Correspondence
Dabigatran versus Warfarin for Venous Thromboembolism
N Engl J Med 2010; 362:1050-1051March 18, 2010
- Article
To the Editor:
The article by Schulman et al. (Dec. 10 issue)1 shows that a fixed dose of the thrombin antagonist dabigatran is noninferior to warfarin in the treatment of acute venous thromboembolism. The authors specifically point out in the Abstract and Discussion sections that laboratory monitoring of dabigatran was dispensable, indicating that this is considered to be a major advantage of dabigatran. Although this may well be true, there are many indications that the fixed dose may not be ideal in all situations. For example, in an open-label study involving patients with atrial fibrillation in which dabigatran was shown to be noninferior to warfarin, dabigatran appeared to have increased effectiveness when administered in patients who weighed less than 50 kg or who had a creatinine clearance rate of less than 50 ml per minute.2 This finding was not significant, but it suggests that anticoagulation was (not unexpectedly) more intense in these subgroups and that treatment with dabigatran could be optimized by therapeutic drug monitoring. It is surprising that in the era of personalized medicine, this is apparently not nearly as appealing to physicians as the prospect of anticoagulation without laboratory monitoring. Why else would the authors stress this point so much?
Dirk Peetz, M.D.
Karl J. Lackner, M.D.
University Medical Center of the Johannes Gutenberg University, Mainz, Germany
lackner@zentrallabor.klinik. uni-mainz. de No potential conflict of interest relevant to this letter was reported.
2 References1
Schulman S ,Kearon C ,Kakkar AK , et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-2352
Full Text | Web of Science | Medline2
Connolly SJ ,Ezekowitz MD ,Yusuf S , et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151
Full Text | Web of Science | Medline
To the Editor:
Schulman et al. do not mention a major downside of oral direct thrombin inhibitors such as dabigatran: cost. More than 30 million outpatient prescriptions for warfarin are filled per year in the United States alone.1 The anticipated cost of dabigatran in the United States, as calculated on the basis of its cost in Canada, would be approximately $7,000 to $9,000 per patient-year (four to five times the cost of warfarin, despite the increased physician and laboratory costs required to monitor the international normalized ratio [INR]).2,3 As a hematologist who also happens to require lifelong anticoagulation, I am particularly sensitive to the burdens of monitoring vitamin K intake and frequent INR checks; their elimination would probably increase adherence to the drug regimen. Nevertheless, these lifestyle benefits do not justify the exorbitant cost of this new agent. If future trials can show that oral direct thrombin inhibitors are superior to warfarin and result in a true reduction in the risk of recurrent venous thromboembolism and subsequent rehospitalization, then a cost–benefit analysis may justify their use.
David T. Teachey, M.D.
Children's Hospital of Philadelphia, Philadelphia, PA
teacheyd@email.chop. edu No potential conflict of interest relevant to this letter was reported.
3 References1
Wysowski DK ,Nourjah P ,Swartz L . Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med 2007;167:1414-1419
CrossRef | Web of Science | Medline2
Report on new patented drug — Pradax. Ottawa: Patented Medicine Prices Review Board. (Accessed February 25, 2010, at http://www.pmprb-cepmb.gc.ca/cmfiles/pradax-e.pdf.)
3
Jonas DE, Bryant Shilliday B, Laundon WR, Pignone M. Patient time requirements of anticoagulation therapy with warfarin. Med Decis Making 2009 September 22 (Epub ahead of print).
Author/Editor Response
I agree with Peetz and Lackner that in certain situations it would be of interest to determine the drug level or a representative clotting time when a person is receiving dabigatran therapy. This could be helpful in deciding whether emergency surgery can be performed or has to be deferred. Additional analysis of data from the phase 3 studies of dabigatran should provide useful information in that respect. However, routine laboratory monitoring of dabigatran levels is not performed in the clinical trials, and the results show that as with most other drug therapies, routine monitoring is not necessary.1,2 A glance at the forest plots may suggest that the dose of dabigatran should be reduced for patients with a creatinine clearance between 30 and 50 ml per minute or with a body weight below 50 kg. However, the P values for interaction are between 0.4 and 0.9, and the confidence intervals for the risk estimates have substantial overlap.1,2 Although personalized medicine is of interest, further studies are required to define the optimal target level and to show any improvement in the ratio of risk to benefit when individual dose adjustments are made to maintain that level. After many decades of struggling with the high maintenance required for personalized treatment with warfarin, a major advantage of dabigatran is that routine monitoring is unnecessary.
The concern of Teachey is understandable. The price in Canada for a 75-mg capsule of dabigatran is $3.95, corresponding to an annual cost of $5,767 for the treatment of venous thromboembolism (150 mg twice daily). Currently, dabigatran is approved only in Canada, Europe, and some other countries for prophylaxis against venous thromboembolism after arthroplasty in the knee or hip, and its main competitor is low-molecular-weight heparin. The price may drop when the main competitor becomes warfarin for long-term indications. It should also be kept in mind that total direct and indirect costs for management of anticoagulation with warfarin far exceed the cost of the drug. In a recent study, the direct costs during the first year of anticoagulation with warfarin in primary care were calculated at Swedish krona 16,244, corresponding to U.S. $2,230. This does not include expenses to patients for travel to the laboratory, lost time from work, or an accompanying caregiver.3
Sam Schulman, M.D.
McMaster University, Hamilton, ON, Canada
schulms@mcmaster.ca Since publication of his article, the author reports no further potential conflict of interest.
3 References1
Connolly SJ ,Ezekowitz MD ,Yusuf S , et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151
Full Text | Web of Science | Medline2
Schulman S ,Kearon C ,Kakkar AK , et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-2352
Full Text | Web of Science | Medline3
Bjorholt I ,Andersson S ,Nilsson GH ,Krakau I . The cost of monitoring warfarin in patients with chronic atrial fibrillation in primary care in Sweden. BMC Fam Pract 2007;8:6-6
CrossRef | Web of Science | Medline
