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Dabigatran vs. Warfarin in Atrial Fibrillation; Reluctant to Rely on RE-LY

Henry I. Bussey, Pharm.D., FCCP, FAHA
March, 2010

The recently published RE-LY study¹ and commentary² drew a lot of attention from various medical news services because the lower dose of dabigatran was "non-inferior" to warfarin and caused less bleeding; and the higher dose of dabigatran was more effective than warfarin without an increase in major bleeding. The overall results are presented in Table 1.

My own view is that once dabigatran is approved for treating atrial fibrillation, warfarin will continue to be the preferred treatment for reasons that can be grouped into two main categories listed below. It is likely that any safety or efficacy advantage of dabigatran is questionable while use of the drug presents several other potential risks (such as increased myocardial infarction, not-yet-identified drug interactions and adverse effects, and the inability to monitor or reverse the effects of this drug).

The two main categories of consideration:

1. New efficient methods of managing warfarin are emerging that may double the safety and efficacy of warfarin while substantially reducing the time and hassle of warfarin management.
   
   
2. Issues of study design and data analysis in the RE-LY study may well suggest that warfarin is less effective and more dangerous than is the case; and the same factors may not adequately define the dangers of using the new drug in "real world" clinical practice.

New efficient methods of warfarin management to double the safety and efficacy:

Our group³ and two others^4-6 have recently examined the potential of combining patient INR (International Normalized Ratio) self-testing with computer-based monitoring and management. The INR time in the therapeutic range (TTR) improved to a median of 74% in one study^5-6 and approximately 80% in the other two trials.^3-4 Further, the two trials that measured clinician time found that less than 10 minutes were required to manage 4 "visits" per patient per month.^4-6 Such improved INR control has been associated with a 50% reduction in stroke, major bleeding, death, and myocardial infarction (MI) in patients with atrial fibrillation (Tables 2 and 3).^7,8

Issues of RE-LY study design and data analysis; and "real world" considerations

The INR control was relatively poor (64% time in the therapeutic range, "TTR") but, probably more importantly, the relationship between events and INR control was not reported. It is well established that the incidence of adverse events increases exponentially as the INR goes below or above certain extreme values. Therefore, it would be very useful to know what the INR values were when events occurred. Similarly, it would be very useful to know the distribution of the INR control of individual patients.

Recently Veeger and colleagues⁷ examined the importance of knowing the INR time in the therapeutic range (TTR) for individual patients (ITTR). As illustrated in Table 2, the lowest quartile of patients based on ITTR had very poor INR control and accounted for more than half of all major events. Similarly, in the report by White, et al.⁸ the bottom third of patients (based on ITTR) had twice the rate of each major event. The combined major event rates, therefore, were 8.2%/yr and 11.53%/yr in the bottom groups in the Veeger and White reports, respectively. Such high rates clearly inflate the event rates for the overall group and appear to be so high that one may question whether anticoagulation should be continued if the ITTR cannot be improved in these patients. Obviously, we do not know what the ITTR values were for patients in the RE-LY study or how such poor control may have affected event rates.

Stroke rates and classification warrant close scrutiny in that the difference in stroke rates was rather modest at < 0.7%/yr and included hemorrhagic strokes. If one focuses on the primary efficacy endpoint of ischemic stroke, one finds that the difference was less impressive with rates ranging from 1.01 to 1.3%/yr.

Aspirin likely increased the rate of warfarin-induced bleeding while reducing the rate of dabigatran-induced myocardial infarction (MI). Aspirin at any dose substantially increases the risk of major bleeding in warfarin-treated patients. Dabigatran was associated with an increased MI rate in this trial just as was seen with another direct thrombin inhibitor (DTI), ximelagatran. Although ximelagatran was found to increase the rate of MI, the ESTEEM trial demonstrated that combining that DTI with aspirin resulted in a reduced MI rate.⁹ Therefore, since 40% of patients were taking aspirin at baseline in RE-LY and 20% had "continuous use" throughout the study, it is likely that the extensive use of aspirin increased bleeding with warfarin while reducing the MI rate with dabigatran.

Intention-to-treat analysis makes it difficult to separate out the effect of the drugs from other factors. Discontinuation of both drugs was relatively high with 10% and 17% of warfarin-treated patients stopping warfarin at 1 and 2 years, respectively. The rates of discontinuation of dabigatran were higher at 15% and 21% at 1 and 2 years, respectively. Any events that occurred after discontinuation or, perhaps, after crossing over to the other therapy would confound attempts to assess the actual effect of the medications.

Changes in inclusion criteria and sample size during the study raise other considerations. The study protocol was modified to enroll 50% of patients who were new to warfarin and to expand the total enrollment to 18,000 patients. It is probable that the change to include more patients new to warfarin was prompted by the findings of the ACTIVE W trial in which patients new to warfarin had a higher event rate.¹⁰ Although some might view such a change as "stacking the deck" against warfarin, there was no statistically different rate of events in this subgroup of patients. One has to wonder, however, what the study results would have been had these two changes not been implemented.

Use of dabigatran in clinical "real world" practice may raise several other issues:

1. Non-adherence is likely to undermine therapeutic outcomes in "real world" practice because of a reduction in patient adherence outside of a controlled trial. Since there is no laboratory test to monitor the effect of dabigatran, clinicians will not have a way to objectively assess and respond to instances of non-adherence. If the increased rate of MI is due to a "rebound" effect of thrombin with missed doses of dabigatran, as some have theorized, then sporadic adherence may result in a higher MI rate.
   
2. No readily available reversal agent means that patients who develop a bleeding complication will not have a method of reversing the effects of dabigatran.
   
3. Drug interactions will be a concern. Although identified drug interactions are few at this point, it can be anticipated that at least some additional medications will interact with dabigatran in some patients with more wide-spread use. But, it will be difficult to identify or study such potential drug interactions because there is no blood test to measure the effect of the drug. The lack of such a test will also complicate adjusting therapy when known drug interactions are encountered.
   
4. Safety vs efficacy at extremes of body weight may be a problem when trying to use a limited number of dosing regimens which can not be individualized with a laboratory test.
   
5. Renal and/or hepatic disease may create similar dosing concerns as mentioned above for patients at extremes of body weight.
   
6. Altered absorption has not been a big problem thus far, but the rather limited absorption of dabigatran creates an opportunity for other drugs or gastrointestinal conditions to either reduce the amount of drug absorbed or, perhaps, cause "dose dumping" into the blood stream.
   
7. Other adverse effects may be identified as wide-spread use occurs
   
8. Cost is likely to be high and, perhaps, justifiably so considering the huge amount of research that has gone into bringing this drug to market.
   
9. Medico-legal issues may arise when major bleeding occurs with this drug that cannot be monitored or reversed.

References:

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-1151.
   
   
2. Gage BF. Can we rely on RE-LY? N Engl J Med 2009; 361:1200-1202.
   
   
3. Bussey HI, Walker MB, Bussey-Smith KL, Frei CR. Interim analysis of triple intervention to improve International Normalized Ratio (INR) in warfarin-treated patients. Abstract #PP-MO-469 International Society of Thrombosis and Haemostasis Congress, July, 2009.
   
   
4. Harper PL and Pollock D. Anticoagulant Self-Management using near patient testing and decision support software provided via an Internet Website improved anticoagulant control in patients on long-term warfarin. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 1278.
   
   
5. Ryan F, Byrne S, O'Shea S. Randomized controlled trial of supervised patient self-testing of warfarin therapy using an Internet based expert system. Blood (ASH Annual Meeting Abstracts) 2008; 112: Abstract 879.
   
   
6. Ryan F, Byrne S, O’Shea S. Randomized controlled trial of supervised patient self-testing of warfarin therapy using an Internet-based expert system. J Thromb Haemost 2009; 7:1284-1290.
   
   
7. Veeger NJGM, Piersma-Wichers M, Hillege HL, Crijns HCGM, van der Meer J. Early detection of patients with poor response to vitamin K antagonists: The clinical impact of individual time within target range in patients with heart disease. J Thromb Haemost 2006; 4:1625-1627.
   
   
8. White HD, Gruber M, Feyzi J, Kaatz S, et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulation control; results from SPORTIF III and V. Arch Intern Med 2007; 167:239-245.
   
   
9. Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: The ESTEEM randomized controlled trial. Lancet 2003; 362:789-797.
   
   
10. ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for prevention of vascular events (ACTIVE W): a randomized controlled trial. Lancet 2006; 367:1903-1912.

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