Dabigatran

Last updated

Dabigatran
Dabigatran etexilate.svg
Clinical data
Trade names Pradaxa, Pradax, Prazaxa, others
Other namesBIBR-953, BIBR-1048
AHFS/Drugs.com Monograph
MedlinePlus a610024
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Direct thrombin inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 3–7% [6]
Protein binding 35% [6]
Elimination half-life 12–17 hours [6]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
Formula C25H25N7O3
Molar mass 471.521 g·mol−1
3D model (JSmol)
  • CN1C=2C(=CC(C(N(CCC(O)=O)C3=CC=CC=N3)=O)=CC2)N=C1CNC4=CC=C(C(=N)N)C=C4

  • as etexilate: CN1C=2C(=CC(C(N(CCC(OCC)=O)C3=CC=CC=N3)=O)=CC2)N=C1CNC4=CC=C(C(NC(OCCCCCC)=O)=N)C=C4
  • InChI=1S/C25H25N7O3/c1-31-20-10-7-17(25(35)32(13-11-23(33)34)21-4-2-3-12-28-21)14-19(20)30-22(31)15-29-18-8-5-16(6-9-18)24(26)27/h2-10,12,14,29H,11,13,15H2,1H3,(H3,26,27)(H,33,34)
  • Key:YBSJFWOBGCMAKL-UHFFFAOYSA-N

  • 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)
  • Key:KSGXQBZTULBEEQ-UHFFFAOYSA-N
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [6] [7] Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. [6] It is used as an alternative to warfarin 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 preventing 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. [8] It is taken by mouth. [6]

Contents

Common side effects include bleeding and gastritis. [6] Other side effects may include bleeding around the spine and allergic reactions such as anaphylaxis. [6] In cases of severe bleeding, it can be reversed with the antidote, idarucizumab. [6] Use is not recommended during pregnancy or breastfeeding. [6] Compared to warfarin it has fewer interactions with other medications. [9] It is a direct thrombin inhibitor. [7]

Dabigatran was approved for medical use in the United States in 2010. [6] It is on the World Health Organization's List of Essential Medicines. [10] In 2020, it was the 306th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [11] Dabigatran is available a generic medication. [12] [13]

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. [4]

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. [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]

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. [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, and myocardial infarction) and major bleeding when compared with warfarin. [4] [18] [19]

Current FDA 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.

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. [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 as idarucizumab 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 or esophagitis. 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]

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. [33]

Pharmacokinetics

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 the bioavailability 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 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. [38]

Dabigatran is available as dabigatran etexilate mesilate, formulated as the prodrug dabigatran etexilate. [4] [6] [38]

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). [39]

In 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. [40]

The 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 anticoagulants. [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 antidote idarucizumab, a humanized monoclonal antibody for intravenous administration, was developed, and received Food and Drug Administration (FDA) approval in 2015. [44]

Pradaxa received a Notice of Compliance (NOC) from Health 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 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. [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]

Related Research Articles

An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation where classical Vitamin K antagonist anticoagulants have minimal effect.

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.

<span class="mw-page-title-main">Warfarin</span> Anticoagulant medication

Warfarin, sold primarily under brand names Coumadin and Marevan, is an anticoagulant medication. While the drug is described as a "blood thinner", it does not reduce viscosity but rather prevents blood clots (thrombus) from forming (coagulating). Accordingly, it is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. Warfarin may sometimes be prescribed following ST-segment elevation myocardial infarctions (STEMI) and orthopedic surgery. It is usually taken by mouth, but may also be administered intravenously. It is a vitamin K antagonist.

<span class="mw-page-title-main">Ximelagatran</span> Anticoagulant

Ximelagatran is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity during trials, and discontinue its distribution in countries where the drug had been approved.

<span class="mw-page-title-main">Rivaroxaban</span> Anticoagulant drug

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth.

Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants by directly inhibiting the enzyme thrombin. Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replace heparin and warfarin in various clinical scenarios.

Ecarin is an enzyme that is derived from the venom of the Indian saw-scaled viper, Echis carinatus, It is the primary reagent in the Ecarin clotting time test.

The CHADS2 score and its updated version, the CHA2DS2-VASc score, are clinical prediction rules for estimating the risk of stroke in people with non-rheumatic atrial fibrillation (AF), a common and serious heart arrhythmia associated with thromboembolic stroke. Such a score is used to determine whether or not treatment is required with anticoagulation therapy or antiplatelet therapy, since AF can cause stasis of blood in the upper heart chambers, leading to the formation of a mural thrombus that can dislodge into the blood flow, reach the brain, cut off supply to the brain, and cause a stroke.

Direct factor Xa inhibitors (xabans) are anticoagulants, used to both treat and prevent blood clots in veins, and prevent stroke and embolism in people with atrial fibrillation (AF).

<span class="mw-page-title-main">Vitamin K antagonist</span> Group of substances

Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonize the action of vitamin K in the pharmacological sense, but rather the recycling of vitamin K. Vitamin K antagonists (VKAs) have been the mainstay of anticoagulation therapy for more than 50 years.

<span class="mw-page-title-main">Left atrial appendage occlusion</span> Medical treatment

Left atrial appendage occlusion (LAAO), also referred to as left atrial appendage closure (LAAC), is a procedure used to reduce the risk of blood clots from the left atrial appendage entering the bloodstream and causing a stroke in those with non-valvular atrial fibrillation.

The management of atrial fibrillation (AF) is focused on preventing temporary circulatory instability, stroke and other ischemic events. Control of heart rate and rhythm are principally used to achieve the former, while anticoagulation may be employed to decrease the risk of stroke. Within the context of stroke, the discipline may be referred to as stroke prevention in atrial fibrillation (SPAF). In emergencies, when circulatory collapse is imminent due to uncontrolled rapid heart rate, immediate cardioversion may be indicated.

<span class="mw-page-title-main">Edoxaban</span> Anticoagulant medication

Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Betrixaban</span> Chemical compound

Betrixaban is an oral anticoagulant drug which acts as a direct factor Xa inhibitor. Betrixaban is FDA approved for venous thrombosis prevention in adults hospitalized for an acute illness who are at risk for thromboembolic complications. Compared to other directly acting oral anticoagulants betrixaban has relatively low renal excretion and is not metabolized by CYP3A4.

<span class="mw-page-title-main">Apixaban</span> Anticoagulant medication

Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. It is used an alternative to warfarin to prevent blood clots following hip or knee replacement and in those with a history of prior clots. and does not require monitoring by blood tests or dietary restrictions. It is taken by mouth.

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

Andexanet alfa, sold under the brand name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding. It has not been found to be useful for other factor Xa inhibitors. It is given by injection into a vein.

The SAMe-TT2R2 score is a clinical prediction rule to predict the quality of vitamin K antagonist anticoagulation therapy as measured by time in therapeutic INR range (TTR) (VKA e.g. warfarin). It has been suggested that it can aid in the medical decision making between VKAs and new oral anticoagulant/non-VKA oral anticoagulant (NOAC e.g. dabigatran, rivaroxaban, apixaban or edoxaban) in patients with atrial fibrillation (AF). This score can be used with patients with ≥1 additional stroke risk factors using the CHA2DS2-VASc score, where oral anticoagulation is recommended or should be considered.

HAS-BLED is a scoring system developed to assess 1-year risk of major bleeding in people taking anticoagulants for atrial fibrillation (AF). It was developed in 2010 with data from 3,978 people in the Euro Heart Survey. Major bleeding is defined as being intracranial bleedings, hospitalization, hemoglobin decrease > 2 g/dL, and/or transfusion.

Idarucizumab, sold under the brand name Praxbind, is a monoclonal antibody used as a reversal agent for dabigatran.

References

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  3. ↑ "Summary of Product Characteristics (SmPC)". (emc). 15 September 2022. Archived from the original on 21 April 2023. Retrieved 13 November 2023.
  4. 1 2 3 4 5 6 7 "Pradaxa- dabigatran etexilate mesylate capsule". DailyMed. 6 July 2020. Archived from the original on 28 June 2021. Retrieved 13 November 2020.
  5. ↑ "Pradaxa EPAR". European Medicines Agency. 22 March 2023. Archived from the original on 5 June 2023. Retrieved 13 November 2023.
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  28. 1 2 Hijazi 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. PMID   24323795.
  29. ↑ 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. PMID   37380555.
  30. ↑ 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. PMID   26102078. S2CID   2601542.
  31. ↑ Bytzer P, Connolly SJ, Yang S, Ezekowitz M, Formella S, Reilly PA, et al. (March 2013). "Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial". Clinical Gastroenterology and Hepatology. 11 (3): 246–252.e5. doi: 10.1016/j.cgh.2012.10.021 . PMID   23103906.
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