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dabigatran

Dabigatran

Dabigatran is a direct thrombin inhibitor,oral anticoagulants of the non vitamin K antagonist group.

It is a direct-acting medication that are selective for one specific coagulation factor, either thrombin (IIa) or activated factor X (Xa).

Dabigatran a direct inhibitor of factor IIa and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa), have been used for at least 5 years but possibly 10 years. Unlike traditional vitamin K antagonists (VKAs), which prevent the coagulation process by suppressing the synthesis of vitamin K-dependent factors, NOACs directly inhibit key proteases (factors IIa and Xa). The important indications of these drugs are the prevention and treatment of deep vein thrombosis and pulmonary embolisms, and the prevention of atherothrombotic events in the heart and brain of patients with acute coronary syndrome and atrial fibrillation. They are not fixed, and dose-various strengths are available. Most studies have reported that more advantages than disadvantages for NOACs when compared with VKAs, with the most important advantages of NOACs including safety issues (ie, a lower incidence of major bleeding), convenience of use, minor drug and food interactions, a wide therapeutic window, and no need for laboratory monitoring. Nonetheless, there are some conditions for which VKAs remain the drug of choice. Based on the available data, we can conclude that NOACs have greater advantages and fewer disadvantages compared with VKAs. New studies are required to further assess the efficacy of NOACs 1).

Dabigatran (Pradaxa in Australia, Canada, Europe and USA, Prazaxa in Japan) is an oral anticoagulation from the class of the direct thrombin inhibitors.

It was developed by the pharmaceutical company Boehringer Ingelheim.

Monitoring

The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available.

A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran.

Indications

It is being studied for various clinical indications and in some cases it offers an alternative to warfarin as the preferred orally administered anticoagulant since it does not require frequent blood tests for international normalized ratio (INR) monitoring while offering similar results in terms of efficacy.

Dabigatran is the first oral anticoagulant approved by the Food and Drug Administration for stroke prevention in non-valvular AF, more than 50 years after warfarin was first approved. The drug has overcome many of the major shortcomings of warfarin, and more importantly has been proven to be comparable to warfarin at a dose of 110 mg two times daily and superior to warfarin at a dose of 150 mg two times daily in preventing stroke in patients with non-valvular AF 2).

Warfarin was associated with a higher stroke and ICH risk than dabigatran 3).

Complications

Dabigatran induces fewer hemorrhagic complications compared with warfarin. However, the natural history of dabigatran-related ICH remains unclear.

A experimental study of a rat ICH model indicates that dabigatran-related ICH may not increase the risk of delayed hematoma expansion 4).

Dabigatran-associated spontaneous acute cervical epidural hematoma 5).

Reversal

Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.)

In the event of bleeding, general support measures are recommended and if severe, the use of non-specific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa must be considered. A specific reversal agent (idarucizumab) is in development 6).

Andexanet alfa and aripazine are currently being evaluated in clinical trials 7) 8) 9).

Intracranial hemorrhage in patients taking anticoagulants and/or antiplatelets can have either a benign or malignant clinical course. All patients with intracranial hemorrhage taking dabigatran should be admitted for close neurological monitoring and serial imaging 10).

1)
Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag. 2015 Jun 24;11:967-77. doi: 10.2147/TCRM.S84210. eCollection 2015. Review. PubMed PMID: 26150723.
2)
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, et al. (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361: 1139–1151
3)
Ho CW, Ho MH, Chan PH, Hai JJ, Cheung E, Yeung CY, Lau KK, Chan KH, Lau CP, Lip GY, Leung GK, Tse HF, Siu CW. Ischemic stroke and intracranial hemorrhage with aspirin, dabigatran, and warfarin: impact of quality of anticoagulation control. Stroke. 2015 Jan;46(1):23-30. doi: 10.1161/STROKEAHA.114.006476. Epub 2014 Nov 18. PubMed PMID: 25406148.
4)
Tanoue S, Inamasu J, Yamada M, Toyama H, Hirose Y. Does dabigatran increase the risk of delayed hematoma expansion in a rat model of collagenase-induced intracerebral hemorrhage? J Stroke Cerebrovasc Dis. 2015 Feb;24(2):374-80. doi: 10.1016/j.jstrokecerebrovasdis.2014.09.010. Epub 2014 Nov 25. PubMed PMID: 25444028.
5)
Bamps S, Decramer T, Vandenbussche N, Verhamme P, Thijs V, Van Loon J, Theys T. Dabigatran-associated spontaneous acute cervical epidural hematoma. World Neurosurg. 2015 Feb;83(2):257-8. doi: 10.1016/j.wneu.2014.10.012. Epub 2014 Oct 16. PubMed PMID: 25463422.
6)
Enriquez A, Baranchuk A, Redfearn D, Simpson C, Abdollah H, Michael K. Dabigatran for the prevention and treatment of thromboembolic disorders. Expert Rev Cardiovasc Ther. 2015 Apr 5:1-12. [Epub ahead of print] PubMed PMID: 25843430.
7)
Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis. 2015 Jan 14. [Epub ahead of print] PubMed PMID: 25586208.
8)
Mo Y, Yam FK. Recent advances in the development of specific antidotes for target-specific oral anticoagulants. Pharmacotherapy. 2015 Feb;35(2):198-207. doi: 10.1002/phar.1532. Epub 2015 Feb 3. PubMed PMID: 25644580.
9)
Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis. 2015 Apr;39(3):395-402. doi: 10.1007/s11239-015-1167-9. PubMed PMID: 25586208.
10)
Wassef SN, Abel TJ, Grossbach A, Viljoen SV, Jackson AW, Howard MA 3rd, Greenlee JD. Traumatic intracranial hemorrhage in patients taking dabigatran: report of 3 cases and review of the literature. Neurosurgery. 2013 Aug;73(2):E368-73; discussion E373-4. doi: 10.1227/01.neu.0000430763.95349.5f. Review. PubMed PMID: 23670031.
dabigatran.txt · Last modified: 2015/12/13 12:42 (external edit)