Pradaxa (Dabigatran Etexilate)

Manufacturer: Boehringer Ingelheim Pharmaceuticals, Inc FDA Approved Date: October 15, 2010

Pradaxa/dabigatran etexilate

Date despre medicament

Farmacologia
Dabigatran exetilate este un pro-medicament, care este convertit in vivo n dabigatran activ, un inhibitor reversibil, ce actioneaza direct asupra trombinei, care inhib att trombina liber cit i cea legat de fibrin. Inhib coagularea, prin prevenirea efectelor mediate de trombina, inclusiv scindarea fibrinogenului n monomeri de fibrin,ce activeaza factorii V, VIII, XI i XIII, i inhibarea trombinei-indusa de agregarea plachetara
http://online.lexi.com.libproxy.lib.unc.edu/crlsql/servlet/crlonline. Accessed on 10/29/2010

Pradaxa/dabigatran etexilate

Aplicatiile clinice
Indicatii: Prevenirea accidentului vascular cerebral embolic i sistemic la pacienii cu fibrilaie atrial nonvalvular

http://online.lexi.com.libproxy.lib.unc.edu/crlsql/servlet/crlonline. Accessed on 10/29/2010

Pradaxa/dabigatran etexilate

Aplicatii clinice
Contraindicatii
Hipersensibilitate severa(anafilaxie) la dabigatran sau la oricare dintre componentele sale Singerare patologica activa

http://online.lexi.com.libproxy.lib.unc.edu/crlsql/servlet/crlonline. Accessed on 10/29/2010

Pradaxa/dabigatran etexilate

Aplicatii clinice
Precautii
Pacienii cu factori de risc pentru sngerare Anticoagulante P-glycoprotein (p-gp) inductori / inhibitori Insuficienta hepatica Folosirea la pacientii cu insuficienta hepatica moderata Child-Pugh class B sau C Transaminazele hepatice crescute> 2 ori
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Pradaxa/dabigatran etexilate

Clinical Application
Warnings and Precautions Renal impairment
Use with caution in patients with severe renal impairment (Clcr 15-30ml/min) Use in patients with Clcr < 15 ml/min is not recommended due to insufficient evidence to support use

Use of dabigatran is contraindicated in severe renal impairment (Clcr < 30ml/min) in Canada labeling
http://online.lexi.com.libproxy.lib.unc.edu/crlsql/servlet/crlonline. Accessed on 10/29/2010

Pradaxa/dabigatran etexilate

Drug Facts

Bereznicki et al New antithrombotics for atrial fibrillation. Cardiovascular Therapeutics 2010 (28) 278286

Pradaxa/dabigatran etexilate

Drug Facts
Sarcina categoria : C

Lactatie: Excretia in laptele matern nu se cunoaste

Pradaxa/dabigatran etexilate

Drug Interactions
Drug Interaction P-glycoprotein inducer
Rifampin - AVOID combination with dabigatran

Drug-Food interactions
Food has no affect on the bioavailability of dabigatran but delays the time to peak concentrations by 2h

Pradaxa/dabigatran etexilate

Reactii adverse
Dispepsia(11.3) [5.8] Oboseala(6.6) [6.2] ameeal(8.3) [9.4] Dispnee(9.5) [9.7] Edeme periferice (7.9) [7.8] Diaree(6.5) [5.7]

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Pradaxa/dabigatran etexilate

Monitoring Parameters
Activated Partial Thromboplastin Time (aPTT): values >2.5 time control may indicate overanticoagulation Ecarin Clotting Test (ECT) if available Thrombin Time (TT) CBC with differential Bleeding

Pradaxa/dabigatran etexilate

Prescriptie
Dozare
Oral: 150mg de 2 ori pe zi
Insuficienta renala:
Clcr 15-30 mL/min : 75mg de 2 ori pe zi Clcr <15 mL/min: nu sunt recomandari

Insuficienta hepatica: nu necesita ajustare

Pradaxa/dabigatran etexilate

Prescription Information
Conversia pentru warfarin: -Se sisteaza administrarea de warfarin si se initiaza dabigatran cind INR < 2.0

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Pradaxa/dabigatran etexilate

Trial Information
Dabigatran versus Warfarin in Patients with Atrial Fibrillation
Objective To compare the safety and efficacy of dabigatran with warfarin for the prevention of stroke and systemic emboli
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Study Design:
Randomized Evaluation of Long Term anticoagulation Therapy (RE-LY)
International, multicenter randomized phase III noninferiority trial Blinded fashion: fixed doses of dabigatran 110mg and 150mg Unblinded fashion: adjusted dose warfarin 18,113 patients were enrolled in the study
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Inclusion Criteria
Patients with atrial fibrillation documented on electrocardiography at screening or within 6 months Have at least one of the following characteristics: Previous stroke or TIA Left ventricular ejection fraction of < 40% NYHA class II or higher heart failure symptoms within 6 months before screening Age 75 years Or age 65-74years plus DM, HTN, or CAD
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Exclusion criteria
Presence of severe heart-valve disorder Stroke within 14 days or severe stroke within 6 months before screening Condition that increased the risk of hemorrhage Clcr < 30 mL/min Active liver disease Pregnancy
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Intervention
Dabigatran was administered in a blinded fashion , in capsules containing either 110mg or 150mg of the drug to be taken twice daily Warfarin was administered in an unblinded fashion in tablets of 1, 3 or 5 mg and was adjusted locally to INR of 2.0 to 3.0 INR was measured at least monthly Treatment duration: 2 years
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Primary outcome:
stroke or systemic embolism

Primary safety outcome:

major hemorrhage

Secondary outcomes:
stroke or systemic embolism and death

Other outcomes:
MI, PE, TIA and hospitalization.
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Results:
Stroke occurred in 182 patients receiving 110mg of dabigatran (1.53% per year), 134 patients receiving 150mg of dabigatran (1.11% per year) and 199 patients receiving warfarin (1.69% per year). Both doses of dabigatran were non-inferior to warfarin (P<0.001) 150mg dose of dabigatran was superior to warfarin (P<0.001) Rates of hemorrhagic stroke were significantly lower in the group that received 150mg of dabigatran than warfarin group (P<0.001)
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Results
The rate of myocardial infarction was higher with both dabigatran groups than with warfarin group Rate of major bleeding of life-threatening bleeding were higher with warfarin than with either 110mg of dabigatran dose or 150mg dose of dabigatran. There was significantly higher rate of major gastrointestinal bleeding with dabigatran at the 150mg dose than with warfarin
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Conclusion
In patient with atrial fibrillation, dabigatran given at a dose of 110mg was associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150mg, as compared with warfarin , was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Strengths of the study
Size of the population studied Blinded comparison of dabigatran etexilate doses Comprehensive strategies to minimize ascertainment and reporting bias Blinded adjudication of outcomes Nearly complete (99.9%) follow-up ( only 20 patients were lost to follow up) Investigators were able to use low dose aspirin (<100mg/day) and the warfarin arm contained both patients who had taken aspirin and those who had not The control of anticoagulation achieved in patients treated with warfarin (time in therapeutic range 64%) was comparable to other large trials of warfarin
Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Pradaxa/dabigatran etexilate

Trial Information
Weaknesses of the trial
Selected group of patients, so the outcomes may not translate to everyone The rate of discontinuation is higher in dabigatran groups than in warfarin group

Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Should we use dabigatran based on this trial?

This trial showed that dabigatran 110mg bid is as effective as warfarin and dabigatran 150mg bid is superior to warfarin for the prevention of stroke in patient with atrial fibrillation As an alternative anticoagulant, dabigatran has its limitations and safety concerns
An excess of dyspepsia Gastrointestinal bleeding Myocardial infarction Potential for accumulation in the presence of renal dysfunction

Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51

Should we use dabigatran based on this trial?

Dabigatran has the advantage of a wide therapeutic window , but drug compliance may still influence its safety and efficacy The need of twice daily dosing of dabigatran may increase a nonadherence to the treatment No specific antidote yet to reverse the antithrombotic activity of dabigatran Safety and efficacy in patients with renal and hepatic impairment Safety and efficacy in patients at high risk of bleeding
Terry K W et al. Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data

Should we use dabigatran based on this trial?

It is important to determine whether or not selective thrombin inhibitors contributes to myocardial infarction .
Future studies are needed : RELY-ABLE study

Terry K W et al. Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data

Pradaxa/dabigatran etexilate

Summary
Pradaxa, dabigatran etexilate, is a direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin Dabigatran 150mg twice a day dosage showed superiority over warfarin in a- fib. RELY trial had shown dabigatran to be as effective as warfarin in the prevention of stroke Other indication : Postoperative thromboprophylaxis in patients who have undergone total hip or knee replacement procedures (Canadian labeling)

Pradaxa/dabigatran etexilate

Summary
No dosage adjustment for hepatic impairment (US labeling)

Usual adult dosing is 150mg twice daily however, patients with CrCl (15ml/min<Clcr<30ml/min) need dose reduction to 75mg twice daily Dabigatran at a dose of 150mg twice daily was associated with risk of myocardial infarction in patient with a-fib
Need for long term use study: RELY-ABLE trial

References
Pradaxa package insert. http://www.pradaxa.com/ Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USA Connoly S J et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. Bereznicki et al New antithrombotics for atrial fibrillation. Cardiovascular Therapeutics 2010;28:27886. Ma, T.K.W., et al., Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data,Pharmacology & Therapeutics 2010: 1-10 http://online.lexi.com.libproxy.lib.unc.edu/crlsql/servlet/crlonline. Accessed on 10/29/2010 Blech S, Ebner T, Ludwig-Schwellinger E, et al, The Metabolism and Disposition of The Oral Direct Thrombin Inhibitor, Dabigatran, in Humans, Drug Metab Dispos, 2008;36:386-99.