bleeding compared with warfarin, but also had a higher risk of gastrointestinal bleeding relative to warfarin.<ref>{{cite journal | vauthors = Romanelli RJ, Nolting L, Dolginsky M, Kym E, Orrico KB | title = Dabigatran Versus Warfarin for Atrial Fibrillation in Real-World Clinical Practice: A Systematic Review and Meta-Analysis | journal = Circulation: Cardiovascular Quality and Outcomes | volume = 9 | issue = 2 | pages = 126–134 | date = March 2016 | pmid = 26812933 | doi = 10.1161/CIRCOUTCOMES.115.002369 | s2cid = 6840541 | doi-access = free }}</ref> It is taken by mouth.<ref name=AHFS2019/>

Common side effects include bleeding and [[gastritis]].<ref name=AHFS2019/> Other side effects may include [[spinal hematoma|bleeding around the spine]] and allergic reactions such as [[anaphylaxis]].<ref name=AHFS2019/> In cases of severe bleeding, it can be reversed with the antidote, [[idarucizumab]].<ref name=AHFS2019/> Use is not recommended during [[pregnancy]] or [[breastfeeding]].<ref name=AHFS2019/> Compared to warfarin it has fewer [[drug interaction|interactions with other medications]].<ref>{{cite book |last1 vauthors = Kiser |first1=KathrynK |title=Oral Anticoagulation Therapy: Cases and Clinical Correlation |date=2017 |publisher=Springer |isbn=9783319546438 |page=11 |url=https://books.google.com/books?id=byYmDwAAQBAJ&pg=PA11 }}</ref> It is a [[direct thrombin inhibitor]].<ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=135–137|edition=76}}</ref>

Dabigatran was approved for medical use in the United States in 2010.<ref name=AHFS2019>{{cite web |title=Dabigatran Etexilate Mesylate Monograph for Professionals |url=https://www.drugs.com/monograph/dabigatran-etexilate-mesylate.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=27 March 2019 |archive-date=27 March 2019 |archive-url=https://web.archive.org/web/20190327102444/https://www.drugs.com/monograph/dabigatran-etexilate-mesylate.html |url-status=live }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In 20172020, it was the 302nd306th most commonly prescribed medication in the United States, with more than one 1{{nbsp}}million prescriptions.<ref>{{cite web | title = Dabigatran Etexilate Mesylate - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/DabigatranEtexilateMesylateDabigatran | access-date = 117 AprilOctober 20202022 | archive-date = 2813 FebruaryNovember 20202022 | archive-url = https://web.archive.org/web/2020022805353820221113223835/https://clincalc.com/DrugStats/Drugs/DabigatranEtexilateMesylateDabigatran | url-status = deadlive }}</ref> Dabigatran etexilateis was approved asavailable a [[generic medication in the United States in 2020]].<ref>{{cite web | title=Office of Generic Drugs 2020 Annual Report | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.fda.gov/drugs/generic-drugs/office-generic-drugs-2020-annual-report | access-date=12 February 2021 | archive-date=12 February 2021 | archive-url=https://web.archive.org/web/20210212163324/https://www.fda.gov/drugs/generic-drugs/office-generic-drugs-2020-annual-report | url-status=live }}</ref><ref>{{cite web | title=Dabigatran Etexilate Accord | website=European Medicines Agency | date=31 May 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/dabigatran-etexilate-accord | access-date=2 June 2023}}</ref>

It appears to be as effective as [[warfarin]] in preventing non-hemorrhagic strokes and embolic events in those with atrial fibrillation not due to valve problems.<ref>{{cite journal | vauthors = Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E | title = Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups | journal = Thrombosis | volume = 2013 | pages = 640723 | date = 2013 | pmid = 24455237 | pmc = 3885278 | doi = 10.1155/2013/640723 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lowenstern A, Al-Khatib SM, Sharan L, Chatterjee R, Allen LaPointe NM, Shah B, Borre ED, Raitz G, Goode A, Yapa R, Davis JK, Lallinger K, Schmidt R, Kosinski AS, Sanders GD | display-authors = 6 | title = Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review | journal = Annals of Internal Medicine | volume = 169 | issue = 11 | pages = 774–787 | date = December 2018 | pmid = 30383133 | pmc = 6825839 | doi = 10.7326/M18-1523 }}</ref><ref>{{cite report | vauthors = Sanders GD, Lowenstern A, Borre E, Chatterjee R, Goode A, Sharan L, LaPointe NM, Raitz G, Shah B, Yapa R, Davis JK, Lallinger K, Schmidt R, Kosinski A, Al-Khatib S | title = Stroke Prevention in Patients With Atrial Fibrillation: A Systematic Review Update | location = Rockville (MD) | work = Agency for Healthcare Research and Quality (US) | date = October 2018 | id = Report No.: 18-EHC018-EFReport No.: 2018-SR-04. | url = https://effectivehealthcare.ahrq.gov/topics/stroke-afib-update/research-2018 | doi = 10.23970/ahrqepccer214 | pmid = 30480925 | access-date = 31 May 2023 | archive-date = 29 March 2019 | archive-url = https://web.archive.org/web/20190329195137/https://effectivehealthcare.ahrq.gov/topics/stroke-afib-update/research-2018 | url-status = live | doi-access = free }}</ref>

Dabigatran is contraindicated in patients who have active pathological bleeding, since dabigatran can increase bleeding risk and can also cause serious and potentially life-threatening bleeds.<ref name="Pradaxa FDA label">{{cite web | title=Pradaxa- dabigatran etexilate mesylate capsule | website=DailyMed | date=6 July 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ba74e3cd-b06f-4145-b284-5fd6b84ff3c9 | access-date=13 November 2020 | archive-date=28 June 2021 | archive-url=https://web.archive.org/web/20210628163240/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ba74e3cd-b06f-4145-b284-5fd6b84ff3c9 | url-status=live }}</ref> Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran (e.g. [[anaphylaxis]] or anaphylactic shock).<ref name="Pradaxa FDA label" /> The use of dabigatran should also be avoided in patients with mechanical prosthetic heart valves due to the increased risk of thromboembolic events (e.g. valve thrombosis, stroke, and [[myocardial infarction]]) and major bleeding associatedwhen compared with dabigatran in this populationwarfarin.<ref name="Pradaxa FDA label" /><ref>{{cite web|title=FDA Drug Safety Communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves|url=https://www.fda.gov/Drugs/DrugSafety/ucm332912.htm|website=U.S. [[Food and Drug Administration]] (FDA) |access-date=29 October 2014|archive-date=2 November 2014|archive-url=https://web.archive.org/web/20141102203846/http://www.fda.gov/Drugs/DrugSafety/ucm332912.htm|url-status=live}}</ref><ref>{{cite journal | vauthors = Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F | display-authors = 6 | title = Dabigatran versus warfarin in patients with mechanical heart valves | journal = The New England Journal of Medicine | volume = 369 | issue = 13 | pages = 1206–141206–1214 | date = September 2013 | pmid = 23991661 | doi = 10.1056/NEJMoa1300615 | doi-access = free }}</ref>

The most commonly reported side effect of dabigatran is gastrointestinal upset. When compared with people anticoagulated with warfarin, patients taking dabigatran had fewer life-threatening bleeds, fewer minor and major bleeds, including intracranial bleeds, but the rate of gastrointestinal bleeding was significantly higher. Dabigatran capsules contain tartaric acid, which lowers the gastric pH and is required for adequate absorption. The lower pH has previously been associated with [[dyspepsia]]; some hypothesize that this plays a role in the increased risk of gastrointestinal bleeding.<ref>{{cite journal | vauthors = Blommel ML, Blommel AL | title = Dabigatran etexilate: A novel oral direct thrombin inhibitor | journal = American Journal of Health-System Pharmacy | volume = 68 | issue = 16 | pages = 1506–191506–1519 | date = August 2011 | pmid = 21817082 | doi = 10.2146/ajhp100348 }}</ref> If a small amount of GI bleeding is diagnosed, the clinicians may consider adding H₂ receptor inhibitor (H₂RA), proton pump inhibitors (PPIs) and mucosal protective agent. In severe bleeding, measures include discontinuation of dabigatran immediately, and administration of prothrombin complex concentrate, packed red blood cells, fresh frozen plasma, the use of specific reversal agents such as [[idarucizumab]] for dabigatran, and emergency endoscopic management.<ref name="Lin 1527–1533">{{cite journal | vauthors = Lin S, Wang Y, Zhang L, Guan W | title = Dabigatran must be used carefully: literature review and recommendations for management of adverse events | language = English | journal = Drug Design, Development and Therapy | volume = 13 | pages = 1527–1533 | date = 6 May 2019 | pmid = 31190734 | pmc = 6511609 | doi = 10.2147/DDDT.S203112 | doi-access = free }}</ref>

A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.<ref name=Uchino2012>{{cite journal | vauthors = Uchino K, Hernandez AV | title = Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials | journal = Archives of Internal Medicine | volume = 172 | issue = 5 | pages = 397–402 | date = March 2012 | pmid = 22231617 | doi = 10.1001/archinternmed.2011.1666 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L | title = Dabigatran versus warfarin in patients with atrial fibrillation | journal = The New England Journal of Medicine | volume = 361 | issue = 12 | pages = 1139–1151 | date = September 2009 | pmid = 19717844 | doi = 10.1056/NEJMoa0905561 | hdl = 11343/221723 | hdl-access = free }}</ref> However, conflicting evidence from another review suggested that dabigatran might not substantially increase the risk of heart attacks, or if it does, then the associated risk is relatively low.<ref>{{cite journal | vauthors = Wei AH, Gu ZC, Zhang C, Ding YF, Liu D, Li J, Liu XY, Lin HW, Pu J | title = Increased risk of myocardial infarction with dabigatran etexilate: fact or fiction? A critical meta-analysis of over 580,000 patients from integrating randomized controlled trials and real-world studies | journal = International Journal of Cardiology | volume = 267 | pages = 1–7 | date = September 2018 | pmid = 29801762 | doi = 10.1016/j.ijcard.2018.05.048 }}</ref>

Dabigatran reversibly binds to the active site on the [[thrombin]] molecule, preventing thrombin-mediated activation of [[Clotting factors|coagulation factors]]. Furthermore, dabigatran can inactivate thrombin even when thrombin is [[fibrin]]-bound; it reduces thrombin-mediated inhibition of [[fibrinolysis]] and, therefore, may enhance fibrinolysis.<ref>{{cite journal | vauthors = Comin J, Kallmes DF | title = Dabigatran (Pradaxa) | journal = AJNR. American Journal of Neuroradiology | volume = 33 | issue = 3 | pages = 426–8426–428 | date = March 2012 | pmid = 22345499 | pmc = 7966436 | doi = 10.3174/ajnr.A3000 | pmc = 7966436 | doi-access = free }}</ref>

Dabigatran has a half-life of approximately 12–1412–17 h and exerts a maximum anticoagulation effect within 2–32 hours after ingestion.<ref>{{citationcite journal needed| vauthors = Muñoz-Corcuera M, Ramírez-Martínez-Acitores L, López-Pintor RM, Casañas-Gil E, Hernández-Vallejo G | title = Dabigatran: A new oral anticoagulant. Guidelines to follow in oral surgery procedures. A systematic review of the literature | journal = Medicina Oral, Patologia Oral y Cirugia Bucal | volume = 21 | issue = 6 | pages = e679–e688 | date = November 20192016 | pmid = 27694780 | pmc = 5116109 | doi = 10.4317/medoral.21202 }} </ref> Fatty foods delay the intestinal absorption of dabigatran, although the [[bioavailability]] of the drug is unaffected.<ref name=prescribing_info>[http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/"Pradaxa FDA label" /Pradaxa.pdf> PradaxaSeveral Fullstudies Prescribinghave Information]demonstrated {{webarchive|url=https://web.archive.org/web/20150810145742/http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=%2FPrescribing%20Information%2FPIs%2FPradaxa%2FPradaxa.pdfthat |date=2015-08-10dabigatran }}.plasma [[Boehringerconcentrations Ingelheim]].are Octoberreduced 2010.</ref>when Oneco-administered studywith showedproton thatpump absorptioninhibitors, mayhowever beit moderatelyis decreasedunclear if takenthis withreduction ais [[protonclinically pump inhibitor]]significant.<ref>{{cite journal | vauthors = Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G, Stähle H, Rathgen K, Svärd R | display-authors = 6 | title = Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement | journal = Journal of Clinical Pharmacology | volume = 45 | issue = 5 | pages = 555–63555–563 | date = May 2005 | pmid = 15831779 | doi = 10.1177/0091270005274550 | s2cid = 26441767 }}</ref><ref>{{cite journal | vauthors = Kuwayama T, Osanai H, Ajioka M, Tokuda K, Ohashi H, Tobe A, Yoshida T, Masutomi T, Kambara T, Inoue Y, Nakashima Y, Asano H, Sakai K | title = Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non-valvular atrial fibrillation | journal = Journal of Arrhythmia | volume = 33 | issue = 6 | pages = 619–623 | date = December 2017 | pmid = 29255511 | doi = 10.1016/j.joa.2017.07.013 | pmc = 5729000 }}</ref><ref>{{cite journal | vauthors = Bolek T, Samoš M, Stančiaková L, Ivanková J, Škorňová I, Staško J, Galajda P, Kubisz P, Mokáň M | title = The Impact of Proton Pump Inhibition on Dabigatran Levels in Patients With Atrial Fibrillation | journal = American Journal of Therapeutics | volume = 26 | issue = 3 | pages = e308–e313 | date = May 2019 | pmid = 28452843 | doi = 10.1097/mjt.0000000000000599 }}</ref> Dabigatran excretion through [[P-glycoprotein]] pumps is slowed in patients taking strong p-glycoprotein pump inhibitors such as [[quinidine]], [[verapamil]], and [[amiodarone]], thus raising plasma levels of dabigatran.<ref name="EMEA2018">[https://www.ema.europa.eu/en/documents/product-information/pradaxa-epar-product-information_en.pdf "Pradaxa Summary of Product Characteristics" (2018)] {{webarchive|url= https://web.archive.org/web/20190705200927/https://www.ema.europa.eu/en/documents/product-information/pradaxa-epar-product-information_en.pdf |date= 5 July 2019-07-05 }}. [[European Medicines Agency]].</ref>

Dabigatran is available as dabigatran etexilate mesilate, [[Pharmaceutical formulation|formulated]] as the [[prodrug]] dabigatran etexilate.<ref name="Pradaxa FDA label" /><ref name=AHFS2019 /><ref name="EMEA2018" />

Dabigatran (then compound BIBR -953) was discovered from a panel of chemicals with similar structure to [[benzamidine]]-based [[thrombin]] inhibitor α-NAPAP (''N''-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various [[serine protease]]s, specifically thrombin, but also [[trypsin]]. Addition of ethyl [[ester]] and hexyloxycarbonyl carbamide hydrophobic side chains led to the [[Oral bioavailability|orally absorbed]] [[prodrug]], BIBR 1048 (dabigatran etexilate).<ref>{{cite journal | vauthors = Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W | title = Structure-based design of novel potent nonpeptide thrombin inhibitors | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 9 | pages = 1757–661757–1766 | date = April 2002 | pmid = 11960487 | doi = 10.1021/jm0109513 }}</ref>

On 18In March 2008, the [[European Medicines Agency]] (EMA) granted marketing authorization for Pradaxa for the prevention of [[thromboembolic disease]] following hip or knee replacement surgery and for [[non-valvular atrial fibrillation]].<ref>{{cite web|url=http://www.emea.europa.eu/ema/humandocs/Humans/EPAR/pradaxa/pradaxa.htm |archive-url=https://archive.today/20120802103810/http://www.emea.europa.eu/ema/humandocs/Humans/EPAR/pradaxa/pradaxa.htm |url-status=dead |archive-date=2 August 2012-08-02 |title=Pradaxa EPAR |work=[[European Medicines Agency]] |access-date=2011-01-30 January 2011 }}</ref>

The [[National Health Service (England)|National Health Service]] (NHS) in Britain authorized dabigatran for use in preventing blood clots in hip and knee replacement surgery patients. According to a BBC article in 2008, Dabigatran was expected to cost the NHS £4.20 per day, which was similar to several other [[anticoagulant]]s.<ref name='bbc1'>{{cite news | title= Clot drug 'could save thousands' | date=2008-04-20 April 2008 | url=http://news.bbc.co.uk/1/hi/health/7354818.stm | work=[[BBC News Online]] | access-date=21 April 2008 | archive-04date=15 January 2009 | archive-21url=https://web.archive.org/web/20090115140437/http://news.bbc.co.uk/1/hi/health/7354818.stm | url-status=live }}</ref>

Initially, there was no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event,<ref name='vanRyn2010'>{{cite journal | vauthors = van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A | title = Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity | journal = Thrombosis and Haemostasis | volume = 103 | issue = 6 | pages = 1116–271116–1127 | date = June 2010 | pmid = 20352166 | doi = 10.1160/TH09-11-0758 | quote = Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. | s2cid = 37404563 }}</ref> unlike for warfarin.<ref name='Hanley2004'>{{cite journal | vauthors = Hanley JP | title = Warfarin reversal | journal = Journal of Clinical Pathology | volume = 57 | issue = 11 | pages = 1132–91132–1139 | date = November 2004 | pmid = 15509671 | pmc = 1770479 | doi = 10.1136/jcp.2003.008904 }}</ref> Since then, the dabigatran-specific antidote [[idarucizumab]], a humanized [[monoclonal antibody]] for intravenous administration, was developed, and received [[Food and Drug Administration]] (FDA) approval in 2015.<ref>{{cite journal | vauthors = Syed YY | title = Idarucizumab: A Review as a Reversal Agent for Dabigatran | journal = American Journal of Cardiovascular Drugs | volume = 16 | issue = 4 | pages = 297–304 | date = August 2016 | pmid = 27388764 | doi = 10.1007/s40256-016-0181-4 | s2cid = 11596083 }}</ref>

Pradaxa received a Notice of Compliance (NOC) from [[Health Canada]] on 10in June 2008,<ref>[http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/sbd_smd_2008_pradax_114887-eng.pdf "Summary Basis of Decision (SBD): Pradax"] {{Webarchive|url=https://web.archive.org/web/20160714123034/http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/sbd_smd_2008_pradax_114887-eng.pdf |date=14 July 2016 }} [[Health Canada]]. 6 November 2008-11-06.</ref> for the prevention of blood clots in patients who have undergone total hip or total knee replacement surgery. Approval for atrial fibrillation patients at risk of stroke came in October 2010.<ref>{{cite news|last vauthors = Kirkey|first=Sharon S |title=Approval of new drug heralds 'momentous' advance in stroke prevention|url=https://montrealgazette.com/health/Approval+drug+heralds+momentous+advance+stroke+prevention/3739714/story.html|access-date=29 October 2010|newspaper=[[The Gazette (Montreal)|Montreal Gazette]]|date=29 October 2010|archive-date=16 June 2011|archive-url=https://web.archive.org/web/20110616140333/http://www.montrealgazette.com/health/Approval+drug+heralds+momentous+advance+stroke+prevention/3739714/story.html|url-status=dead}}</ref><ref>[http://www.medicalnewstoday.com/articles/205933.php "Pradax (Dabigatran Etexilate) Gains Approval In Canada For Stroke Prevention In Atrial Fibrillation"] {{Webarchive|url=https://web.archive.org/web/20110424125802/http://www.medicalnewstoday.com/articles/205933.php |date=24 April 2011 }} Medical News Today. 28 October 2010.</ref>

The U.S. [[Food and Drug Administration]] (FDA) approved Pradaxa on 19in October 2010, for prevention of stroke in patients with non-valvular atrial fibrillation.<ref name=connolly>{{cite journal | vauthors = Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L | display-authors = 6 | title = Dabigatran versus warfarin in patients with atrial fibrillation | journal = The New England Journal of Medicine | volume = 361 | issue = 12 | pages = 1139–511139–1151 | date = September 2009 | pmid = 19717844 | doi = 10.1056/NEJMoa0905561 | hdl-access = 11343/221723free | urlhdl = http:11343//research-repository.uwa.edu.au/en/publications/dabigatran-versus-warfarin-in-patients-with-atrial-fibrillation(f739041d-c71a-4df4-ab1b-8f36781d83f7).html221723 | hdl-accesss2cid = free7425216 }}</ref><ref>{{cite journal | vauthors = Turpie AG | title = New oral anticoagulants in atrial fibrillation | journal = European Heart Journal | volume = 29 | issue = 2 | pages = 155–65155–165 | date = January 2008 | pmid = 18096568 | doi = 10.1093/eurheartj/ehm575 | doi-access = free }}</ref><ref name=WSJ>{{cite news | title=Boehringer wins first US OK in blood-thinner race | date=2010-10-19 October 2010 | publisher=[[Reuters]] | url=https://www.reuters.com/article/boehringer-pradaxa-idUSN1916563620101019 | access-date=20 October 2010 | archive-10date=4 May 2016 | archive-20url=https://web.archive.org/web/20160504230021/http://www.reuters.com/article/boehringer-pradaxa-idUSN1916563620101019 | url-status=live }}</ref><ref name=FDA>{{cite press release | title=FDA approves Pradaxa to prevent stroke in people with atrial fibrillation | date=2010-10-19 October 2010 | publisher=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm | archive-url=https://web.archive.org/web/20101020170354/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm | url-status=dead | archive-date=2010-10-20 October 2010 }}</ref> The approval came after an advisory committee recommended the drug for approval on 20in September 2010,<ref>{{cite news | title=New Blood-Thinner Recommended by FDA Panel | author = Shirley S. Wang | date=2010-09-20 September 2010 | work=[[The Wall Street Journal]] | url=https://blogs.wsj.com/health/2010/09/20/new-blood-thinner-recommended-by-fda-panel/ | access-date=20 October 2010 | url-10access=subscription | archive-date=24 April 2016 | archive-url=https://web.archive.org/web/20160424000048/http://blogs.wsj.com/health/2010/09/20/new-blood-thinner-recommended-by-fda-panel/ | url-accessstatus=subscriptionlive }}</ref> although caution is still urged by some outside experts.<ref name="pmid19638915">{{cite journal | vauthors = Merli G, Spyropoulos AC, Caprini JA | title = Use of emerging oral anticoagulants in clinical practice: translating results from clinical trials to orthopedic and general surgical patient populations | journal = Annals of Surgery | volume = 250 | issue = 2 | pages = 219–28219–228 | date = August 2009 | pmid = 19638915 | doi = 10.1097/SLA.0b013e3181ae6dbe | s2cid = 44917732 }}</ref>

On 14In February 2011, the American College of Cardiology Foundation and the American Heart Association added dabigatran to their guidelines for management of non-valvular atrial fibrillation with a class I recommendation.<ref name="pmid21321155">{{cite journal | vauthors = Wann LS, Curtis AB, Ellenbogen KA, Estes NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Heuzey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Jacobs AK, Anderson JL, Albert N, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Yancy CW | display-authors = 6 | title = 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 | journal = Circulation | volume = 123 | issue = 10 | pages = 1144–501144–1150 | date = March 2011 | pmid = 21321155 | doi = 10.1161/CIR.0b013e31820f14c0 | last20 = Kay | last21 = Le Heuzey | last22 = Lowe | last23 = Olsson | last24 = Prystowsky | last25 = Tamargo | last26 = Wann | last27 = Jacobs | last28 = Anderson | last29 = Albert | last15 = Cannom | last14 = Rydén | last17 = Curtis | last16 = Crijns | last19 = Halperin | last18 = Ellenbogen | last30 = Creager | doi-access = free }}</ref>

In May 2014, the FDA reported the results of a large study comparing dabigatran with warfarin in 134,000 Medicare patients. The agency concluded that dabigatran is associated with a lower risk of overall mortality, ischemic stroke, and bleeding in the brain than warfarin. Gastrointestinal bleeding was more common in those treated with dabigatran than in those treated with warfarin. The risk of heart attack was similar between the two drugs. The FDA reiterated its opinion that dabigatran's overall risk/benefit ratio is favorable.<ref>{{cite web |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-study-medicare-patients-finds-risks-lower-stroke-and-death-higher |title=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 |website=U.S. [[Food and Drug Administration]] (FDA) |date=21 June 2019 |access-date=13 November 2020 |archive-date=11 November 2020 |archive-url=https://web.archive.org/web/20201111202320/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-study-medicare-patients-finds-risks-lower-stroke-and-death-higher |url-status=live }}</ref>

On 26In July 2014, the ''[[British Medical Journal]]'' (BMJ) published a series of investigations that accused the privately held [[Boehringer Ingelheim]] pharmaceutical group of withholding critical information about the need for monitoring to protect patients from severe bleeding, particularly in the elderly. Review of internal communications between Boehringer researchers and employees by the FDA and the EMA revealed that Boehringer researchers had found evidence that serum levels of dabigatran vary widely. The BMJ investigation suggested that Boehringer had a financial motive to withhold this concern from regulatory health agencies because the data conflicted with their extensive marketing of dabigatran as an anticoagulant that does not require monitoring.<ref>{{cite journal | vauthors = Cohen D | title = Dabigatran: how the drug company withheld important analyses | journal = BMJ | volume = 349 | pages = g4670 | date = July 2014 | pmid = 25055829 | doi = 10.1136/bmj.g4670 | doi-access = free }}</ref><ref name="PMID25056265">{{cite journal | vauthors = Moore TJ, Cohen MR, Mattison DR | title = Dabigatran, bleeding, and the regulators | journal = BMJ | volume = 349 | pages = g4517 | date = July 2014 | pmid = 25056265 | doi = 10.1136/bmj.g4517 | s2cid = 29090410 }}</ref> In August 2012, Pradaxa claims filed in U.S. federal courts were consolidated into a multi-district litigation in the Southern District of Illinois before Chief Judge David R. Herndon. On 28In May 2014, a $650 million settlement was announced on behalf of approximately 3,900 claimants who were injured by the drug Pradaxa made by Boehringer Ingelheim Pharmaceuticals, Inc. The drug was alleged to cause severe bleeding events and/or hemorrhaging to those who were taking the drug.<ref>{{cite news | title=$650 Million to Settle Blood Thinner Lawsuits | authorvauthors=Thomas, KatieK | url=https://www.nytimes.com/2014/05/29/business/international/german-drug-company-to-pay-650-million-to-settle-blood-thinner-lawsuits.html | work=[[The New York Times]] | date=28 May 2014 | access-date=26 November 2020 | archive-date=11 June 2021 | archive-url=https://web.archive.org/web/20210611223143/https://www.nytimes.com/2014/05/29/business/international/german-drug-company-to-pay-650-million-to-settle-blood-thinner-lawsuits.html | url-status=live }}</ref>

[[Category:Drugs developed by Boehringer Ingelheim]]