as etexilate: InChI=1S/C34H41N7O5/c1-4-6-7-10-21-46-34(44)39-32(35)24-12-15-26(16-13-24)37-23-30-38-27-22-25(14-17-28(27)40(30)3)33(43)41(20-18-31(42)45-5-2)29-11-8-9-19-36-29/h8-9,11-17,19,22,37H,4-7,10,18,20-21,23H2,1-3H3,(H2,35,39,44)
Dabigatran, sold under the brand namePradaxa among others, is ananticoagulant used to treat and preventblood clots and to preventstroke in people withatrial fibrillation.[6][7] Specifically it is used to prevent blood clots followinghip orknee replacement and in those with a history of prior clots.[6] It is used as an alternative towarfarin and does not require monitoring by blood tests.[6] In a meta analysis of 7 different studies, there was no benefit of dabigatran over warfarin in preventingischemic 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.[8] It is taken by mouth.[6]
It appears to be as effective aswarfarin in preventing non-hemorrhagic strokes and embolic events in those with atrial fibrillation not due to valve problems.[14][15][16]
In 2022, an observational meta-analysis study was performed on direct oral anticoagulants for patients with atrial fibrillation. The study found that dabigatran had comparable rates of ischemic stroke or systemic embolism, intracerebral haemorrhage, and all-cause mortality when compared to other anticoagulants like apixaban, edoxaban, and rivaroxaban. Notably, apixaban was associated with a lower risk of gastrointestinal bleeding than dabigatran and the others. This finding was generally steady for patients aged 80 years or older and those with chronic kidney disease.[17]
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.[4] Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran (e.g.anaphylaxis or anaphylactic shock).[4] 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, andmyocardial infarction) and major bleeding when compared with warfarin.[4][18][19]
CurrentFDA guidelines states that patients with mechanical heart valves should not be using dabigatran. The safety and efficacy of Pradaxa (dabigatran) were evaluated in the European RE-ALIGN trial in 2012. RE-ALIGN was terminated early because the Pradaxa treatment group had significantly more thromboembolic events and major bleeding than warfarin and determined to be contraindicated for use in patients with mechanical heart valves.[20] Further studies are needed in order to determine effects of dabigatran on patients with bioprosthetic valves.
Dabigatran is poorly excreted in breastmilk and does not appear to require any limitations to breastfeeding.[21] However, data is limited and further studies are needed.
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 withdyspepsia; some hypothesize that this plays a role in the increased risk of gastrointestinal bleeding.[22] 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 asidarucizumab for dabigatran, and emergency endoscopic management.[23]
A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[24][25] 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.[26]
For patients with moderately reduced kidney function, lower dabigatran doses are recommended due to increased drug exposure and bleeding risk.[27][28][29] Alternative anticoagulants should be considered in severe kidney impairment due to insufficient safety and efficacy data.[28]
Dabigatran intake has also been reported to cause esophageal injury oresophagitis. In a 2016 study by Toya et al., roughly 20% of patients suffered esophageal mucosa damage.[30] It has been theorized that the tartaric-acid core in the drug adheres and damages the esophagus, and then the damaged esophageal mucosa exfoliates after peristalsis.[31] Additionally, patients with limited mobility, reduced salivary secretion, and low water consumption will increase the possibility of contact by dabigatran with the esophageal mucosa.[23]
The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial showed that impairment of liver function caused by dabigatran occurred in the same frequency as warfarin.[32]
Dabigatran reversibly binds to the active site on thethrombin molecule, preventing thrombin-mediated activation ofcoagulation factors. Furthermore, dabigatran can inactivate thrombin even when thrombin isfibrin-bound; it reduces thrombin-mediated inhibition offibrinolysis and, therefore, may enhance fibrinolysis.[33]
Dabigatran has a half-life of approximately 12–17 h and exerts a maximum anticoagulation effect within 2 hours after ingestion.[34] Fatty foods delay the intestinal absorption of dabigatran, although thebioavailability of the drug is unaffected.[4] Several studies have demonstrated that dabigatran plasma concentrations are reduced when co-administered with proton pump inhibitors, however it is unclear if this reduction is clinically significant.[35][36][37] Dabigatran excretion throughP-glycoprotein pumps is slowed in patients taking strong p-glycoprotein pump inhibitors such asquinidine,verapamil, andamiodarone, thus raising plasma levels of dabigatran.[38]
Dabigatran is available as dabigatran etexilate mesilate,formulated as theprodrug dabigatran etexilate.[4][6][38]
Dabigatran (then compound BIBR-953) was discovered from a panel of chemicals with similar structure tobenzamidine-basedthrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of variousserine proteases, specifically thrombin, but alsotrypsin. Addition of ethylester and hexyloxycarbonyl carbamide hydrophobic side chains led to theorally absorbedprodrug, BIBR 1048 (dabigatran etexilate).[39]
TheNational 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 otheranticoagulants.[41]
Initially, there was no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event,[42] unlike for warfarin.[43] Since then, the dabigatran-specific antidoteidarucizumab, a humanizedmonoclonal antibody for intravenous administration, was developed, and receivedFood and Drug Administration (FDA) approval in 2015.[44]
Pradaxa received a Notice of Compliance (NOC) fromHealth Canada in June 2008,[45] 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.[46][47]
The U.S.Food and Drug Administration (FDA) approved Pradaxa in October 2010, for prevention of stroke in patients with non-valvular atrial fibrillation.[48][49][50][51] The approval came after an advisory committee recommended the drug for approval in September 2010,[52] although caution is still urged by some outside experts.[53]
In 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.[54]
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.[55]
In July 2014, a series of investigations accused the privately heldBoehringer 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.[56][57] 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. In 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.[58]
^World Health Organization (2019).World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Lau WC, Torre CO, Man KK, Stewart HM, Seager S, Van Zandt M, et al. (November 2022). "Comparative Effectiveness and Safety Between Apixaban, Dabigatran, Edoxaban, and Rivaroxaban Among Patients With Atrial Fibrillation : A Multinational Population-Based Cohort Study".Annals of Internal Medicine.175 (11):1515–1524.doi:10.7326/M22-0511.PMID36315950.S2CID253238819.
^"Dabigatran",Drugs and Lactation Database (LactMed®), Bethesda (MD): National Institute of Child Health and Human Development, 2006,PMID29999803,archived from the original on 2 May 2023, retrieved27 February 2023
^Blommel ML, Blommel AL (August 2011). "Dabigatran etexilate: A novel oral direct thrombin inhibitor".American Journal of Health-System Pharmacy.68 (16):1506–1519.doi:10.2146/ajhp100348.PMID21817082.
^Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. (September 2009). "Dabigatran versus warfarin in patients with atrial fibrillation".The New England Journal of Medicine.361 (12):1139–1151.doi:10.1056/NEJMoa0905561.hdl:11343/221723.PMID19717844.
^Wei AH, Gu ZC, Zhang C, Ding YF, Liu D, Li J, et al. (September 2018). "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".International Journal of Cardiology.267:1–7.doi:10.1016/j.ijcard.2018.05.048.PMID29801762.
^Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clinical pharmacokinetics. 2010 Apr; 49:259-68.
^abHijazi Z, Hohnloser SH, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW, et al. (March 2014). "Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis".Circulation.129 (9):961–970.doi:10.1161/circulationaha.113.003628.PMID24323795.
^An J, Cheetham TC, Luong T, Lang DT, Lee MS, Reynolds K (July 2023). "Effectiveness and safety of Dabigatran 110 mg versus 150 mg for Stroke Prevention in Patients with Atrial Fibrillation at High Bleeding Risk".Clinical Therapeutics.45 (7):e151 –e158.doi:10.1016/j.clinthera.2023.05.007.PMID37380555.
^Toya Y, Nakamura S, Tomita K, Matsuda N, Abe K, Abiko Y, et al. (March 2016). "Dabigatran-induced esophagitis: The prevalence and endoscopic characteristics".Journal of Gastroenterology and Hepatology.31 (3):610–614.doi:10.1111/jgh.13024.PMID26102078.S2CID2601542.
^Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. (September 2009). "Dabigatran versus warfarin in patients with atrial fibrillation".The New England Journal of Medicine.361 (12):1139–1151.doi:10.1056/NEJMoa0905561.hdl:11343/221723.PMID19717844.S2CID7425216.
^Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G, Stähle H, et al. (May 2005). "Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement".Journal of Clinical Pharmacology.45 (5):555–563.doi:10.1177/0091270005274550.PMID15831779.S2CID26441767.
^Bolek T, Samoš M, Stančiaková L, Ivanková J, Škorňová I, Staško J, et al. (May 2019). "The Impact of Proton Pump Inhibition on Dabigatran Levels in Patients With Atrial Fibrillation".American Journal of Therapeutics.26 (3):e308 –e313.doi:10.1097/mjt.0000000000000599.PMID28452843.
^van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. (June 2010). "Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity".Thrombosis and Haemostasis.103 (6):1116–1127.doi:10.1160/TH09-11-0758.PMID20352166.S2CID37404563.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.
^Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. (September 2009). "Dabigatran versus warfarin in patients with atrial fibrillation".The New England Journal of Medicine.361 (12):1139–1151.doi:10.1056/NEJMoa0905561.hdl:11343/221723.PMID19717844.S2CID7425216.
^Merli G, Spyropoulos AC, Caprini JA (August 2009). "Use of emerging oral anticoagulants in clinical practice: translating results from clinical trials to orthopedic and general surgical patient populations".Annals of Surgery.250 (2):219–228.doi:10.1097/SLA.0b013e3181ae6dbe.PMID19638915.S2CID44917732.
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