Warfarin Interactions: Update on the Most Common and Clinically Significant

Numerous factors, including other drugs, diseases, and diet, affect the response to warfarin(. Some of these factors decrease the response and may lead to therapeutic failure; others enhance the response and may result in life-threatening bleeding. My goal here is to heighten your awareness of these factors when you prescribe warfarin. I provide examples of drugs and diseases that may interact with oral anticoagulants, and I also offer guidance on how to avoid or minimize these interactions.WARFARIN-DRUG INTERACTIONSThe list of warfarin-drug interactions is long and continues to grow.^1-5Many of these interactions have been well documented both in controlled trials and in the clinical setting.² Several potential interactions require further study to establish their clinical relevance. The most frequently reported warfarin-drug interactions involve antimicrobial, cardiovascular, anti-inflammatory, GI, and CNS agents. Tables 1 and 2 provide a few examples of specific drugs within these classes that increase or decrease the response to warfarin.Pharmacokinetic interactions.Most warfarin-drug interactions are pharmacokinetic. For example, trimethoprim(-sulfamethoxazole (TMP-SMX) decreases the clearance of S-warfarin, which has 5 times greater anticoagulant activity than R-warfarin.³ Another type of pharmacokinetic interaction is alteration of absorption; cholestyramine decreases the absorption of warfarin.¹Pharmacodynamic interactions.Concurrent aspirin( therapy increases the risk of bleeding because it reduces platelet aggregation and has local GI effects. Although low-dose aspirin may be given with warfarin when the benefits outweigh risks (for example, after myocardial infarction), the patient must be monitored carefully. Advise patients who are receiving warfarin not to take aspirin for headache or other minor pain; acetaminophen can be used instead. Occasional acetaminophen use is safe; however, if the dosage is 9.1 g or more per week, monitor the prothrombin time (PT)/international normalized ratio (INR) for possible increased anticoagulant effect.⁶ Although the potential interaction of regular acetaminophen use with warfarin has been debated, it is prudent to err on the side of safety until more studies are done.Tips for avoiding and minimizing drug interactions. Often it is possible to circumvent interactions by prescribing an alternative agent. For example, if it is appropriate for the patient, prescribe ampicillin( rather than TMP-SMX for empiric treatment of a urinary tract infection. If an H2-blocker is indicated, select one other than cimetidine(. By careful monitoring of PT/INR, some warfarin interactions can be managed safely. When an interacting drug, such as rifampin,^1-3,5,7must be given concomitantly with warfarin, monitor the PT/INR when starting or stopping the drug and anticipate the need to change the warfarin dosage.Herbal medicines. Millions of patients take these substances, some of which (eg, dong quai⁸) are reported to interact with warfarin.⁹Ask the patient about intake of herbal medications and then search the literature for potential interactions. Much remains to be learned about these substances, and solid documentation of clinically relevant interactions is frequently lacking.EFFECT OF DISEASE ON RESPONSE TO WARFARINSome disease states alter the response to oral anticoagulant therapy (Table 3).^2-4,10 Hyperthyroidism increases the response to warfarin by increasing the catabolism of vitamin K–dependent clotting factors.^10-12 In contrast, hypothyroidism decreases the response by slowing the catabolism of these clotting factors.^10,13The liver is the site of synthesis of vitamin K–dependent clotting factors, and hepatic dysfunction is associated with increased PT. Thus, liver disease enhances the response to warfarin and other coumarin anticoagulants.^10,14Other diseases may alter the response to warfarin, but their effects are less well documented. One example is heart failure: some patients with decompensated congestive heart failure (CHF) appear to have increased responsiveness to oral anticoagulants.^4,10 Possible mechanisms for this effect include CHFinduced hepatic congestion and plasma volume expansion during CHF. The latter mechanism is supported by evidence that diuresis can decrease the response to warfarin.^15,16This decreased response may result from an increased concentration of clotting factors secondary to plasma volume reduction.^15,16The possible effects of other disorders on the response to warfarin have recently been reviewed.¹⁰EFFECT OF DIETARY FACTORSTake dietary factors into account when you assess the response to warfarin.^1,2 Vitamin K deficiency may increase the response, whereas excessive intake of vitamin K–rich foods, such as green leafy vegetables, may decrease the response. Large amounts of avocado, which is low in vitamin K, have also been reported to inhibit the response to warfarin.¹As long as the diet is consistent, the warfarin dosage can remain stable. However, major changes in vitamin K intake can markedly alter the response and may necessitate a change in warfarin dosage. Although some clinicians counsel patients to avoid foods high in vitamin K, the most appropriate advice is to encourage a consistent, balanced diet.EFFECT OF GENETIC FACTORSA recent study suggests that the response to warfarin is influenced by polymorphisms in cytochrome P-450 2C9.¹⁷ Patients with these polymorphisms have impaired S-warfarin metabolism and increased response. Future investigations need to take into account patients’ CYP 2C9 genotype. This is because a markedly increased response to warfarin early in the course of therapy may be attributable to a polymorphism rather than— or in addition to—a disease state or drug interaction.