Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational studyBMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j4323 (Published 17 October 2017) Cite this as: BMJ 2017;359:j4323
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I note with interest the work of Jun et al in which they conducted a retrospective, propensity score matched cohort study to investigate the safety of direct oral anticoagulant (DOAC) use compared with warfarin use for the treatment of venous thromboembolism (VTE) (Ref 1).
However I am disappointed that they may have missed an opportunity to address the issue of cardiovascular events relating to the use of DOACs for VTE treatment.
DOACs has been documented to have significant risk of coronary events; this is often related to the use of Dabigatran for atrial fibrillation (Ref 2) and possibly other indications as well (Ref 3) although there are suggestion this effect may occur with other DOACs as well (Ref 4, 5).
Many other studies and re-analysis of various data attempted to dismiss this concerning finding, especially for Dabigatran, but the true effect of these drugs in coronary event risk are still uncertain.
Jun et al's retrospective study could have included the incidence of coronary events as one of the secondary outcomes, afterall the idea of "safety" of DOACs would and should go beyond simply the assessment of major bleeding or all cause mortality in the 90 days after cohort entry, in which a reasonable person would include the risk of myocardial infarction or other cardiovascular events as a valid safety indicator, particularly when this issue has been raised repeatedly.
This also brings another issue with the choices made in the study, specifically in the cut-off of 90 days after cohort entry while assessing outcome measurement. Although the authors may have hinted at the justification of this duration as "guideline recommended treatment of venous thromboembolism of at least 90 days", other landmark trials (used to support drug for FDA approval) had consistently used 6 months or longer as a therapeutic benchmark for VTE treatment (Ref 7,8,9) . Unless Jun et al can demonstrate in their cohort the risk of their measured outcomes linear over time rather than exponential gain, I cannot extrapolate their findings beyond 90 days and applicability in the practice of many clinicians worldwide adhering to recommendations of 6 months anticoagulation for VTE events.
Certainly I would expect the opportunity to consider and obtain data up to 6 months therapy would have been well within the capabilities of the research group, hence the surprise in limiting their studies to a duration which is possibly irrelevant or inapplicable to much of real world practice.
The issue of coronary event measure, and the 90 days post cohort entry cut-off for outcome measurement , compromised the relevance of this study research to an estimated 10 millions of people put on anticoagulation for VTE worldwide every year.
1. Jun Min, Lix Lisa M, Durand Madeleine, Dahl Matt, Paterson J Michael, Dormuth Colin R et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study BMJ 2017; 359 :j4323
2. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RELY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl JMed. 2010;363(19):1877]. N Engl JMed. 2009; 361(12):1139-1151.
3. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events. Arch Intern Med. 2012; Mar 12;172(5):397-402
4. Leo M. Stolk, Frank de Vries, Chiel Ebbelaar, Anthonius de Boer, Tom Schalekamp, Patrick Souverein, Arina Ten Cate-Hoek, Andrea M. Burden. Risk of myocardial infarction in patients with atrial fibrillation using vitamin K antagonists, aspirin or direct acting oral anticoagulants. Br J Clin Pharmacol. 2017 Mar 22
5. Artang R, Rome E, Nielsen JD, et al. Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors. Am J Cardiol. 2013; Dec 15;112(12):1973-9
6. Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in ‘real world’ patients with atrial fibrillation: A prospective nationwide cohort study. J Am Coll Cardiol. 2013 Jun 4;61(22):2264-73
7. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–2352.
8. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–2510
9. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.
Competing interests: No competing interests
In a recently published paper, Jun et al reported the results of a retrospective matched cohort study, investigating the safety of direct oral anticoagulant (DOAC) use compared with warfarin use in the first 90 days of treatment for venous thromboembolism. During this period, of the 59 525 participants, 3.3% had a major bleed while 1.7% died. The risk of major bleeding was similar for DOAC and warfarin use (pooled hazard ratio [HR]: 0.92; 95% confidence interval [CI]: 0.82 to 1.03). Similarly, no difference was found in the risk of death (pooled HR: 0.99; CI: 0.84 to 1.16) between DOACs and warfarin use. Reporting the incidence rates of major bleeding and all-cause mortality, the authors specified that 1967 (3.3%) patients had a major bleed, of whom 131 (6.7%), 758 (38.7%), and 1070 (54.6%) were due to an intracranial, gastrointestinal (GI), and other bleed, respectively. Bleeding rates at 30 days ranged between 0.2% and 2.9% for DOACs, and 0.2% and 2.9% for warfarin. Bleeding rates at 60 days ranged between 0.4% and 4.3% for DOACs, and 0.4% and 4.3% for warfarin. Describing HRs for major bleeding and all-cause mortality, the risk of major bleeding associated with DOAC use was similar to that with warfarin use (HR: 0.92; 95% CI: 0.82 to 1.03), with the direction of the association favouring DOACs.1
We would like to highlight some points useful to clinicians. It is well-known that therapy with oral anticoagulant is an independent risk factor for upper and lower GI bleeding.2,3 Importantly, Helicobacter pylori (H. pylori), a Gram-negative bacterium, whose natural habitat is the luminal surface of the gastric epithelium, is also an independent risk factor for gastroduodenal ulcers and associated bleeding.4 Hence, it seems reasonable to assume that H.pylori-infected individuals may be exposed to a greater risk for ulcer bleeding when oral anticoagulants are administered than uninfected subjects.5 Jun et al did not report details either about H.pylori-status of the included patients or about their use of proton pump inhibitors, a class of drugs employed to prevent GI bleeding. Since these parameters could influence the outcome and can confound the interpretation of the reported data, it would be important to know if the authors could enrich their work adding details on these.
1. Jun M, Lix LM, Durand M, et al. Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study. BMJ 2017;359:j4323 | doi: 10.1136/bmj.j4323
2. Holster IL, Valkhoff VE, Kuipers EJ, Tiwa ET. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 2013;145:105-12.
3. Lanas-Gimeno A, Lanas A. Risk of gastrointestinal bleeding during anticoagulant treatment. Expert Opin Drug Saf 2017;16:673-85.
4. Pellicano R, Ribaldone DG, Fagoonee S, Astegiano M, Saracco G, Mégraud F. A 2016 panorama of Helicobacter pylori infection: key messages for clinicians. Panminerva Med 2016;58:304-17.
5. Malfertheiner P, Mégraud F, O'Morain CA, et al. Management of Helicobacter pylori infection – The Maastricht V/Florence Consensus Report. Gut 2017;66:6-30.
Competing interests: No competing interests
Re: Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study
What would also be very interesting, in addition to the results presented in this study, is the bleeding and mortality associated with emergent surgical intervention (and morbidity caused by delayed surgery secondary to DOAC anticoagulation). Many patients are unaware that there is not always an immediate reversal agent for a DOAC, and on discovering this they choose to stay on Warfarin.
Competing interests: No competing interests