To provide an overview of the mechanism of action, dosing regimens and side-effects of warfarin and other vitamin K antagonists.Warfarin is an indirect anticoagulant producing its effect by decreasing the ability of the liver to produce fully functional coagulation factors II, VII, IX, and X, as well as the endogenous anticoagulants, protein C and protein S. Current Clinical Practice Guidelines generally recommend direct oral anticoagulants (DOACs) over warfarin for most patients with venous thromboembolism (VTE) and atrial fibrillation (AF) as DOACs are as effective and cause similar or less bleeding, but there are still circumstances where warfarin is preferable or indicated. This guide will try to address these issues.# INDICATIONS:
Common uses of warfarin include:
- prevention of stroke or systemic embolism in patients with AF, especially those with rheumatic mitral stenosis - treatment of acute VTE (overlapped with parenteral anticoagulation) - long-term secondary prevention of VTE - prevention of thrombosis or systemic embolization in patients with mechanical heart valves or with certain diseases of the native heart valves Less common uses include:
- management of patients with acute anterior myocardial infarction - prevention of systemic embolization from the heart, e.g. mural thrombus - prevention of recurrent stroke in selected patients without AF - to maintain hemodialysis access and arterial graft patency - prevention of VTE in high risk patients, e.g. hip or knee arthroplasty - prevention of recurrent venous and arterial embolism in those with antiphospholipid antibody syndrome DOSING:
- The maintenance dose of warfarin varies widely among patients, from less than 1 mg/day to greater than 20 mg/day. - In general, warfarin should be started at the dose estimated to be required for long-term therapy. For most adults, a reasonable starting dose is 5 mg daily. In those who are frail, underweight or of Asian descent, starting a lower dose at 1 -2 mg daily may be more suitable.
- Factors affecting the maintenance dose of warfarin include:
- Age - Body weight - Race - Nutritional status, diet
- Genetic variation in the enzyme that is the site of warfarin action (VKOR)
- Genetic variation in the enzyme system that metabolizes warfarin (CYP450)
- Concomitant drugs - Alcohol intake - Comorbidity, e.g. liver disease, heart failure - Activity level MONITORING:
- Routine laboratory monitoring is required for all patients taking warfarin.
- The target INR (international normalizing ratio) for most patients is 2.0-3.0. For most patients with mechanical mitral valves the target INR is 2.5-3.5. - The time it takes for warfarin to produce a change in the INR depends on the time for preexisting vitamin K-dependent clotting factors to be metabolized. Depending on the dose of warfarin and individual factors, the timeframe for this process is approximately 3 to 7 days. Therefore, it is recommended that monitoring be performed no earlier than 2 to 3 days after the first dose and subsequent dose changes. - There are a variety of tools to aid in the management of warfarin therapy, including:
- Computerized monitoring - Paper-based dosing algorithms - Point-of-care INR testing A summary of advantages, disadvantages and examples of each of these approaches is provided in the Table 1. All approaches used to monitor the effectiveness and safety of warfarin therapy should incorporate clear patient education and a system of data management to record and track all INRs and warfarin doses. 

# DRUG INTERACTIONS:
- Most drug interactions with warfarin occur because of concurrent antiplatelet effect or drugs that compete for cytochrome P450, the enzyme system that metabolizes warfarin. - Antiplatelet agents: Most patients who take warfarin should not also use an antiplatelet agent, since the risk of bleeding is more than doubled and many patients do not derive additional protection with the combination. Reasons for use of an antiplatelet agent in patients who also have an indication for anticoagulation include, but are not limited to: patients with acute coronary syndrome and/or those with new coronary artery stents, some patients with high-risk mechanical heart valves, and patients with a proven stroke or transient ischemic attack (TIA) while therapeutically anticoagulated with warfarin. For each patient, the risk-benefit of using warfarin with an antiplatelet agent must be carefully and repeatedly assessed. - Non-steroidal anti-inflammatory drugs (NSAIDs): The risk-benefit assessment also applies to using traditional NSAIDs with warfarin. In addition, many of these NSAIDs are metabolized in the liver by CYP 2C9 which also metabolizes warfarin. For patients who require both anticoagulation and an NSAID, strategies to reduce the risk of gastrointestinal bleeding include a COX2 inhibitor such as celecoxib or a traditional NSAID plus a proton pump inhibitor. - Alterations in concomitant medications and new concurrent illness should result in more frequent INR testing. - Antibiotics typically increase INR through multiple mechanisms.
- For drugs that may affect warfarin metabolism or clearance, the simplest approach is to obtain an INR 3-4 days after the addition of the new drug and then adjust the dose, if necessary. In general, very few drugs will need to be avoided when using this approach. - Acute infections or other changes in health status (e.g. diarrhea, vomiting, heart failure) can also alter warfarin response and should also prompt more frequent INR monitoring. - Alcohol and a number of health supplements (e.g. St. John's Wort) can also change the INR.

# ADVERSE EFFECTS:
- The major adverse effect of warfarin is bleeding. On average, the annual rate of major bleeding is 1-2% in patients on chronic warfarin, while minor bleeding events occur in 10-20% of warfarin users per year. - Other, uncommon, side effects include hair loss and skin rash.

# INITIAL TREATMENT OF ACUTE VTE
Initial treatment of acute VTE with warfarin should be combined with an immediate-acting parenteral anticoagulant such as low molecular weight heparin (LMWH) for at least 5 days and until the INR reaches at least 2.0 for 2 consecutive days. Initial dosing is best guided by using standardized nomograms. Frequent monitoring is required until a stable, in-range INR is reached, after which time reduced frequency of testing is appropriate.

# SPECIAL CONSIDERATIONS:
- The anticoagulant effect of warfarin can be reversed using vitamin K. For emergency reversal, intravenous vitamin K should be administered along with a four-factor prothrombin complex concentrate (Octaplex  , Beriplex  

# PEDIATRICS:
- Warfarin can be used for the treatment and prevention of thrombosis in children.
- Therapy is complicated by the need for regular blood work, which may be difficult to obtain in small children. Point-of-care devices may be of assistance in this setting. - Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.

# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:

# Date of Version: 07August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.