Acetaminophen and Warfarin Can Be a Deadly Mix
By Barbara A. Biedrzycki, RN, MSN, AOCN, CRNP
Summary-A study at Massachusetts General Hospital and Harvard Medical School found that two tablets of 325 mg (regular strength) acetaminophen bid for more than a week increased tenfold the odds of having an International Normalized Ratio (INR) greater than 6.0. Taking more warfarin than prescribed significantly increases INR levels, which results in a potentially fatal outcome for patients who self-medicate. Health care providers need to coordinate care and agree on who has primary prescribing authority for warfarin. When initiating a new medication that may potentiate (106 drugs) or inhibit (40) anticoagulating effects of warfarin, the clinician must monitor INR levels closely or seek alternative therapy. Diets rich in vitamin K promote less fluctuation in warfarin's anticoagulation effect. Advanced malignancy, decreased oral intake, and diarrhea were all significant risk factors for elevated INR levels.
An alarming correlation was discovered between the most popular over-the-counter (OTC) medication, acetaminophen, and the most widely used anticoagulation medication, warfarin, when a study revealed a highly significant dose-response between acetaminophen and warfarin's anticoagulation effect. As more acetaminophen was ingested, the INR levels increased. While advanced practice nurses knew that acetaminophen had the potential to increase INR levels, the magnitude of the danger for patients on warfarin therapy taking acetaminophen within ordinary medically acceptable doses was not known.
Warfarin, patented by DuPont Pharma in Wilmington, DE, as Coumadin, inhibits vitamin K-dependent coagulation factors to produce therapeutic anticoagulation. It is indicated for prophylaxis and treatment of venous thromboembolism, pulmonary embolism, atrial fibrillation, post-myocardial infarctions, mechanical and bioprosthetic heart valves, and recurrent systemic embolism.
A narrow therapeutic index with an INR of 2.0-3.0 for most anticoagulation therapy or more intense warfarin therapy of 2.5-3.5 is indicated for mechanical heart valve and post-myocardial infarction. INR is a standardized reporting mechanism for prothrombin time (PT) that was developed to control for differences in various reagents and laboratories. Created in 1983 by the World Health Organization in Geneva, Switzerland, the INR level provides a basis for communicating results and establishing therapeutic ranges.1
Elaine Hylek, MD, and colleagues at Massachusetts General Hospital and Harvard Medical School set out to identify causes for excessive anticoagulation, defined as INR greater than 6.0.2 A risk of major bleeding, including potentially fatal intracranial hemorrhage, occurs with INR levels greater than 4.0. Hylek et al used a higher INR of 6.0 as an inclusion criterion into the case group because so little is known about extremely high INR levels.
The researchers' goal was to target patients at high risk for complications related to warfarin therapy. Daily logs from the anticoagulation outpatient clinic identified almost 2000 potential study subjects with a target INR of 2.0 to 3.0. - which did not trigger a dose change - who were taking warfarin for at least a month. The study drew 96 research participants with INR levels greater than 6.0 and 196 controls with INR levels of 1.7 and 3.3.
Interview Focuses on Meds and Diet
In addition, study criteria required that the patient (or a proxy) must be able to participate in a telephone interview within 24 hours of the PT test. This is critical because previous research shows recall of symptoms, medications, and diet decrease with time.
The interview, lasting 10-15 minutes, focused on medical therapy for the past seven days, including prescription and OTC medications. Medications were classified according to reported effects on warfarin's metabolism as potentiators, inhibitors, or having no effect. Research participants were asked specifically about their acetaminophen, aspirin, and nonsteroidal anti-inflammatory drug use. They were asked about dietary changes in general, particularly about 12 foods identified as being rich in vitamin K, which may affect the anticoagulation response to warfarin. (See Table.) Other variables included alcohol consumption, episodes of diarrhea and fever, recent hospitalization, advanced malignancy, compliance with warfarin therapy, age, sex, and race.
Extent of Use Surprises Researchers
William Bell, MD, of Johns Hopkins Hospital explained the normal metabolism of warfarin and acetaminophen because both involve hepatic cytochrome P-450: "Thus, depending on the number and quantity of concomitant medications, acetaminophen can exhaust the capacity of cytochrome P-450 system, prevent the normal metabolism of warfarin, and increase concentration of warfarin in the blood. Through first-order kinetics, warfarin inhibits the normal synthesis of vitamin K-dependent procoagulant glycoprotein factors II, VII, and X and proteins C, S, and Z, prolonging the prothrombin time and producing multiple defects in normal homeostasis."3
In Bell's study, 56% (52) of case participants reported taking acetaminophen. Statistical significance (p<0.002) was reached when 7-14 tablets of 325 mg acetaminophen were taken in a week. With 28 or more 325 mg tablets per week (p<0.001), the odds of having an INR level of greater than 6.0 increased tenfold compared with those taking no acetaminophen. Even more surprising, the study by Hylek et al found that 36% (70) of control cases use acetaminophen at any given time, and more than a third of all patients on anticoagulation therapy may use it. Patients who occasionally use acetaminophen, which may not produce a dramatic change in INR, may assume there is no danger in an increased or regular dose.
Analgesic combinations and cold remedies contain hidden sources of acetaminophen, including codeine, oxycodone, and propoxyphene napsylate. Prescribing practitioners and patients should use caution in not exceeding the maximum dose of 4 g (4000 mg) per day.
Of even greater concern was the finding by Hylek and colleagues that 11 case patients (12%) and five control patients (3%) were taking more warfarin than prescribed by the anticoagulation unit provider. More than half of the case patients indicated another treating physician advised increasing the warfarin dose without consulting the anticoagulation unit.
Patients need to understand the importance of having only one primary health care provider prescribe warfarin and consulting with that medication manager before taking other medications, both prescription and OTC. The risk of internal bleeding and death that can occur with INR levels greater than 6.0 provides sufficient indication to justify preaching to patients about the hazards of self-medicating.
Alcohol consumption and increased ingestion of foods rich in vitamin K were inversely correlated with INR levels greater than 6.0. Caution is advised in assessing the statistical significance of alcohol ingestion in this study because too few patients reported drinking more than two drinks per day - only three (3%) in case group and four (2%) in the control group - to support any firm conclusions. This study supports previously held beliefs that diets rich in vitamin K promote less fluctuation in the body's response to warfarin therapy.
Implications for Practice
Other statistically significant results for advanced practice nurses to consider include the following: advanced malignancy, diarrhea, decreased oral intake, initiation of a potentiating medication, and ingestion of higher warfarin dose than prescribed. Diminished nutritional status may explain the relationship between advanced malignancy, diarrhea, decreased oral intake, and INR levels greater than 6.0. When less dietary vitamin K is available, there is decreased binding of warfarin to plasma proteins, which allows more free-circulating warfarin.
Forty-four classes of drugs and 106 specific drugs are known to increase the PT/INR response.1 This study showing that initiating a potentiating medication increased the INR to greater than 6.0 alerts advanced practice nurses to use caution. You may want to monitor the INR levels more often or seek alternative therapy.
The study by Hylek et al provides multiple implications for advanced practice nurses to hone their warfarin management skills and supports the importance of patient education. One weakness in the study is that it does not address whether patients used brand name Coumadin, generic coumadin, or a combination of the two. As with other drugs, primarily digoxin and Dilantin, clinicians express concern about the bioequivalence of generic warfarin and Coumadin. If their anticoagulation effect shown by the INR is not equivalent, monitoring and adjusting medications for patients could be hit or miss at best. (See related story, below.)
References
1. DuPont Pharma. Package insert: Coumadin prescribing information. Wilmington, DE: 1996.
2. Hylek E, Heiman H, Skates S, et al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998;279:657-662.
3. Bell W. Acetaminophen and warfarin: Undesirable synergy. JAMA 1998;279:702-703.
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