Dabigatran

Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation.[3][4] Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots.[3] It is used as an alternative to warfarin and does not require monitoring by blood tests.[3] It is taken by mouth.[3]

Dabigatran etexilate
Clinical data
Trade namesPradaxa, Pradax, Prazaxa, others
Other namesDabigatran etexilate (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa610024
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability3–7%[3]
Protein binding35%[3]
Elimination half-life12–17 hours[3]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC34H41N7O5
Molar mass627.746 g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

Common side effects include bleeding and gastritis.[3] Other side effects may include bleeding around the spine and allergic reactions such as anaphylaxis.[3] In cases of severe bleeding, it can be reversed with the antidote, idarucizumab.[3] Use is not recommended during pregnancy or breastfeeding.[3] Compared to warfarin it has fewer interactions with other medications.[5] It is a direct thrombin inhibitor.[4]

Dabigatran was approved for medical use in the United States in 2010.[3] It is on the World Health Organization's List of Essential Medicines.[6] In 2017, it was the 302nd most commonly prescribed medication in the United States, with more than one million prescriptions.[7]

Medical uses

Dabigatran is used to prevent strokes in those with atrial fibrillation not caused by heart valve issues, as well as deep vein thrombosis and pulmonary embolism in persons who have been treated for 5–10 days with parenteral anticoagulant (usually low molecular weight heparin), and to prevent deep vein thrombosis and pulmonary embolism in some circumstances.[2]

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.[8][9]

Contraindications

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.[2] Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran (e.g. anaphylaxis or anaphylactic shock).[2] 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 associated with dabigatran in this population.[2][10][11]

Adverse effects

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.[12]

A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[13]

Reduced doses should be used in those with poor kidney function.[14]

Pharmacology

Mechanism of action

Dabigatran reversibly binds to the active site on the thrombin molecule, preventing thrombin-mediated activation of 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.[15]

Pharmacokinetics

Dabigatran has a half-life of approximately 12–14 h and exerts a maximum anticoagulation effect within 2–3 h after ingestion. Fatty foods delay the absorption of dabigatran, although the bio-availability of the drug is unaffected.[16] One study showed that absorption may be moderately decreased if taken with a proton pump inhibitor.[17] Drug 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.[18]

It is formulated as the prodrug dabigatran etexilate.[18]

History

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 proteases, specifically thrombin, but also trypsin. Addition of ethyl ester and hexyloxycarbonyl carbamide hydrophobic side chains led to the orally absorbed prodrug, BIBR 1048 (dabigatran etexilate).[19]

On 18 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.[20]

The National Health Service (NHS) in Britain authorized the use of dabigatran for use in preventing blood clots in hip and knee 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 anticoagulants.[21]

Initially, there was no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event,[22] unlike for warfarin.[23] 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.[24]

Pradaxa received a Notice of Compliance (NOC) from Health Canada on 10 June 2008,[25] 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.[26][27]

The U.S. Food and Drug Administration (FDA) approved Pradaxa on 19 October 2010, for prevention of stroke in patients with non-valvular atrial fibrillation.[28][29][30][31] The approval came after an advisory committee recommended the drug for approval on 20 September 2010[32] although caution is still urged by some outside experts.[33]

On 14 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.[34]

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 Agency reiterated its opinion that dabigatran's overall risk/benefit ratio is favorable.[35]

On 26 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.[36][37] In August 2012, Pradaxa claims filed in U.S. federal courts were consolidated in a multi-district litigation in the Southern District of Illinois before Chief Judge David R. Herndon. On 28 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 is alleged to cause severe bleeding events and/or hemorrhaging to those who were taking the drug.[38]

References
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  2. "Pradaxa- dabigatran etexilate mesylate capsule". DailyMed. 6 July 2020. Retrieved 13 November 2020.
  3. "Dabigatran Etexilate Mesylate Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 27 March 2019.
  4. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 135–137. ISBN 9780857113382.
  5. Kiser, Kathryn (2017). Oral Anticoagulation Therapy: Cases and Clinical Correlation. Springer. p. 11. ISBN 9783319546438.
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  25. "Summary Basis of Decision (SBD): Pradax" Health Canada. 2008-11-06.
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