DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Overview of Product(s)

Vitamin K antagonists (VKAs) like warfarin have been the primary choice for oral anticoagulation, particularly for preventing stroke or systemic embolism in patients with atrial fibrillation (AF).¹ More recently, direct oral anticoagulants (DOACs) have been introduced and approved, demonstrating noninferiority or even superiority to warfarin in stroke prevention, along with a more favourable bleeding risk profile.^1,2 In Malaysia, there are 69 warfarin and DOAC-containing products registered with the Drug Control Authority (DCA).³

Overview of Safety Concern

Atraumatic splenic rupture is rare but can be potentially fatal.⁴ As the spleen is a highly vascular organ, its rupture can lead to intraperitoneal haemorrhage and subsequent hypovolaemic shock due to loss of circulatory blood volume.⁵ Atraumatic splenic rupture can be classified as pathological or idiopathic,^4,6 with drug-associated rupture considered a form of pathological rupture.⁴ Case series have reported that drug-related causes account for approximately 7.2% to 50% of atraumatic splenic rupture cases. Among these, 33% of the drug-related cases have been found to be due to anticoagulant use.

Source of Safety Concern

The National Pharmaceutical Regulatory Agency (NPRA) received information from Health Canada regarding the risk of atraumatic splenic rupture associated with the use of oral anticoagulants, comprising  apixaban, dabigatran, edoxaban, rivaroxaban and warfarin.⁷ The safety review was initiated following international reports of this risk in rivaroxaban-treated patients, in which no trauma or other identifiable risk factors were present.

After reviewing available information from the Canada Vigilance database and scientific literature, Health Canada found a possible link between oral anticoagulants and the risk of atraumatic splenic rupture, and concluded that the product information of these oral anticoagulants should be updated accordingly.⁷

Background of the Safety Issue

The exact mechanism underlying oral anticoagulant-induced atraumatic splenic rupture has not yet been fully elucidated.⁸ It has been hypothesized that the use of anticoagulant may disrupt splenic haemostasis, increasing susceptibility to microtrauma and triggering macrophage infiltration, which ultimately leads to splenic rupture.⁴ In patients taking warfarin, apixaban or rivaroxaban, the occurrence of splenic rupture has been reported to range from 2 weeks to years.^4,8,9 In another case, although the time to onset of the reaction was not explicitly stated, the rupture occurred within hours of hospital discharge in a patient who had recently started on apixaban.¹⁰

The diagnosis of atraumatic splenic rupture is often delayed because of its non-specific presentation.⁴ In patients receiving anticoagulant therapy presenting with acute severe abdominal pain and signs of shock, the diagnosis of splenic rupture should be considered regardless of a history of trauma or known risk factors for spontaneous rupture.⁸ A thorough history and broad initial differential are important to support early diagnosis.⁴

Local Adverse Drug Reaction Reports¹¹

To date, the NPRA has received a total of 1,749 reports with 2,903 adverse events suspected to be related to products containing warfarin, dabigatran, rivaroxaban, apixaban or edoxaban. There have been no local reports of splenic rupture associated with oral anticoagulant use.

Advice for Healthcare Professionals

• Be aware that atraumatic splenic rupture can occur with oral anticoagulant use.
• Educate patients to seek medical advice if they have symptoms such as abdominal pain, decreased appetite, fatigue or dizziness.
• Consider performing CT scans in patients on oral anticoagulants presenting with abdominal pain, hypotension and anaemia.
• If atraumatic splenic rupture is identified in the context of DOAC use, management should prioritize hemodynamic stabilization and DOAC reversal if necessary, with attention to timing of the last anticoagulant dose, cost, and availability of reversal agents.
• Report all adverse events suspected to be related to the use of oral anticoagulant-containing products to the NPRA.

References:

1. Monaco L, Biagi C, Conti V, Melis M, Donati M, Venegoni M, Vaccheri A, Motola D. Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions. Br J Clin Pharmacol. 2017 Jul;83(7):1532-1543. Available from: https://doi.org/10.1111/bcp.13234
2. Liang X, Xie W, Lin Z, Liu M. The efficacy and safety of edoxaban versus warfarin in preventing clinical events in atrial fibrillation: A systematic review and meta-analysis. Anatol J Cardiol. 2021 Feb;25(2):77-88. Available from: https://doi.org/10.14744/anatoljcardiol.2020.18049
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 Apr 3]. Available from: https://www.npra.gov.my
4. Jessica B, Zayd A, Robert P, Christopher H. Atraumatic Splenic Rupture on Direct Oral Anticoagulation. J Community Hosp Intern Med Perspect. 2022 Sep 9;12(5):84-87. Available from: https://doi.org/10.55729/2000-9666.1098
5. Ahmed MM, Khan ZH, Zaidi SR, Mukhtar K. A Delayed Splenic Tragedy Beyond the Scope of a Colonoscope: A Rare Find. Cureus. 2020 Apr 23;12(4):e7805. Available from: https://doi.org/10.7759/cureus.7805
6. Labaki ML, De Kock M. Atraumatic splenic rupture in a patient treated with rivaroxaban: A case report and a narrative review. Clin Case Rep. 2022 Nov 3;10(11):e6462. Available from: https://doi.org/10.1002/ccr3.6462
7. Health Canada. Summary Safety Review - Oral Anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban and warfarin) - Assessing the Potential Risk of Splenic Rupture [Internet]. 2025 Apr 2 [cited 2025 Apr 2]. Available from: https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SSR1740076495316
8. Kapan M, Kapan S, Karabicak I, Bavunoglu I. Simultaneous rupture of the liver and spleen in a patient on warfarin therapy: report of a case. Surg Today. 2005;35(3):252-5. Available from: https://doi.org/10.1007/s00595-004-2898-y
9. Gonzva J, Patricelli R, Lignac D. Spontaneus splenic rupture in a patient treated with rivaroxaban. Am J Emerg Med. 2014 Aug;32(8):950.e3. Available from: https://doi.org/10.1016/j.ajem.2014.01.049
10. Janke A, Ikejiani S, Mize C. Spontaneous splenic hemorrhage in a patient on apixiban. Am J Emerg Med. 2020 May;38(5):1044.e1-1044.e2. Available from: https://doi.org/10.1016/j.ajem.2019.12.006
11. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 Apr 7]. Available from: https://www.npra.gov.my (access restricted)

Written by: Wo Wee Kee
Reviewed/Edited by: Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali