Bleeding risk higher with rivaroxaban than dabigatran for stroke prevention, head-to-head trial shows
BMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i5362 (Published 04 October 2016) Cite this as: BMJ 2016;355:i5362All rapid responses
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Dear Editors
As doctors around the world have come to believe the hype around NOACs (non-vitamin K oral anticoagulants) and pushed into prescribing these expensive drugs over warfarin because of "predictable pharmacokinetics", "less bleeding" and "no need to monitor with regular blood tests", the JAMA Internal Medicine's post-marketing trial reveals more uncertainty about what we think we know rather than confirming what we thought we should know.
So the authors have found "Patients with non-valvular atrial fibrillation treated with rivaroxaban for stroke prevention were more likely to experience both intracranial haemorrhage and major extracranial bleeding than those treated with dabigatran"; does that mean that dabigatran is safer to use than rivaroxaban?
Not necessarily so.
Let me remind fellow readers that The BMJ has been in the forefront in promoting awareness of issues with trials studying dabigatran.
Significant concerns has been raised with regard to how the manufacturer of dabigatran may have withheld some data in the RE-LY trial (Ref 1) , with the possibility that there may be bleeding issue far more than acknowledged, particularly with its "fickle pharmacokinetics" resulting in highly variable plasma concentrations (Ref 2) as well as the differences on how regulators in different continents manage this issue (Ref 3)
Furthermore there is evidence already published just in Th BMJ that the trials involving dabigatran vs warfarin may have underestimated major bleeding rates (Ref 4) even though it is possible that the risk of gastrointestinal bleeding related to novel oral anticoagulants (both dabigatran and rivaroxaban) was similar to that for warfarin (Ref 5) despite their touted safety profile.
Together with the known controversy with the ROCKET-AF trial with Rivaroxaban (Ref 6) in which serious allegations that a defective point of care device was used in the warfarin arm of the trial, which may have significantly affected the trial results, this is a timely reminder that post-marketing trials should always be done to authenticate company-sponsored trials used to support applications for FDA approval for use.
Even the monoclonal antibody idarucizumab, the antidote to dabigatran (both drugs made by Boehringer Ingelheim), comes with a certain caveat not widely known beneath the fanfare of its release in the US last year:
In the company-sponsored trial (Ref 7) the median time to the cessation of bleeding was 11.4 hours for those with overt, uncontrollable, or life-threatening bleeding that was judged by the treating clinician to require a reversal agent (Group A patients).
I hope that whatever "life-threatening bleed" is, 12 hours delay (before bleeding stops) is consistent with meaningful life.
In the same study the effect of reversal is complete for up to 24 hours. However they found "subsequent increases in dabigatran concentrations that occurred 12 hours after the administration of idarucizumab in 6 patients and 24 hours after the administration of idarucizumab in 16 patients were also evident by increases in the clotting times and may reflect the redistribution of extravascular dabigatran into the intravascular compartment."
Unless I am mistaken, in other words, the anticoagulation effect of dabigatran, which may take 2-4 days post cessation to be safe for significant bleeding or major surgery, may still relapse after 24 hours after the last dose of idarucizumab.
As we consider taking up new drugs based on recent evidence, it is important to double check the basis of treatment.
There are increasing evidence that we are OVERESTIMATING the risk of stroke from AF based on popular scoring methods like CHA2DS2-VASc.
Comparative Performance of ATRIA, CHADS2, and CHA2DS2-VASc Risk Scores Predicting Stroke in Patients With Atrial Fibrillation Results From a National Primary Care Database (Ref 8)
Comparison of the ATRIA, CHADS2, and CHA2DS2-VASc stroke risk scores in predicting ischaemic stroke in a large Swedish cohort of patients with atrial fibrillation (Ref 9)
GARFIELD-AF Score substantially superior to CHA2DS2-VASc (Ref 10)
Just like the story of Aladdin from Antoine Galland's Les Mille et Une Nuits (The Book of One Thousand and One Nights), there is always some cause for caution when there is a cry out to exchange "new lamps for old"; it is not to say that we should resist change and new ideas, but we should be more vigilant and careful to rely more than opinion leaders and published guidelines (even those funded by governments) to amass enough gasp of the data and the known unknowns, so as to assist patients to participate equally in a shared decision making about embarking onto a life-long treatment regimen, like anti-coagulation for atrial fibrillation.
Such is our duty as sentinels of health and disease in this fast moving world with overwhelming information load.
References:
1. http://www.bmj.com/content/349/bmj.g4670
2. http://www.bmj.com/content/349/bmj.g4681
3. http://www.bmj.com/content/349/bmj.g4517
4. http://www.bmj.com/content/353/bmj.i2607
5. http://www.bmj.com/content/350/bmj.h1857
6. http://www.bmj.com/content/352/bmj.i575
7. http://www.nejm.org/doi/full/10.1056/NEJMoa1502000#t=article
8. http://content.onlinejacc.org/article.aspx?articleid=2461789
9. http://eurheartj.oxfordjournals.org/content/early/2016/03/02/eurheartj.e...
10. https://www.radcliffecardiology.com/news-items/garfield-af-score-substan...
Competing interests: No competing interests
Re: Bleeding risk higher with rivaroxaban than dabigatran for stroke prevention, head-to-head trial shows
Dear Editor,
This news item may mislead the reader by describing the study as a head-to-head trial.
In fact, as stated in the original publication (1), it was a retrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older, enrolled in fee-for-service Medicare, and who initiated treatment with dabigatran or rivaroxaban from November 4, 2011, through June 30, 2014.
A report of a head-to-head trial of DOACs would be welcome news while another retrospective study on a database is much less so.
1. Graham DJ, Reichman ME, Wernecke M, et al. Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. JAMA Intern Med. Published online October 03, 2016. doi:10.1001/jamainternmed.2016.5954.
Competing interests: No competing interests