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

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.

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

Cohort and case-crossover study using data from English general practices in the Clinical Practice Research Datalink Aurum from 1 January 2011 to 31 December 2019.

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

Of 397 459 patients who were prescribed DOACs, 70 318 people co-prescribed atorvastatin and 38 724 co-prescribed simvastatin were selected. The cohort analysis showed no difference in risk of all outcomes comparing patients prescribed DOACs and atorvastatin/simvastatin versus those prescribed DOACs and other statins. In the case-crossover analysis, odds ratios (ORs) for other bleeding (OR 5.06, 99% confidence interval [CI] = 3.79 to 6.76) among those initiating DOACs while taking atorvastatin and the ORs for gastrointestinal bleeding (OR 6.05, 99% CI = 4.28 to 8.54) and other bleeding (OR 6.81, 99% CI = 4.74 to 9.78) among 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.

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