Adverse interaction of warfarin and paracetamol: evidence from a post-mortem study.
OBJECTIVE
The aim of the study was to establish the prevalence and nature of potential adverse drug combinations of warfarin in a large post-mortem toxicology database. The concomitant use of warfarin and non-steroidal anti-inflammatory drugs (NSAIDs) was of interest as these drugs have been associated with internal bleeding both in clinical and post-mortem study settings. Another purpose was to obtain facts related to the questioned safety of warfarin-paracetamol and warfarin-tramadol combinations.


METHODS
The post-mortem database was searched for a 1-year period. All warfarin-positive cases and cases containing interacting drugs, as defined by the SFINX interaction database (Swedish, Finnish, Interaction X-referencing), were included. For controls, all cases containing paracetamol or tramadol were also included, and for each warfarin-positive case, an age-, sex- and alcohol-matched control case was sourced. The contribution of anticoagulant use to the deaths was evaluated from the death certificates based on medico-legal autopsies.


RESULTS
In 33% of the 328 warfarin-positive cases, at least one interacting drug was present, and paracetamol was the most abundant, accounting for 49% (n = 53). When paracetamol and warfarin were detected simultaneously, the number of fatal bleeds was 4.6 and 2.7 times higher compared to paracetamol or warfarin use alone respectively. The presence of an NSAID in combination with warfarin was rare, as only six cases were identified. A majority (66%) of the post-mortem blood samples had a warfarin concentration below 0.5 mg/l, and for the rest of the cases, the mean concentration was 0.70 mg/l.


CONCLUSIONS
This study supports the clinical evidence suggesting that warfarin-paracetamol interactions may create significant life-threatening conditions. It also accentuates the significant role post-mortem database research can have in improving drug safety.
Launiainen
Terhi
T
Department of Forensic Medicine, University of Helsinki, Helsinki, Finland. terhi.launiainen@helsinki.fi
Sajantila
Antti
A
Rasanen
Ilpo
I
Vuori
Erkki
E
Ojanperä
Ilkka
I
D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects*; D001344:Autopsy; D002423:Cause of Death; D016208:Databases, Factual; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014147:Tramadol / Q000008:administration & dosage / Q000009:adverse effects; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects*
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000925:Anticoagulants; D000082:Acetaminophen; D014147:Tramadol; D014859:Warfarin