Warfarin Institute of America

DEDICATED TO YOUR HEALTH SINCE 2000

DABIGATRAN (Pradaxa), A POSSIBLE REPLACEMENT FOR WARFARIN (Coumadin, Jantoven)

PLEASE NOTE THAT THE INFORMATION ON THIS PAGE IS EVOLVING RAPIDLY.  IT IS WRITTEN IN ROUGHLY REVERSE CHRONOLOGICAL ORDER.

On March 27, 2008 the European Union approved the use of Dabigatran for clot prevention after Total Hip Replacement and Total Knee Replacement Surgery

This is a press release from Boehringer Ingelheim

    The following was written by Adrienne Light, Doctor of Pharmacy Candidate at the University of Colorado at Denver and Health Sciences Center.

It is written in the form that would be used if a hospital were to consider adding it to their formulary (a list of medications used in that hospital).  It is current as of October 27, 2007.

GENERIC NAME:                                DABIGATRAN

PROPRIETARY NAME:                       PRADAXA

APPROVAL RATING:                         Currently undergoing phase III trials

THERAPEUTIC CLASS:                      ANTICOAGULANT

SIMILAR DRUGS:                              warfarin and enoxaparin

Indications:  Currently under investigation for the short-term prevention of venous thromboembolism (VTE) after orthopedic surgery, longer term VTE prophylaxis, stroke prophylaxis in patients with atrial fibrillation, and the acute treatment of VTE.¹

Table 1:  Comparison of FDA-Approved Indications for anticoagulant therapy: ^1,2

Clinical Pharmacology:  Dabigatran is the active moiety of the orally bioavailable prodrug dabigatran etexilate.  Dabigatran is a direct thrombin inhibitor.  By binding directly to exosite 1 on thrombin, a site specific for fibrin, dabigatran prevents cleavage of fibrinogen to fibrin to block the final step of the coagulation cascade and thrombus development.  Unlike heparin, dabigatran reversibly inhibits fibrin-bound thrombin as well as free circulating fibrin.^1,2,3

Figure courtesy of http://www.images.google.com 

The onset of action of dabigatran is within one hour of dosing and the anticoagulant effects parallel plasma concentration.  Twelve hours after a dose approximately 50% of the drug is gone and 75% is excreted within 24 hours of the last dose.⁴

Pharmacokinetics:  Dabigatran etexilate is rapidly absorbed with peak plasma concentrations 2 to 3 hours after an oral dose.  Oral bioavailability is low, averaging 6.5% Administration with food  delays time to peak concentration.  Dabigatran is 25% to 30% protein bound.  Steady state conditions are reached within 3 days with multiple dosing.^4,5 

The average terminal elimination half-life is 15 hours.  Dabigatran is excreted unchanged via the kidneys (~80%).  The remainder undergoes conjugation with glucuronic acid to form acylglucuronides which are excreted via the bile.  These conjugates are pharmacologically active and demonstrate almost identical properties to free, nonconjugated dabigatran.^4,6 

Subjects with poor renal function (crcl <50ml/min) may have prolonged excretion rates and elevated plasma concentrations of dabigatran. Dabigatran is dialyzable.  Pharmacokinetic studies have not been performed in the pediatric or elderly population.⁶

Pharmacodynamics:  Dabigatran exhibits dose-dependent increases in mean aPTT prolongation, INR, TT, and ECT values, and a close correlation between prolongation of blood coagulation assays and dabigatran plasma concentrations.  Variability in the coagulation parameters is low with interindividual coefficient of variation below 30%.⁴

Monitoring:  Dabigatran is not a vitamin K antagonist, thus in clinical trials the anticoagulation effect of dabigatran is not routinely monitored. 

INRs should not be used as a measure of the anticoagulant effect of dabigatran.  Dabigatran effects on INR are variable and cannot be predicted.  Under controlled conditions therapeutic concentrations of dabigatran have resulted in modest elevations of INR in healthy subjects.⁶ 

Activated partial thromboplastin time (aPTT) can provide a qualitative indication of anticoagulant therapy.  aPTT prolongation is linearly related to the square root of the plasma concentration which  should not be used for a for precise quantification of effect.⁴ 

Ecarin clotting time (ECT) is a specific test that shows a close linear correlation with the plasma concentrations of dabigatran and more sensitive and precise than aPTT , however is not generally available in most hospital laboratories.⁴ 

Thrombin Time (TT) is very sensitive to dabigatran  and increases in direct proportion to dabigatran plasma concentration.  Under control conditions a TT ratio (versus controls) of 10-20 indicate therapeutic plasma concentrations of dabigatran.  However at this time TT assays have not been standardized.^4,6

Table 2:  Comparison of the Pharmacokinetic Parameters of  anticoagulant therapies ^1,2,3

Comparative Efficacy: Dabigatran is undergoing phase III trials to determine comparative safety and efficacy against warfarin and enoxaparin.  A pooled analysis of 7 trials under the name RE-VOLUTION has shown efficacy and safety in the prevention of and treatment of VTE in 27,000 patients worldwide.⁷  The analysis includes 2 randomized trials focused on DVT prevention following total knee replacement, namely the RE-MODEL and RE-MOBILIZE trials and one trial focused on DVT prevention following total hip replacement called RE-NOVATE.  The REMODEL trial included 2,076 patients in Europe, South Africa and Australia, undergoing total knee replacement. Patients were randomized to dabagitran at either 150 mg or 220 mg once daily, with half of the assigned dose being given on the day of surgery, one to four hours post-operatively, or to Lovenox at 40 mg once-daily by subcutaneous injection, beginning 12 hours before the start of surgery. Patients were treated for six to 10 days, and were followed up for three months after surgery.  The results of the study demonstrated that once daily doses of both 150mg and 229mg of dabigatran are as effective and safe as once daily 40mg enoxaparin for preventing VTE and all-cause mortality following total knee replacement.  In the safety analysis, they found that were no significant differences in major bleeding rates in 1.3% of patients on dabigatran at 150 mg, 1.5% on dabigatran at 220 mg, and 1.3% on enoxaparin.^7,9 

                                                    RE-MODEL Results⁹

The RE-MOBILIZE was very similar to the RE-MODEL trial.  It included 2,176 patients in North America undergoing total knee replacement.  Patients were randomized to dabagitran at either 150 mg or 229 mg once daily, or to Lovenox at 30 mg twice daily by subcutaneous injection.  The primary endpoint of a composite of total VTE, and all cause mortality was not achieved.  The results were concluded to be due to the incidence of asymptomatic DVT detected at the end of therapy.  However, major VTE events occurred at similar rates across all treatment groups.  The incidence of major bleeding events was not significantly different between groups.^7,8 The RE-NOVATE trial involved 3494 patients in Europe, South Africa, and Australia undergoing total hip replacement.¹⁰ Patients were randomized to receive 150mg or 220mg of dabigatran once daily or enoxaparin 40mg once daily by subcutaneous injection started 12 hours  before surgery.  The primary efficacy outcome was VTE and death from all causes.  The results determined that both doses of dabigatran were non-inferior to enoxaparin.  There was no significant difference in major bleeding with either dose of dabigatran compared to enoxaparin or in frequency of increase in liver enzymes. 

There are currently two studies investigating dabigatrran for acute treatment and secondary prevention of venous thromboembolism.  The RE-COVER study aims to demonstrate non-inferiority of dabigatran compared with warfarin in 2,550 patients with acute symptomatic VTE.   The RE-MEDY study is attempting to compare dabigatran with warfarin in secondary prevention of symptomatic VTE.  Both studies are expected to conclude by the end of 2009.⁸

The use of dabigatran for stroke prevention in patients with atrial fibrillation is also currently being investigated.  The PETRO study was a phase II, randomized 3 month comparison of dabigatran with warfarin in 502 patients with atrial fibrillation and additional risk factors for thromboembolism including hypertension, diabetes mellitus, congestive heart failure or left ventricular dysfunction, previous ischemic stroke or transient ischemic attack, or age >75 years.⁵  Patients were randomized to dabigatran 50mg, 150mg, or 300mg twice daily with or without aspirin 81mg or 325mg daily, versus warfarin INR 2-3 for a total of 12 weeks of treatment.  Main study endpoints were changes in D-dimer and thrombotic and bleeding events.  Before the end of the study patients on dabigatran the 300mg dose taking aspirin were to discontinue the aspirin due to 4 reports of major bleeding.  The results of the study showed that at 150mg twice daily of dabigatran there were no thrombotic events or change in D-dimer.  Warfarin INR 2-3

demonstrated the same results.  Major or relevant bleeding occurred in 8% of patient on dabigatran 150mg bid and 6% of warfarin patients.  Patients receiving 50mg twice daily of dabigatran had a higher stroke rate than warfarin and both of the other doses of dabigatran.  The 300mg twice daily dose of dabigatran resulted in an 11% bleeding rate.  The PETRO study suggested that 150mg twice daily is an appropriate dose for further study in the prevention of stroke in high-risk patients with atrial fibrillation.   The RELY study is a phase III trial evaluating long-term anticoagulant therapy comparing the efficacy and safety of 150mg twice daily and 300mg once daily doses of dabigatran with warfarin for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.  Total enrollment for this study is targeted for 15,000 patients from 1,000 study centers worldwide.  It is expected to conclude by 2010.⁶ 

Contraindications, Warnings, and Precautions: Have not been established.  Exclusion criteria for the various studies involving dabigatran include: patients who are hypersensitive to any component of the product, those with severe renal dysfunction (crcl <30ml/min), history of acute intracranial disease, hemorrhagic stroke; major surgery, trauma, uncontrolled hypertension, or myocardial infarction in the past 3 months; gastrointestinal or urogenital bleeding, or ulcer disease in past 6 months; severe liver disease.  Caution patients with alanine or aspartate aminotransferase concentrations greater than two times the upper limit of normal or the use of long-acting non-steroidal anti-inflammatory drugs.^{4, 10} 

Safety and effectiveness in pediatric, geriatric, or pregnant patients have not been established.

Table 3:  Comparisons of Exclusion Criteria, Contraindications, and Precautions Associated with the Use of Anticoagulant therapy ^1,2,4,10

Adverse Reactions:  Dabigatran is well tolerated after oral doses of up to 600mg daily divided.  Adverse events occurring in at least 3% of patients included; nausea, vomiting, constipation, pyrexia, wound secretion, hypotension, insomnia, peripheral edema, anemia, dizziness, DVT, diarrhea, and headache.  Moderate increases in alanine transferase of more than three times the upper limit of normal has a 2% frequency after 12 months.  Hemorrhage occurs rarely in 1% of patients^.4,10

Drug Interactions:  Concomitant use of aspirin, other platelet inhibitors, and NSAIDs significantly increase the risk of bleeding.  Co-administration with pantoprazole decreases the AUC of dabigatran by 30%.  Dabigatran does not alter the metabolism of drugs that are substrates of the major CYP isoenzymes CYP2C9 and 3A4 and does not affect the drug efflux transporter p-glycoprotein.  Dabigatran is not metabolized by and does not induce or inhibit cytochrome P-450 drug metabolizing enzymes.

Dosing:  Based upon the results of the RE-MODEL study, 150mg or 220mg po once daily appear to be effective for preventing venous thromboembolism after orthopedic surgery.   The PETRO  study showed acceptable safety and efficacy at 150mg po twice daily for the prevention of embolic and thrombotic events in patients with chronic atrial fibrillation. An ongoing Phase III trials (RE-COVER and RE-MEDY) in the acute treatment of VTE and for long-term prevention of secondary VTE are comparing dabigatran 150mpo twice daily to adjusted dose warfarin (goal INR 2-3).^4,6,10

Table 4:  Comparative Doses of Anticoagulant Therapies ^1,2,4,6

Product Availability:  Dabigatran is currently in Phase III trials.   FDA approval is pending for 2010.

Table 5:  Available Dosage Forms of Anticoagulant Therapies ^1,2

Conclusion:  Dabigatran specifically and reversibly inhibits thrombin.  It is a promising novel, oral anticoagulant with several advantages over warfarin and enoxaparin.  Dabigatran has a predictable pharmacokinetic profile, rapid onset of action, wide therapeutic window, is administered orally, does not require routine anticoagulation checks, frequent dose adjustments, or a consistent dietary regiment, and has few drug interactions.  Therefore, dabigatran has the potential to offer physicians and patients a simple and convenient alterative to the present anticoagulant options.^3,4,6

References:

1.  Gold Standard, Inc (accessed on [10/02/2007].  Clinical Pharmacology, [Dabigatran].  URL:http://clinicalpharmacology.com

2.  Micromedex® Healthcare Series, (electronic version).  Thomson Micromedex, Greenwood Village, Colorado, USA.  Available at http://0-www.thomsonhc.com.library.uchsc.edu:80 (cited: 10/23/07).212222

3.  Di Nisio M, Middelderp S, Buller H.  Direct Thrombin Inhibitors.  NEJM 2005; 353(26): 2827.

4.  Stangier J, Rathgen K, Stahle H, Gansser D, and Roth W.  The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects.  British Journal of Clinical Pharmacology 2007; 64(3): 292-303.

5.  PETRO-EX: Prevention of Embolic and Thrombotic Events in Patients with Persistent Atrial Fibrillation—Extension Trial.  Medscape.  Available at:  http://www.medscape.com/viewarticle/5363769.  Accessed on 10/15/2007.

6.  RELY.  Boehringer-Ingelheim U.S. corporate Website: Dabigatran.  Available at:  https://www.rely-trial.com/RELYWeb/resources/jsp/emergency/dabigatran_bg.jsp.  Accessed on 10/8/2007.

7.  Eriksson Bi, Dahl OE, van Dijk CN, et al.  A New Oral Anticoagulant, Dabigatran Etexilate, is effective and safe in preventing venous thromboembolism after total knee replacement surgery (The RE-MODEL Trial).  Blood (ASH Annual Meeting Abstracts) 2006; 108:  Abstract 573.

8.  Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism.  Clinical trials.gov.  Available at:  http://www.clinicaltrials.gov.  Accessed on 10/17/2007.

9.  Dabigatran as Good as Enoxaparin, but More Convenient.  Medscape.  Available at:  http://www.medscape.com/viewarticle/549204.  Accessed on 10/8/2007.

10.  Eriksson B, et al.  Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial.  The Lancet 2007; 370: 949-955.

©2007 Adrienne Light   Used By Permission

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Last updated May 7, 2008