Warfarin and Acetaminophen
The interaction between warfarin and acetaminophen has been a well-kept secret for 30 years. Roughly every 10 years, there's another study that shows this important interaction between acetaminophen and warfarin. Each study may lead to a brief flurry of attention in the popular press that then fades away.
To begin 30 years ago, the first study published in 1984 was a double-blind crossover trial of 15 healthy volunteers who were first anticoagulated on warfarin and then treated with acetaminophen 4 g/day—the maximum recommended dose noted on bottles sold OTC—or placebo. After 2 weeks, an INR was obtained. Patients were then crossed over, and those initially given acetaminophen were now given placebo and vice versa. After an additional 2 weeks, INR measurement was repeated. On average, the INR was 1.75 times higher—almost double—when patients were taking 4 g of acetaminophen daily.
The second study was published 14 years later, in JAMA in 1998.[2] It was conducted at an anticoagulant therapy unit, in patients who had a target INR of 2.0 to 3.0. An INR was obtained 4 weeks after initiation of warfarin therapy. There were 93 patients with an INR of more than 6.0 (range, 6.1 to 30). Control patients were chosen whose INR was close to the target range (actual values were between 1.7 and 3.3).
Cases and controls were similar in age (mean, 70 years), sex (50% women), race (97% white), duration of warfarin therapy, and reason for anticoagulation. All participants were interviewed and asked about medicines, including any newly prescribed or OTC medications, alcohol consumption, and prescribed and consumed warfarin doses. They were also queried about dietary habits, including recent changes and specifically about intake of foods with high vitamin K content.
Although a range of factors were identified that contributed to an increase in INR, acetaminophen ingestion was independently associated in a dose-dependent manner with having an INR greater than 6.0 (P for trend < .001). Patients taking more than 9 g of acetaminophen per week (eighteen 500-mg tablets) had an odds ratio 0 of 10 (95% confidence interval, 2.6-37.9) for an INR greater than 6.0. Even one half of that dose—nine 500-mg tablets per week—gave an odds ratio of 7.
Another 9 years, and a third study.[3] A total of 36 patients with stable INRs who were seen at an anticoagulation clinic were randomly assigned to receive acetaminophen 1 g twice daily, acetaminophen 1 g four times daily, or placebo four times daily (12 patients per group) for 4 weeks. The study was terminated early after it was determined that 15 patients experienced an elevation in INR. Just over one half (54%) of the patients receiving acetaminophen exceeded their INR therapeutic range by 0.3 or greater, vs 17% of those taking placebo.
Finally, a study published in 2011 examined 45 patients on stable warfarin therapy.[4] Patients in this prospective, randomized, parallel (three arms), placebo-controlled study received either 2 or 3 g of acetaminophen daily for 10 days or placebo. The mean maximal increases in INR were 0.70 ± 0.49 and 0.67 ± 0.62 in patients receiving acetaminophen at 2 g/day and 3 g/day, respectively (P = .01). The INR increase became significant on day 3.
So this is real. The take-home message is that the INR should be obtained after 3-5 days in patients taking daily acetaminophen for pain relief. This is not necessary in patients taking an occasional 1-g dose for a headache or another intermittent concern.
Although the bleeding risks of nonsteroidal anti-inflammatory medications and aspirin are well appreciated, leading to a common recommendation for use of acetaminophen as an alternative, acetaminophen must also be recognized as having some degree of risk. In patients using acetaminophen for chronic pain relief, this is an important interaction that should lead to a change in monitoring strategies.
References
- Rubin RN, Mentzer RL, Budzynski AZ. Potentiation of anticoagulant effect of warfarin by acetaminophen [abstract]. Clin Res. 1984;32:698A.
- Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA. 1998;279:657-662. Abstract
- Parra D, Beckey NP, Stevens GR. The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy. 2007;27:675-683. Abstract
- Zhang Q, Bal-dit-Sollier C, Drouet L, et al. Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial. Eur J Clin Pharmacol. 2011;67:309-314. Abstract
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