Acetaminophen and Other Risk Factors for Excessive Warfarin Anticoagulation

Abstract

Context.-Warfarin is highly effective in preventing thromboembolism, but increases the risk of hemorrhage, particularly at an international normalized ratio (INR) greater than 4.0. Identifying causes of excessive anticoagulation in clinical practice could help target patients at risk for elevated INRs. Objective.-To determine causes of INRs greater than 6.0 in a clinical practice setting. Design.-Case-control study. Setting.-Outpatient anticoagulant therapy unit. Patients.-Outpatients followed up prospectively from April 1995 to March 1996 who had been taking warfarin for more than 1 month, had a target INR of 2.0 to 3.0, and were able to be interviewed within 24 hours of their reported INR. Case patients had INRs greater than 6.0; controls were randomly selected from patients having INRs between 1.7 and 3.3. Main Outcome Measures.-Factors associated with INRs greater than 6.0, including medication use, recent diet, illness, alcohol consumption, and actual warfarin use. Results.-A total of 93 cases and 196 controls were interviewed; they did not differ in age, indication for warfarin, length of therapy, warfarin dose, number of prescription medications, or previous INR or long-term INR variability. Acetaminophen ingestion was independently associated in a dose-dependent manner with having an INR greater than 6.0 (P for trend Ͻ.001). For the highest-dose category of acetaminophen intake, 9100 mg/wk or more, the odds of having an INR greater than 6.0 were increased 10-fold (95% confidence interval [CI], 2.6-37.9). Other factors independently associated with an INR greater than 6.0 were new medication known to potentiate warfarin (odds ratio [OR], 8.5; 95% CI, 2.9-24.7), advanced malignancy (OR, 16.4; 95% CI, 2.4-111.0), recent diarrheal illness (OR, 3.5; 95% CI,1.4-8.6), decreased oral intake (OR, 3.6; 95% CI, 1.3-9.7), and taking more warfarin than prescribed (OR, 8.1; 95% CI, 2.2-30.0). Higher vitamin K intake (OR, 0.7; 95% CI, 0.5-0.9) and habitual alcohol consumption of from 1 drink every other day to 2 drinks a day (OR, 0.2; 95% CI, 0.1-0.7) were associated with decreased risk. Conclusions.-These data suggest that acetaminophen is an underrecognized cause of overanticoagulation in the outpatient setting. Several other clinically important risk factors were identified. Increased monitoring of INR values when such risk factors are present or modification of the risk factors themselves should reduce the frequency of dangerously high levels of anticoagulation.

Protein binding interaction of warfarin and acetaminophen in presence of arsenic and of the biological system

“…The mechanism of this interaction has only recently been elucidated (Thijssen et al, 2004) and likely results from the independent inhibitory effect of an acetaminophen metabolite on enzymes of the vitamin K cycle. Although several case reports and controlled studies have reported that acetaminophen potentiates the anticoagulant effect of warfarin (Hylek et al, 1998), others have not found a clinically relevant interaction (Fattinger et al, 2002). NSAIDs such as mefenamic acid (Holmes, 1966) etodolac (Ermer et al, 1994;ibuprofen (Penner and Abbrecht, 1975) and tenidap (Apseloff et al, 1995) may also displace coumarin anticoagulants from protein binding sites.…”

“…This interacttion is proposed to be due to inhibition of its metabolism and interference with formation of clotting factors. Gingival bleeding and hematuria were observed in case reports when paracetamol is given with warfarin (Hylek et al, 1998). However, due to lack of a safer alternative, paracetamol is still the analgesic and antipyretic of choice in patients receiving warfarin therapy, as long as excessive amounts and prolonged administration are avoided (Shek et al, 1999).…”

Drug Treatment of Chronic Pain

“…31.8). The analysis by Hylek et al shows a relationship between higher paracetamol doses and greater anticlotting efficacy of warfarin [5]. The catch is that this relationship was found in those who had higher INR values, so the moral of the story is that the sensitive should avoid high-dose paracetamol if they take warfarin.…”

Primary and Secondary Stroke Prevention in Nonrheumatic Atrial Fibrillation by Oral Anticoagulation

“…Observational studies demonstrate that the risk of intracranial hemorrhage rises dramatically at INR values of 4.0–5.0 [64]. Factors leading to INRs >6.0 are medications known to potentiate OAC (table 2), advanced malignancy, recent diarrhea and taking more oral anticoagulants than prescribed [65]. …”