PHILADELPHIA — Drug interactions involving warfarin are among the most dangerous that occur commonly in clinical practice, Dr. Douglas S. Paauw said at the annual meeting of the American College of Physicians.
As many as one-third of all hospitalizations in the United States are associated with drug interactions or side effects, and warfarin is one of the main culprits. “If you look statistically at what are the drug interactions that kill people, warfarin interactions are at the top of the list,” noted Dr. Paauw, professor of medicine at the University of Washington, Seattle.
With binders such as cholestyramine, for example, the interference actually happens twice. Cholestyramine directly binds the anticoagulant and decreases its absorption when the two drugs are taken together. In addition, the enterohepatic circulation of warfarin—in which it is excreted in the bile and then reabsorbed—results in a “second pass” anticoagulant effect and a second interaction with the binder, which can lead to a further decrease in warfarin effectiveness. This secondary effect can't be prevented by separating the doses.
If possible, try to avoid using binders in patients taking warfarin, Dr. Paauw advised. If both must be taken, be sure to separate them so that the warfarin is taken at night and the binder taken in the morning and perhaps in the afternoon. Very close monitoring of the international normalized ratio (INR) is essential when initiating the binder. “But if you can get away from [using the two concurrently], that's a safer way to go,” he said.
Interactions between antibiotics and warfarin are also quite common, with trimethoprim-sulfamethoxazole (TMP-SMX) having the greatest potential to cause a severe interaction. Other antibiotics that can lead to overanticoagulation when taken with warfarin include erythromycin, amiodarone, ketoconazole/fluconazole (in high doses), itraconazole, and metronidazole. None, however, is as powerful as the interaction with TMP-SMX, because it has a shorter half-life than other antimicrobials and therefore the effect can occur within 2–3 days. With the others, there is usually enough time for the increase in INR to be picked up and treated before it gets out of hand, Dr. Paauw noted.
Other antibiotics that may increase the INR in some, but not all, anticoagulated patients include quinolones, omeprazole, clarithromycin, and azithromycin. These drugs are more likely to cause problems in elderly patients and in those who are taking many concurrent medications.
In a retrospective study involving 104 patients on stable warfarin therapy, INR increased by 0.51 with azithromycin, 0.85 with levofloxacin, and 1.76 with TMP-SMX, compared with an insignificant drop of 0.15 with terazocin, which was used as the control. The incidence of overanticoagulation was 5% with terazocin, 31% with azithromycin, 33% with levofloxacin, and 69% with TMP-SMX (J. Gen. Intern. Med. 2005;20:653–6).
Over-the-counter medications might also interact with warfarin. Acetaminophen, which is often recommended for pain relief to patients taking warfarin specifically because it doesn't increase the risk of gastrointestinal bleeding, can actually increase bleeding by interacting with the anticoagulant. In one study, acetaminophen doses of greater than 9,100 mg/week led to a 10-fold risk of having an INR greater than 6 (JAMA 1998;279:657–62). That amount of acetaminophen is the equivalent of just 2–3 extra-strength Tylenol tablets a day, Dr. Paauw pointed out.
In a randomized, double-blind crossover trial of patients on daily warfarin, adding 4 g/day of acetaminophen (the upper limit recommended on the bottle) resulted in an INR 1.75 times greater than that which occurred with placebo.
Still, acetaminophen is much safer for anticoagulated patients than are nonsteroidal drugs and shouldn't cause a problem in a patient who takes only a couple of tablets every few weeks for occasional pain. For patients with chronic pain who need daily analgesia, INR should be measured within 4–5 days after starting the analgesic, he advised.
Alternative treatments also can cause problems with warfarin. Garlic, ginger, ginkgo biloba, feverfew (used for migraines), and the herb dong quai (for menstrual cramps) can all increase the anticoagulant effect, while ginseng can decrease it. Ginkgo, used to treat a variety of vascular problems, has its own anticoagulant effect, and there have been case reports of spontaneous subdural hematomas in patients taking it. No data are available to quantify the risk, but “it makes sense not to take it when you're anticoagulated,” Dr. Paauw said.
St. John's wort, a metabolically active supplement used to treat depression, can both increase and decrease warfarin's anticoagulant effect and therefore should be avoided in patients on warfarin, he recommended.
Dr. Paauw is on the speakers' bureau for Pfizer Inc.