Continuing Education Activity

Warfarin has FDA approval for the prophylaxis and treatment of venous thrombosis and its complications, such as a pulmonary embolus. It is also indicated to prevent thromboembolic complications associated with conditions such as atrial fibrillation, cardiac valve replacement, and inherited genetic factors like C and S protein deficiency or Factor V Leiden. Additionally, warfarin is FDA approved as an adjunct to reduce the risk of myocardial infarction (MI) and other thromboembolic events in high-risk patients. However, warfarin falls in the narrow therapeutic index drug category and is subject to numerous interactions. This activity outlines the indications, mechanism of action, interactions, significant adverse effects, contraindications, toxicity, and warfarin monitoring so providers can direct patient therapy where anticoagulation is indicated as part of the interprofessional team.

Objectives:

• Identify the mechanism of action of warfarin.

• Review the agents that can either increase or decrease the anticoagulant effect of warfarin.

• Summarize the target INR levels for warfarin therapy based on conditions that affect INR targets.

• Describe the importance of collaboration and coordination among the interprofessional team and how it can enhance patient care with warfarin therapy in conjunction with the patient's entire medication regimen to improve patient outcomes for patients with conditions where anticoagulation is indicated.

Indications

Warfarin has FDA approval for the prophylaxis and treatment of venous thrombosis and its complications, such as a pulmonary embolus. It is also indicated to prevent thromboembolic complications associated with conditions such as atrial fibrillation, cardiac valve replacement, and inherited genetic factors like C and S protein deficiency or Factor V Leiden.[1][2] Additionally, warfarin is FDA approved as an adjunct to reduce the risk of myocardial infarction (MI) and other thromboembolic events in high-risk patients.[3][4]

Mechanism of Action

Warfarin's anticoagulant effects help prevent clot formation and the extension of any current clots, but it has no direct impact on clot removal or reversing ischemic tissue damage. Warfarin exhibits its anticoagulation effects via the intrinsic and extrinsic pathways in the clotting cascade. This activity occurs through effects on vitamin K-dependent clotting factors (II, VII, IX, and X) and the anticoagulant proteins C and S. Warfarin interferes with the activation of clotting factors by blocking the vitamin K oxidation-reduction cycle needed for the carboxylation of clotting factors, which ultimately lessens the amount of active vitamin K reserves available to act as a cofactor in the formation of glutamic acid residues within the clotting factors mentioned above. These actions render clotting factors inactive and unable to participate in the clotting cascade.

Warfarin's hepatic metabolism and protein binding are the most common mechanisms for the occurrence of drug-drug interactions. Warfarin is metabolized via the cytochrome P450 system by CYP 2C9, 1A2, and 3A4. It is a racemic mixture, with the S-enantiomer being 2.7 to 3.8 times more potent than the R-enantiomer. Since the S-enantiomer is more potent and primarily metabolized by CYP 2C9, drug-drug interactions affecting this pathway may be more significant. Medications with a higher protein binding affinity than warfarin can displace warfarin creating more free warfarin within the bloodstream.[5][6] However, this mechanism is less clinically significant than enzyme inhibition.

Administration

Warfarin is an oral medication administered once daily. Patients can take the drug at any time of day, but dosing recommendations are usually for the afternoon or evening. By taking warfarin later in the day, healthcare providers have the opportunity to individualize the dose based on a patient's current international normalized ratio (INR). An INR provides a standardized measurement of the prothrombin time (PT), reflecting how quickly a patient's blood clots via the extrinsic and common clotting pathways. The INR allows for the standardization of specific laboratory variances in the measurement of the PT. A healthy patient who is not taking warfarin should have an INR of approximately 1.0. Most patients have a goal INR of 2.0 to 3.0, but some indications, such as a mechanical mitral heart valve, require an INR goal of 2.5 to 3.5.[4][7] 

If a patient misses a dose, the individual should take the dose as soon as possible on the same day, but the patient should never double a dose the next day to make up for a missed dose. Regarding potential drug-drug interactions, changing the administration time of warfarin does not typically avoid an interaction except in the cases of patients taking a medication that affects warfarin absorption, such as bile acid sequestrants and sucralfate.[5][6]

Adverse Effects

Signs and symptoms of bleeding require vigilant monitoring upon initiation of warfarin since this is the most common adverse effect. Rare yet severe adverse effects include tissue necrosis, calciphylaxis, systemic atheroemboli, and cholesterol microemboli. Tissue necrosis usually begins within days of starting warfarin and has been associated with patients having deficiencies of proteins C or S. Warfarin reduces the synthesis of both of these naturally occurring anticoagulant proteins, which leads to a prothrombotic state. Concomitant administration of heparin for 5 to 7 days may minimize the incidence of necrosis when initiating warfarin. Calciphylaxis or calcium uremic arteriolopathy in patients with or without end-stage renal disease on warfarin can result in vascular calcification and cutaneous necrosis.[5][8] Systemic atheroemboli and cholesterol microemboli may result due to the release of plaque emboli after the initiation of warfarin.  Various locations within the body can be affected, including the feet. Specifically, purple toe syndrome occurs when microemboli travel to a patient's toes and may occur months after the initiation of warfarin. Alternative anticoagulation therapy merit consideration in patients with severe adverse effects while on warfarin.[5]

There are multiple medications and herbal products that can potentiate or inhibit the effects of warfarin. Any drug that affects the ability to clot, such as other anticoagulants, antiplatelets, nonsteroidal anti-inflammatory agents (NSAIDs), and selective serotonin reuptake inhibitors (SSRIs), will increase the risk of bleeding even if the INR does not increase.[9] However, drug-drug interactions usually lead to an increased INR unless the concomitant medication is a CYP P450 inducer. Drugs that are enzyme inducers may lower the INR.[5][6]

Antimicrobial agents are one of the most common medication classes that can interact with warfarin. There are multiple proposed theories, including the eradication of gut bacteria that produce vitamin K2, which would result in less antagonism of warfarin.[5] This type of interaction is usually considered minor. Some antimicrobials directly interfere with the metabolism of warfarin due to CYP inhibition, including metronidazole, trimethoprim-sulfamethoxazole, and ciprofloxacin.[6][10] These are usually considered major interactions, and if possible, avoid concomitant therapy. Another major interaction is with amiodarone, which can potentiate the effects of warfarin via two different mechanisms. It can decrease warfarin metabolism via CYP inhibition, and with prolonged use, it may also affect thyroid function by causing hyperthyroidism or hypothyroidism.[11][12][13] 

With any increase in thyroid function, there is potential for an increase in the INR of a patient taking warfarin due to increased catabolism of vitamin K-dependent clotting factors.[13][14] Cimetidine may increase the INR by inhibiting the metabolism of R-warfarin. Concomitant use of salicylates with warfarin can lead to increased bleeding risk because salicylates inhibit platelet aggregation, can lead to gastric irritation, and result in increased free warfarin due to salicylates having a higher affinity for protein binding sites.[5] 

Although the mechanism is not fully understood, fibric acid derivatives have correlations with potentiating the effects of warfarin.[15] Phenytoin can lead to increases or decreases in the INR. Upon initiation of phenytoin, the INR may increase due to the displacement of warfarin from protein binding sites. Long-term phenytoin use with warfarin can decrease the INR since it is a CYP inducer.[5] Rifampin is also a CYP enzyme inducer. Due to the increase in warfarin metabolism, a higher daily dose may be necessary. Patients on warfarin should avoid or minimize alcohol consumption. Acutely, drinking more alcohol will inhibit the metabolism of warfarin, but chronic use of alcohol can induce liver enzymes and result in a lower INR.[16] Ongoing alcohol use is a concern for the risk of gastrointestinal bleeding, which will complicate anticoagulation management.

Since there is limited standardization of herbal products, it is difficult to demonstrate when clinically significant drug-herbal interactions exist with warfarin.[17][18] American ginseng has led to a decrease in INR for individuals concomitantly taking warfarin in a small randomized, controlled study.[19] Green tea has been associated with inhibiting the effects of warfarin and decreasing the INR due to its high amount of vitamin K.[5][20][21] The previously mentioned drug-drug and drug-herbal interactions are some of the more commonly encountered ones, but a clinician should always reference a drug information source when determining a potential interaction with warfarin. Although not discussed in this review, it is worth noting that drug-food and drug-disease interactions may occur and should merit consideration as another possible cause of INR variation.

Contraindications

Warfarin has both absolute and relative contraindications. Most of the absolute contraindications are related to conditions and procedures with active bleeding or the tendency to bleed. Warfarin use is also contraindicated in pregnancy (except in those with mechanical heart valves with a high risk for thromboembolism) due to a risk of fetal warfarin syndrome, which manifests with fetal malformations and an increased risk of spontaneous abortions and stillbirth.[22] Patients with malignant hypertension should not use warfarin due to the risk of hemorrhagic stroke with extremely high blood pressure. Potential drug-drug interactions require evaluation based on the clinical risk and benefit of the medications.

Monitoring

The laboratory parameter used to determine if warfarin anticoagulation is therapeutic is the INR. During warfarin therapy, a blood sample is taken to determine the INR. Once a patient is in the maintenance phase of treatment, the INR is typically collected at least every four weeks. If a patient's INR becomes supratherapeutic or subtherapeutic, another INR will need to be collected within 1 to 7 days to ensure the patient's level has returned to the therapeutic range. An INR may also be collected when starting, discontinuing, or changing doses of medications known to interact with warfarin.[7]

Since warfarin is an anticoagulant, monitoring for signs and symptoms of bleeding such as black tarry stools, nosebleeds, or hematomas is imperative. Hemoglobin and hematocrit levels should be obtained before the initiation of warfarin and approximately every six months while taking warfarin. Other laboratory tests may be indicated based on a given patient's presentation, including a urinalysis, occult blood, and liver function tests. Drug-drug, drug-herbal, drug-food, and drug-disease state interactions are all important factors that require monitoring to help avoid potential adverse effects related to supratherapeutic or subtherapeutic anticoagulation.

Toxicity

For a patient with warfarin toxicity, treatment depends on the INR and the presence of bleeding.[23][24] The first step in treating a patient is to discontinue warfarin and consider administering vitamin K. If the INR is over 10 without bleeding, oral vitamin K 1 to 5 mg is an option. Oral vitamin K may take up to 24 hours to fully reverse warfarin-induced coagulopathy. If a patient is bleeding, intravenous vitamin K may be dosed at 1 to 10 mg, depending on the severity. Intravenous vitamin K can often reverse coagulopathy within 4 to 6 hours. Subcutaneous vitamin K should be reserved for select patients since vitamin K is a fat-soluble vitamin and is subject to erratic absorption from the subcutaneous tissue.[7][25] 

If a more rapid reversal is necessary, the clinician can order fresh frozen plasma (FFP), though administration often takes several hours. If the clinician desires emergent reversal, four-factor prothrombin complex concentrates (4F-PCCs) can be rapidly administered with a full reversal of coagulopathy within 15 to 30 minutes with less volume compared to plasma.[7][24]

Enhancing Healthcare Team Outcomes

Managing drug-drug interactions related to warfarin and its sequelae should involve an interprofessional approach involving laboratory technicians, nurses, pharmacists, and physicians. The first step in managing these interactions often comes at the time of warfarin prescribing. Physicians should work closely with pharmacists to avoid prescribing medications that have interactions. If these medications are essential, adjusting the patient's warfarin dose may be necessary with close follow-up and monitoring early in the treatment regimen. The patient should also receive education on the prevalence of these interactions, many of which exist with drugs or supplements that do not require a prescription.

In the event of toxicity, physicians must rapidly assess bleeding risk or the degree of bleeding and identify less common complications of warfarin therapy. Coordination with a pharmacist, blood bank technician, and nursing staff are often required to quickly obtain and administer appropriate reversal agents and appropriately monitor response to therapy. Pharmacists can recommend dosing changes and/or reversal agents, which the nursing staff will deliver. Emergent bleeding can represent an "all hands on deck" situation, and coordinated care across professional lines is critical for efficient therapeutic action. Only by working together can the interprofessional healthcare team minimize drug-drug interactions with warfarin and rapidly treat those that were not preventable, leading to optimal patient care. [Level 5]