Dabigatran and Bleeding

This page is due for an update… mostly because the reversal agent is now in general circulation and is very effective (Idarucizumab aka. Praxbind). Please bare with us while we update this series.

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

CCC Transfusion Series
Blood Products	Cryoprecipitate, Fresh Frozen Plasma (FFP), Platelets, Red Cells (RBCs) Concentrates: Prothrombinex, Factor VIIa, Fibrinogen Concentrate
Reversal	Rivaroxaban / Apixaban / Enoxaparin: Andexanet Alfa, Rivaroxaban and Bleeding Dabigatran: Idarucuzimab, Dabigatran and bleeding Heparin: Protamine Warfarin: Vitamin K / FFP / PTx, Warfarin Reversal, Warfarin Toxicity
Testing	Coagulation Studies, TEG / ROTEM (Thromboelastography), Platelet function assays
General Topics	Acute Coagulopathy of Trauma, Blood Bank, Blood conservation strategies, Blood Product Compatibilities, Blood transfusion risks, Disseminated Intravascular Coagulation, Massive blood loss, Massive transfusion protocol (MTP), Modifications to blood components,Procedures and Coagulopathy, Storage Lesions, TRALI, Transfusion Literature Summaries, Transfusion Reactions

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)