Rates of hemorrhage during warfarin therapy for atrial fibrillation

I read with interest, the CMAJ early release article "Rates of hemorrhage during warfarin therapy for atrial fibrillation" (November 26, 2012) by Gomes et al. It is of great importance as it is Canadian data, a huge sample size (125,195 patients) and represents the real world. The ICH rate in this study is 0.2% over 5 years for warfarin, including all comers and the warfarin initiation period (first 30 days) during which the ICH rate was 0.4% (personal communication with the author). This rate of 0.2% accurately reflects the management of warfarin in Ontario over a 13 year period (mean 5 years).

To put the ICH rate in perspective, I have attached the following list showing comparative ICH rates in each of the NOAC trials (RE-LY - 44 countries, Rocket AF - 45 countries, Aristotle - 39 countries and Sportif V - US and Canada only). None beats warfarin as managed in Ontario.

Warfarin (Ontario) Real World 0.2% - Tara Gomes et al, Dabigatran 110 mg (RE-LY) 0.23%, Ximelegatran (Sportif V) 0.23%, Dabigatran 150 mg (RE-LY) 0.3%, Warfarin (Sportif V) 0.3%, Apixaban (Aristotle) 0.33%, Rivaroxaban (Rocket AF) 0.5%, Warfarin (Rocket AF) 0.7%, Warfarin (RE-LY) 0.74%, Warfarin (Aristotle) 0.8%.

The bottom line: The NOACs have been promoted heavily on the basis of a much lower rate of ICH than warfarin. We now know that this is clearly not true for Ontario (and likely Canada as a whole - more data required) in the real world. The reason for the disparity is trial bias based on the NOAC trials using 39-45 countries except for Sportif V (North American trial). In these trials most of the countries manage warfarin poorly compared to Canada (e.g. Canada ranked 8th out of 44 countries in RE-LY).

This demonstrates the fallacy in using international data to come to local conclusions (internal validity issue) in situations where the quality of healthcare systems is a pivotal factor. Physicians and consumers need to know that higher ICH rates with warfarin vs. NOAC trial data do not exist in Ontario in the real world at present.

If the ICH rates do not hold up, it is highly unlikely that the primary end-points in the pivotal NOAC trials will hold up either, as stroke and systemic embolism includes hemorrhagic stroke (a component of ICH). Further analysis is required.

Of additional note is a December 18, 2012 Australian Ministry of Health report on anticoagulation management noting "that patients would benefit greatly if barriers to the use of existing therapies such as warfarin were dealt with" (Hon Tanya Plibersek MP, Minister for Health, Australia - Media Release).

Quo vadis?

1. The current 2012 CCS CPG needs to be reconsidered as the new evidence (relatively low rates of ICH with warfarin) no longer supports the earlier assumptions and recommendations.

2. We need to recognize that some international studies cannot rationally drive national CPGs in Canada. This is true where the trial results and conclusions are directly dependent upon the quality of the health care system managing the therapy and there is significant performance variability across the participating systems.

3. It is possible to improve warfarin therapy in Canada through the use of computer decision support software and INR point of care testing. Perhaps, we should follow Australia's lead and deal with the "barriers" to the use of warfarin in our country. We have the tools to significantly raise our performance. We need the will and support to implement their use.

4. It is time to embrace the routine measurement of warfarin management performance through the use of real time INR average time in therapeutic range (TTR) measurements. TTR is the gold standard for measuring the quality of warfarin management and can only be readily measured using computer software. All warfarin managers (self testing patients and healthcare professionals alike) need to have access to this technology, in order to properly measure the quality of warfarin dosing performance and to reduce the incidence of strokes and hemorrhages in Canada.

Conflict of Interest:

Dr. Trusler is VP of INR Online Canada Ltd., a company that develops a computer decision support tool for warfarin management.