Potential interactions between direct oral anticoagulants and atorvastatin/simvastatin: cohort and case-crossover study

Angel Ys Wong; Charlotte Warren-Gash; Krishnan Bhaskaran; Clemence Leyrat; Amitava Banerjee; Liam Smeeth; Ian Douglas

doi:10.3399/BJGP.2024.0349

Potential interactions between direct oral anticoagulants and atorvastatin/simvastatin: cohort and case-crossover study

Br J Gen Pract. 2024 Nov 28:BJGP.2024.0349. doi: 10.3399/BJGP.2024.0349. Online ahead of print.

Authors

Angel Ys Wong¹, Charlotte Warren-Gash², Krishnan Bhaskaran², Clemence Leyrat³, Amitava Banerjee⁴, Liam Smeeth², Ian Douglas²

Affiliations

¹ London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, Department of Non-communicable Disease Epidemiology, London, United Kingdom angel.wong@lshtm.ac.uk.
² London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, Department of Non-communicable Disease Epidemiology, London, United Kingdom.
³ London School of Hygiene and Tropical Medicine Faculty of Epidemiology and Population Health, ENCD, London, United Kingdom.
⁴ University College London, London, United Kingdom.

PMID: 39609078
DOI: 10.3399/BJGP.2024.0349

Abstract

Background: Direct oral anticoagulants (DOACs) are commonly co-prescribed with statins. Although biologically plausible, whether there is a drug interaction between DOACs and atorvastatin/simvastatin is unclear.

Aim: To investigate the association between co-prescribed DOACs and atorvastatin/simvastatin and bleeding, cardiovascular disease and mortality.

Design and setting: Clinical Practice Research Datalink Aurum(1/1/2011-31/12/2019).

Method: We used a cohort design to estimate hazard ratios for clinically relevant pharmacological interaction safety outcomes (intracranial bleeding, gastrointestinal bleeding, other bleeding) comparing DOACs+atorvastatin/simvastatin with DOACs+other statins (fluvastatin, pravastatin and rosuvastatin which are not anticipated to interact with DOACs). Effectiveness outcomes (ischaemic stroke, myocardial infarction, venous thromboembolism, cardiovascular mortality, and all-cause mortality) were also included. A case-crossover design comparing odds of exposure to different drug initiation patterns in hazard window versus referent window within an individual was also conducted.

Results: Of 397,459 DOAC users, we selected 70,318 people co-prescribed atorvastatin, and 38,724 co-prescribed simvastatin. The cohort analysis showed no difference in risk of all outcomes comparing DOACs+atorvastatin/simvastatin versus DOACs+other statins. In case-crossover analysis, ORs for other bleeding (OR:4.04; 99%CI:3.07-5.31) amongst those initiating DOACs while taking atorvastatin, and the ORs for gastrointestinal bleeding (OR:5.16; 99%CI:3.66-7.28) and other bleeding (OR:5.12; 99%CI:3.61-7.26) amongst those initiating DOACs while taking simvastatin were greater than those initiating DOAC monotherapy. Similar patterns were also observed for cardiovascular mortality and all-cause mortality.

Conclusion: This study shows no evidence of interaction between DOACs and atorvastatin/simvastatin. However, people starting a DOAC whilst taking atorvastatin/simvastatin, were at high risk of bleeding and mortality, likely due to temporal clinical vulnerability.