Summary Safety Review - Oral Anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban and warfarin) - Assessing the Potential Risk of Splenic Rupture

Review decision

A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.


Product
Oral anticoagulants (apixaban-, dabigatran-, edoxaban-, rivaroxaban- and warfarin-containing products)
Potential Safety Issue
Splenic rupture (tear in the spleen’s surface that can cause life-threatening internal bleeding)
Key Messages

  • Health Canada’s safety review found a possible link between oral anticoagulants and the risk of atraumatic (without apparent cause) splenic rupture.

  • Health Canada will work with the manufacturers to update the product safety information in the Canadian product monograph (CPM) for all oral anticoagulants to include the risk of atraumatic splenic rupture.

Overview

Health Canada reviewed the potential risk of splenic rupture with the use of oral anticoagulants. The safety review was triggered by international reports concerning this risk in patients taking rivaroxaban where no trauma or other risk factor was identified.

Use in Canada

  • Oral anticoagulants are prescription drugs, also known as blood thinners, authorized for sale in Canada to:

    • prevent blood clots from forming after knee or hip replacement surgery,

    • reduce the risk of stroke (damage to part of the brain caused by an interruption of its blood supply) or systemic embolism (the sudden blocking of a blood vessel by a blood clot) in people who have a heart condition called atrial fibrillation (irregular heart beat), and

    • treat deep vein thrombosis (blood clots in the veins of the legs) and pulmonary embolism (blood clots in the blood vessels of the lungs), and reduce the risk of them occurring again.

  • There are currently 5 oral anticoagulants available in Canada (apixaban, dabigatran, edoxaban, rivaroxaban and warfarin) under different brand names and generic versions. Warfarin has been marketed in Canada for more than 65 years, while the other drugs came to the Canadian market between 2008 and 2017.

  • Oral anticoagulants are widely prescribed. Approximately 12 million prescriptions were dispensed annually by Canadian retail pharmacies between 2020 and 2023.

Safety Review Findings

  • Health Canada reviewed the available information from searches of the Canada Vigilance databasea and the scientific literature.

  • Health Canada reviewed 42 cases (3 Canadian and 39 international) of splenic rupture in patients taking oral anticoagulants, including 39 from the published literature1-39. Of the 42 cases, 1 was found to be probably linked to the use of oral anticoagulants, 21 (1 Canadian) were found to be possibly linked, 16 were unlikely to be linked, and 4 (2 Canadian) could not be assessed due to missing information.

  • Besides having taken oral anticoagulants, in 9 of the 21 possible cases, there was no other possible explanation (for example, trauma or existing medical condition) reported for the splenic rupture. However, atraumatic rupture of the spleen is known to occasionally occur.

  • Given the known increased risk of bleeding associated with anticoagulants, patients taking these drugs are at an increased risk of bleeding within their spleen, which can lead to a rupture of its capsule (the outer layer surrounding the spleen).

  • Health Canada also reviewed the findings from a study that examined over 27,000 international reports of suspected adverse drug reactions associated with oral anticoagulants40. The findings showed that events of splenic rupture were more frequently reported than expected with these drugs, thereby supporting a link.

Conclusions and Actions

  • Health Canada’s review of the available information found a possible link between oral anticoagulants and the risk of atraumatic splenic rupture.

  • Health Canada will work with the manufacturers to update the CPM for all oral anticoagulants to include the risk of atraumatic splenic rupture.

  • Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of oral anticoagulants, and other health products, to the Canada Vigilance Program.

  • Health Canada will continue to monitor safety information involving oral anticoagulants, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

Additional Information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of oral anticoagulants both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

References

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  2. Kaufman N, Ferraro D. Splenic rupture following synchronised direct current cardioversion. BMJ Case Rep. 2017;2017:bcr2017221288. Published 2017 Aug 7. doi:10.1136/bcr-2017-221288

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  15. Moore CH, Snashall J, Boniface K, Scott J. Spontaneous splenic hemorrhage after initiation of dabigatran (Pradaxa) for atrial fibrillation. Am J Emerg Med. 2012;30(9):2082.e1-2082.e20822. doi:10.1016/j.ajem.2011.10.031

  16. Gonzva J, Patricelli R, Lignac D. Spontaneus splenic rupture in a patient treated with rivaroxaban. Am J Emerg Med. 2014;32(8):950.e3. doi:10.1016/j.ajem.2014.01.049

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  19. Nagaraja V, Cranney G, Kushwaha V. Spontaneous splenic rupture due to rivaroxaban. BMJ Case Rep. 2018;2018:bcr2017223237. Published 2018 Mar 5. doi:10.1136/bcr-2017-223237

  20. Wood D, Donato P, Dale J. Splenic capsular rupture secondary to large perinephric haematoma. BJU Int. 2019;123.

  21. Owens RE, Hetzler J. Acute management of rivaroxaban-induced splenic rupture: A case report. JACCP J Am Coll Clin Pharm. 2020;3(8).

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  40. Monaco L, Biagi C, Conti V, et al. Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions. Br J Clin Pharmacol. 2017;83(7):1532-1543. doi:10.1111/bcp.13234

Footnotes

  1. Canadian reports can be accessed through the Canada Vigilance Online Database.

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