Dabigatran and Bleeding
Reviewed and revised 11 July 2014
OVERVIEW
- Dabigatran is a direct thrombin inhibitor
- It is viewed as a warfarin replacement
- It’s use is controversial because the management of bleeding complications is difficult and there is no definitive antidote
RATIONALE FOR DABIGATRAN USE
- predictable pharmacokinetics
- no cytochrome P450 interactions
- no monitoring
- simple bd dosing
- evidence from RE-LY trial of stroke prevention for non-valvular AF:
— mortality rate was lower in the dabigatran group than in the warfarin group (3.6 vs. 4.1 per 100 patient-years)
— Although major gastrointestinal bleeding events were more frequent in the dabigatran group than in the warfarin group (1.6 vs. 1.1 per 100 patient-years), the rate of intracranial bleeding events was lower for dabigatran than for warfarin (0.3 vs. 0.8 per 100 patient-years) - the large number of reported cases of bleeding associated with dabigatran following it’s release are a salient example of stimulated reporting (‘reports decrease over time’ aka Weber effect)
MECHANISM OF ACTION
- reversible competitive thrombin inhibitor
- blocks the last stages of the coagulation cascade: cleavage of fibrinogen into fibrin, activation of platelets, and stabilization of forming clots.
- dabigatran blocks both fibrin- and clot-bound thrombin – unlike heparin which inhibits only free thrombin
- aPTT and TT elevation give a qualitative measure of effect, but not quantitative – may not be high, but will be in overdose
DOSE
- PO dose = 150mg BD, 110mg BD (> 80 yrs)
INDICATIONS
- VTE prophylaxis in elective TKJR or THJR
- non-valvular atrial fibrillation with at least one additional risk factor for stroke
CONTRA-INDICATIONS
- bleeding diathesis
- falls risk
- renal failure
PHARMAKOKINETICS
A – inactive pro-drug dabigatran etexilate with good oral absorption, peak anticoagulant effect occurs 1 -3 hours after ingestion
D – low binding to plasma proteins and a moderate volume of distribution
M – progrdug metabolised to dabigatran rapidly; little further metabolism (few drug interactions)
E – renal excretion with half-life of ~12 hours (much higher if renal impairment: 28h if CrCl <30)
INTERACTIONS
- rifampicin decreases dabigatran levels
- dose reduction needed with some P-glycoprotein inhibitors (e.g. ketoconazole) but not others (e.g. quinidine, clarithromycin, amiodarone, and verapamil)
RISK ASSESSMENT
History
- time of last dose
- dose taken
- indication for rivaroxaban
Risk factors for adverse events with dabigatran include:
- Age >75 years
- Low body weight (<50kg)
- Moderate or severe renal impairment (Creatinine Clearance < 50mL/min)
Mild bleeding
- Local soft tissue hematomas or bleeding from minor wounds to non-life threatening regions
Moderate to severe bleeding
- Reduction in Hb of 20g/L
- Transfusion of 2 units of RBCs
- Bleeding into critical regions
- Intraocular
- Intracranial
- Intrapulmonary
- Pericardial space
- GI tract
- Retroperitoneum
- Peri or Intraspinal
- Major muscle group with resulting compartment syndrome.
Life-threatening bleeding
- uncontrolled progression of the above with worsening symptoms
- Reduction in Hb of 50 g/L
- Transfusion of 4 units of RBCs
- Circulatory shock
- Bleeding that requires surgical intervention
The above considerations should also take into account comorbidities and other situational factors
INVESTIGATIONS
In the patient with clinically relevant bleeding:
- FBC (Hb, platelets)
- Coagulation profile
- INR (unreliable)
- APTT (crude measure, but a normal APTT means it is unlikely that dabigatran is contributing to clinically significant bleeding)
- tests should still be done as there may be other contributors to a bleeding diathesis
- TCT (dilute thrombin clotting time assay, such as HEMOCLOT, is the most sensitive test for quantitative measurement of dabigatran effect)
- UEC, glucose, Ca
- Calcium level
- Blood group and hold or Cross match as clinically indicated.
MANAGEMENT
- stop Dabigatran
- assess severity (if mild just skip a dose)
- control source of haemorrhage
- do coagulation screen (APTT, TT)
- check time of last dose and discuss with Haematology
- correct co-existant bleeding diathesis e.g. platelets if < 80
- oral charcoal if ingested within 2 hours
- consider: FFP, prothrombinex 25-50IU/kg, FVIIa 100 mcg/kg
- haemodialysis (particularly if in renal failure) -> removes ~60% over 2-3 hours
VIDEO
From HQMEDED
References and Links
LITFL
Journal articles
- Bauer KA. Pros and cons of new oral anticoagulants. Hematology Am Soc Hematol Educ Program. 2013;2013:464-70. doi: 10.1182/asheducation-2013.1.464. PubMed PMID: 24319220. [Free Full Text]
- Berger R, Salhanick SD, Chase M, Ganetsky M. Hemorrhagic complications in emergency department patients who are receiving dabigatran compared with warfarin. Ann Emerg Med. 2013 Apr;61(4):475-9. doi: 10.1016/j.annemergmed.2013.02.008. PubMed PMID: 23522810.
- Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2011 Apr 5;123(13):1436-50. doi: 10.1161/CIRCULATIONAHA.110.004424. Review. PubMed PMID: 21464059. [Free Full Text]
- Redondo S, Martínez MP, Ramajo M, Navarro-Dorado J, Barez A, Tejerina T. Pharmacological basis and clinical evidence of dabigatran therapy. J Hematol Oncol. 2011 Dec 21;4:53. doi: 10.1186/1756-8722-4-53. Review. PubMed PMID: 22189016; PubMed Central PMCID: PMC3262761.
- Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med. 2013 Apr 4;368(14):1272-4. doi: 10.1056/NEJMp1302834. Epub 2013 Mar 13. PubMed PMID: 23484796. [Free Full Text]
- Tran H, Joseph J, Young L, McRae S, Curnow J, Nandurkar H, Wood P, McLintock C. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Intern Med J. 2014 Jun;44(6):525-36. doi: 10.1111/imj.12448. PubMed PMID: 24946813.
FOAM and web resources
- TPR — Dabigatran Toxicity: The Top 10 Questions (2012)