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PRADAXA (DABAGATRAN), A New Anticoagulant for Stroke and Embolism Prevention

By Jennifer Freidman

2011 Doctor of Pharmacy Candidate, University of Florida

Atrial fibrillation currently affects about 2.2 million Americans. If left untreated it can cause embolism and stroke. The American Heart Association’s current recommendations for stroke prevention include anticoagulation therapy with warfarin being the agent of choice. Warfarin is a drug with a very narrow therapeutic range. It requires stringent monitoring which is costly. 

According to the study by Björholt et al, monitoring in the first three months of therapy costs approximately $895, in the first year the cost is over $2000, and in the second year of monitoring the cost is over $1100. Monitoring is necessary in an effort to avoid its most dangerous adverse effect, bleeding. Wouldn’t it be great if there was an alternative medication with fewer side effects and one that didn’t require monitoring? Well now, after over 50 years, there is. Pradaxa (dabigatran) gained FDA approval for prevention of stroke and embolism in  atrial fibrillation on October 19, 2010.

Pradaxa (dabigatran)

Dabigatran is a direct, reversible thrombin inhibitor which is FDA approved for prevention of stroke and systemic embolism in patients with atrial fibrillation. It does not require INR monitoring or dose adjustments. It does not have extensive food and drug interactions like warfarin does. Dabigatran’s half-life is also less than half of warfarin’s half-life. In addition to the benefit of many fewer adverse reactions, dabigatran has also been proven to be more effective at preventing embolism and stroke than warfarin as proven in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial which was an international, multicenter randomized noninferiority trial in which 18,113 patients with AF at increased risk for stroke (CHADS2 score ≥1 or equivalent) were randomly assigned to receive dabigatran, 110 mg twice daily (low dose); dabigatran, 150 mg twice daily (high dose); or adjusted-dose warfarin (18). After a median 2-year follow-up, the rates of stroke and systemic embolism were similar in the low-dose dabigatran and warfarin groups, but the low-dose dabigatran group had lower rates of intracranial hemorrhage (ICH) and major hemorrhage. Patients in the high-dose dabigatran group had lower rates of stroke, systemic embolism, and ICH compared with warfarin recipients, although rates of any major hemorrhage were similar. Studies, such as the one by Freeman et al, and Björholt et al, have also shown dabigatran to be a cost effective alternative to warfarin use.

Table 1: Comparative Properties of warfarin and dabigatran
                                                            Warfarin                                 Pradaxa (dabigatran)
 
Target
       Vitamin K epoxide
        reductase (VKORC1)
Thrombin
Prodrug
No
Yes
Bioavailability
>95%
~6%

T max

72-96 h

2 h
Half-life
40 h

14-17 h

Monitoring

INR – adjusted

Not needed

Administration

Once daily

Once or twice daily

Metabolism and elimination

CYP 2C9, 3A4, 1A2

80% renal, 20% fecal

Drug interactions

CYP 2C9, 1A2, and 3A4

P-gp inhibitors

 

Mechanism of Action

Dabigatran and its active metabolites are competitive, direct thrombin inhibitors that inhibit both free and clot bound thrombin. Dabigatran prevents thrombin-induced platelet aggregation.

Mechanism of Action
http://en.wikipedia.org/wiki/Coagulation
 
Pharmacokinetics

Dabigatran is an oral medication that is ~35% plasma protein bound with a 50-70 L volume of distribution. Dabigatran is a substrate of the efflux transporter P-glycoprotein, but is not an inhibitor, inducer, or substrate of CYP450 enzymes. Dabigatran is eliminated primarily in the urine. The half-life of dabigatran is 12-17 hours in healthy subjects. Dabigatran prolongs the activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and thrombin time (TT) at recommended therapeutic doses. In patients receiving the 150 mg dose in the RE-LY trial, the median trough aPTT was 52 (40-76) seconds and the median trough ECT was 63 (44-103) seconds. The INR may or may not be elevated in patients receiving dabigatran and is relatively insensitive to the activity of dabigatran.

Dosing

The recommended dose of dabigatran is 150mg twice daily in healthy individuals. The dose should be adjusted for those with renal impairment. In individuals with CrCl of 15-30 the dose should be reduced to 75mg twice daily. Dabigatran can be taken without regard to meals.

Adverse Reactions

In the RE-LY trial, major gastrointestinal bleeding was more prevalent in patients taking dabigatran than patients taking warfarin. The most common adverse reactions were dyspepsia (including abdominal pain, upper abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer). These occurred more commonly in patients taking dabigatran (35%) when compared to warfarin (24%).

Adverse Reactions

**In the RE-LY trial, dabigatran 150 mg was proven to be a more effective treatment in preventing stroke and embolism than warfarin.

RE-LY_Trial
 

Cost Effectiveness

While warfarin is a generic medication at generally low cost, the necessary monitoring and subsequent dose-adjusting result in higher costs. Treating complications from over and under-coagulation also contribute to higher costs associated with warfarin therapy. Multiple strategies to reduce costs and improve effectiveness in warfarin-treated patients, including genotype-guided warfarin dosing and patient self-testing of INR, have been evaluated. Results to date suggest that these strategies are not cost-effective for the typical patient. Pradaxa has been proven to be cost effective even though it is a brand medication which costs more initially, it does not carry with it the additional monitoring costs nor does it require dose adjusting.

Conclusion

In conclusion, Pradaxa (dabigatran) has been proven, in the RE-LY trial, to be a more effective alternative to warfarin in preventing stroke and systemic embolism. Pradaxa does not have the extensive dietary and drug interactions that warfarin does. Pradaxa has also been proven to be a cost effective alternative to warfarin therapy in atrial fibrillation patients to prevent stroke and embolism.

References
  1. “Atrial Fibrilation.” AHA (2011): n. pag. Web. 09 Feb 2011.
  2. Björholt, Ingela. “The cost of monitoring warfarin in patients with chronic atrial fibrillation in primary care in Sweden.” BMC Family Practice 8.6 (2007): n. pag. Web. 10 Feb 2011.
  3. Clinical Pharmacology. Warfarin and Pradaxa. Accessed 09 February 2011.
  4. Freeman, JV. “Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation…” Annals of Internal Medicine 154.1 (2011): 1-11. Web. 11 Feb 2011.
  5. “Pradaxa.” Official Pradaxa homepage. N.p., 2011. Web. 11 Feb 2011.
  6. “Warfarin.” Wikipedia. 26 Jan 2011.
  7. Wood, Shelley. “FDA approves dabigatran for stroke prevention, embolism, in AF patients.” Arrhythmia & EP October 20, 2010: n. pag. Web. 08 February 2011.
 
(c) Diabetes in Control, Inc. 2011