New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding: A Systematic Review and Meta-analysis.

Holster IL, Valkhoff VE, Kuipers EJ, Tjwa ET
Gastroenterology. 2013 Jul;145(1):105-112.e15. doi: 10.1053/j.gastro.2013.02.041

Background

New oral anticoagulants (NOACs) such as factor IIa (thrombin) or factor Xa inhibitors are as effective as current treatment strategies, including vitamin K antagonists (VKA) and heparins. Anticoagulants and antiplatelet agents are known to give rise to in increased risk of gastrointestinal bleeding (GIB)[1-3]. Use of traditional antithrombotic agents requires monitoring of the international normalised ratio. NOACs do not have this limitation. Some studies have, however, reported an isolated higher risk of GIB for NOACs [4,5].
This systematic review analyses the literature on GIB risk attributable to use of NOAC. Not all trials separately reported GIB (19 trials, 44%, did report GIB separately), thus also risk of clinically relevant bleeding associated with NOAC use was reviewed. A total of 43 trials were included, comprising data on 125354 patients.

Main results

• 1101 GIB events were reported in 75081 patients (1.5%, data of 17 trials). These GIBs were predominantly major bleeds (89%).
• The percentage of GI bleeds per trial was low for the NOAC group in trials on orthopedic surgery (0.1% for NOAC, 0.2% for controls), intermediate in trials on atrial fibrillation (NOACs: 2.1%, control: 1.6%) and deep venous thrombosis/pulmonary embolism (DVT/PE) (NOAC: 3.0% vs 1.9% in control), and high in trials on acute coronary syndrome (ACS)(NOACs: 5.3%, control: 1.0%).
  Four out of 17 studies showed an increased risk of GIB with NOACs instead of standard care, 12 a comparable risk and 1 a lower risk.
• Pooling of the results yielded a higher risk of GIB associated with NOACs: OR: 1.45, 95%CI: 1.07-1.97. Substantial heterogeneity was seen. Much of the increased risk could be attributed to the two trials on ACS (pooled OR: 5.21, 95%CI: 2.58-10.53). The pooled OR for the two trials investigating risk of GIB in DVT/PE was 1.59, 95%CI: 1.03-2.44.
  Other indications for NOAC did not show an increased risk of GIB.
• No difference was seen in GIB risk between therapeutic or prophylactic use of NOACs.
• Excluding studies that compared NOAC to placebo therapy in a sensitivity analysis, yielded similar results, with the exception of the risk of GIB at DVT/PE, which was no longer statistically significantly increased (OR: 1.53, 95%CI: 0.99-2.36).
• When including data from all 43 trials on clinically relevant bleeding, the overall risk was significantly higher with the use of NOACs as compared to standard care (OR: 1.16, 95%CI: 1.00-1.34), again showing considerable heterogeneity. Again, patients treated for ACS had an increased risk of bleeding (OR: 2.06), while other indications did not show a statistically significant increased risk.
• Excluding studies that compared NOAC to placebo therapy in a sensitivity analysis did not yield an overall increased risk of clinically relevant bleeding (OR: 0.98, 95%CI: 0.88-1.10).

Conclusion

NOACs were associated with a modestly increased risk of GIB in comparison to standard care. This risk is highest in patients treated for thrombosis (ACS and DVT/PE). The higher risk in ACS is possibly due to the fact that NOACs were administered on top of other antithrombotic medication, thereby cumulating risks.
This meta-analysis is based on a highly selected patient group with a low bleeding risk, thus may not truly reflect future patients in daily clinical practice.

Editorial comment [6]

The NOACs represent landmark advancements in anticoagulant care since they overcome many of the limitations of traditional antithrombotic therapies. The increased risk of GI bleeding as observed in this meta-analysis showed substantial heterogeneity, where indication formed a significant source of heterogeneity. While patients with ACS and VTE seemed to account for much of the increased risk, no increased risk of GIB was observed with NOACS when used for prevention of stroke and systemic embolism in AF, the medically ill or after orthopaedic surgery.
The biggest issue with NOACs is that there are currently no antidotes. Specific reversal agents are in development, but likely still need some time. For now physicians need to be acutely aware of NOACs and their associated bleeding risk. Guidelines to support the management of acute bleeding should be developed.   

References

1. Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006;333:726.
2. Sung JJ, Kuipers EJ, Barkun AN. Gastrointestinal bleeding. Chichester, UK: Wiley-Blackwell; 2012.
3. Lanas A, Wu P, Medin J, et al. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol 2011;9:762–768e6.
4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139–1151.
5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:1557–1559.
6. Heitman SJ, Mackay E, Hilsden R, Rstome A. Novel Oral Anticoagulants: Is the Convenience Worth the Risk? Gastroenterology. 2013 Jul;145(1):42-45

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