- ACRONYMS AND DEFINITIONS
- ACCP - American College of Chest Physicians
- AHA - American Heart Association
- APA - Antiphospholipid antibody syndrome
- DVT - Deep vein thrombosis
- EF - Ejection fraction
- FFP - Fresh frozen plasma
- INR - International normalized ratio
- PCC - Prothrombin complex concentrate
- PE - Pulmonary embolism
- PT - Prothrombin time
- TIA - Transient ischemic attack
- Vitamin K antagonist - drugs that inhibit vitamin K and prevent the production of clotting Factors II, VII IX, and X. In the U.S., warfarin is the only vitamin K antagonist available.
- VTE - Venous thromboembolism (DVT and PE)
- DRUGS IN CLASS
- Vitamin K antagonists
- Warfarin (Coumadin®, Jantoven®)
- MECHANISM OF ACTION
- Vitamin K-dependent clotting factors
- Warfarin inhibits vitamin K. Vitamin K is required for the synthesis of clotting Factors II, VII, IX, and X (see coagulation cascade for more details)
- Warfarin decreases these factors and coagulation is inhibited
- FDA-APPROVED INDICATIONS
- Warfarin is FDA-approved for the following:
- Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE)
- Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement
- Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction
- ATRIAL FIBRILLATION
- Overview
- Atrial fibrillation is a common heart arrhythmia that increases a person's risk of stroke. Warfarin reduces the risk of stroke in patients with A fib.
- For many years, warfarin was the only oral anticoagulant available to prevent VTE in A fib. Then in 2010, the direct thrombin inhibitor dabigatran became available, and in 2011, the first Factor Xa inhibitor was approved. Both classes of drugs have been compared to warfarin for stroke prevention in A fib in large trials. See dabigatran vs warfarin and Factor Xa inhibitors vs warfarin for a review of those studies. Warfarin has also been compared to antiplatelet therapy (see warfarin vs antiplatelet therapy).
- A review published in the JAMA looked at the effects of warfarin on stroke risk when compared to placebo. The table below details findings from that review.
| Annual risk of stroke (% per year) in patients with Atrial fibrillation | |||
|---|---|---|---|
| < 65 years | |||
| Placebo | Warfarin | ||
| No risk factors |
1 or more risk factors |
No risk factors |
1 or more risk factors |
| 1% | 4.9% | 1% | 1.7% |
| 65 - 75 years | |||
| Placebo | Warfarin | ||
| No risk factors |
1 or more risk factors |
No risk factors |
1 or more risk factors |
| 4.3% | 5.7% | 1.1% | 1.7% |
| > 75 years | |||
| Placebo | Warfarin | ||
| No risk factors |
1 or more risk factors |
No risk factors |
1 or more risk factors |
| 3.5% | 12% | 1.7% | 4% |
- AHA recommendations
- DEEP VEIN THROMBOSIS (DVT)
- Overview
- Deep vein thrombosis is a blood clot that forms in the deep veins of the legs. The clot may break off and travel to the lungs where it becomes a pulmonary embolism. Pulmonary embolisms can be fatal.
- For many years, warfarin was the only oral anticoagulant available to treat and prevent DVTs. Then in 2010, the direct thrombin inhibitor dabigatran became available, and in 2011, the first Factor Xa inhibitor was approved. Both classes of drugs have been compared to warfarin for DVT treatment and prevention in large trials. See dabigatran and Factor Xa inhibitors for a review of those studies.
- Professional recommendations
- PULMONARY EMBOLISM
- Overview
- Pulmonary embolism is a blood clot that travels to the lungs and lodges in the lung tissue. The affected tissue cannot oxygenate properly. Pulmonary embolisms can be fatal.
- For many years, warfarin was the only oral anticoagulant available to treat and prevent PEs. Then in 2010, the direct thrombin inhibitor dabigatran became available, and in 2011, the first Factor Xa inhibitor was approved. Both classes of drugs have been compared to warfarin for PE treatment and prevention in large trials. See dabigatran and Factor Xa inhibitors for a review of those studies.
- Professional guidelines:
- HEART VALVE DISEASE AND REPLACEMENT
- Warfarin is currently the only anticoagulant that is recommended for the long-term prevention of stroke in patients who have heart valve disease or have undergone heart valve replacement
- Recommendations for anticoagulant therapy depend on the type of heart valve disease and the type of valve replacement (see heart valve disease for more)
- A study published in 2013 compared dabigatran to warfarin in patients with mechanical heart valves. The study was stopped after 252 patients were enrolled because the dabigatran group had a significantly higher incidence of stroke and major bleeding. [PMID 23991661]
- ANTIPHOSPHOLIPID ANTIBODY (APA) SYNDROME
- Antiphospholipid antibody syndrome is an autoimmune syndrome that increases a person's risk for thrombosis. Patients with APA syndrome who are triple positive (positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies) are at greatest risk for thrombosis.
- A small study that compared rivaroxaban to warfarin in patients with triple-positive APA syndrome was stopped early when rivaroxaban was found to be clearly inferior to warfarin for preventing thromboembolic events. [PMID 30002145] Another study that compared rivaroxaban to warfarin for preventing recurrent thrombosis in patients with APA syndrome did not prove that rivaroxaban was noninferior to warfarin. [PMID 31610549] If this study had more power, it's likely rivaroxaban would have been inferior.
- After these studies were published, the manufacturers of Factor Xa inhibitors and dabigatran updated their package inserts to recommend against their use in APA syndrome, especially triple-positive APA syndrome
- Based on current information, warfarin remains the preferred anticoagulant in patients with APA syndrome
- SIDE EFFECTS
- Bleeding
- The therapeutic effect of warfarin is to inhibit clot formation, therefore it will inherently increase the risk of unwanted bleeding
- The risk of bleeding on warfarin depends on a number of factors
- In trials where warfarin was compared to placebo in atrial fibrillation (INR 1.4 - 4.5), the overall risk of major bleeding ranged from 0.6% - 2.7% in the warfarin-treated group and 0% - 1.9% in the control group [10]
- In studies, risk factors associated with a higher risk of bleeding:
- Higher CHADS score (CHADS score calculation: 1 point for each of the following: heart failure, hypertension, age ≥ 75 years, diabetes. Two points for previous stroke)
- Older age (≥ 65 years)
- History of highly variable INRs
- History of gastrointestinal bleeding
- Hypertension
- Anemia
- Malignancy
- Kidney disease
- Initiation of therapy (first 30 days after starting) [10, 11]
- Tissue necrosis and organ infarction
- Calciphylaxis
- Calciphylaxis or "calcium uremic arteriolopathy" is a rare disorder that occurs in patients with end-stage renal disease
- The pathology behind calciphylaxis is not completely understood, but it appears to involve vascular calcification that leads to inflammation, fibrosis, thrombosis, and reduced blood flow. Calciphylaxis typically presents as skin necrosis.
- Warfarin therapy may be a risk factor for calciphylaxis, and it should be stopped in affected patients
- Systemic emboli
- Therapy with warfarin may enhance the release of atheromatous plaque emboli and cholesterol microemboli into the systemic circulation. Emboli may result in tissue infarction and necrosis.
- The most common organ affected by the emboli is the kidneys followed by the pancreas, spleen, and liver
- Emboli to the feet may cause a condition known as "purple toes syndrome"
- Discontinue warfarin if emboli are suspected
- CONTRAINDICATIONS
- Pregnancy - except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism
- Active bleeding
- High-risk for bleeding
- Blood dyscrasias
- Surgery - see stopping before procedures
- Threatened abortion, eclampsia, and preeclampsia
- Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding
- Known hypersensitivity
- Noncompliant patients
- Major regional or lumbar block anesthesia
- Malignant hypertension
- PRECAUTIONS
- Kidney disease
- No dose adjustment is necessary in kidney disease
- Liver disease
- Liver disease can affect warfarin metabolism, and it can also affect the production of clotting factors (see coagulopathy of liver disease for more details)
- Use warfarin with caution in patients with significant liver disease
- Heparin-induced thrombocytopenia (HIT syndrome)
- Heparin-induced thrombocytopenia is a syndrome where platelet counts drop (thrombocytopenia) when a person is given the anticoagulant heparin
- The syndrome is caused by autoimmune antibodies to heparin complexes
- Warfarin should not be given to patients with HIT syndrome because it may induce ischemia, necrosis, and gangrene
- Warfarin should only be considered once the platelet count has normalized [10]
- Protein C and S deficiency
- Protein C deficiency and protein S deficiency are rare disorders that increase a person's risk of forming a blood clot
- Patients with these disorders may be at increased risk of warfarin-induced tissue necrosis
- When starting warfarin in these patients, concomitant heparin for 5 - 7 days may reduce the risk of necrosis [10]
- Pregnancy
- Warfarin is a known teratogen and can be harmful to the fetus
- Warfarin should not be used by pregnant women or in women who are trying to become pregnant
- In very rare circumstances, warfarin may be indicated in pregnant women with mechanical heart valves who are at high risk for blood clots [9, 10]
- Elderly patients
- Elderly patients (≥ 60 years) may be more sensitive to warfarin, and therefore require lower doses
- Older patients are also more likely to have bleeding complications while taking warfarin [10]
- Asian patients
- Asian patients may be more sensitive to warfarin, and therefore require lower doses [10]
- MONITORING THERAPY
- Dosage form
- Warfarin is made by a number of manufacturers. One of the generic versions has a proprietary name called Jantoven. Brand name Coumadin® is also still available.
- Warfarin is cheap, costing less than $20 for 90 tablets
- Tablet
- 1 mg
- 2 mg
- 2.5 mg
- 3 mg
- 4 mg
- 5 mg
- 6 mg
- 7.5 mg
- 10 mg
- Initiating therapy
- A typical warfarin starting dose is 4 - 5 mg once daily. Some experts recommend a loading dose, while others do not. The ACCP guidelines state that a loading dose of 10 mg a day for 2 days may shorten the time to a therapeutic INR. Elderly patients, Asian patients, and those at increased risk of bleeding should use a starting dose between 2 and 3 mg.
- An anticoagulant effect from warfarin is seen within 2 - 7 days. Check the INR daily until the therapeutic range has been achieved for 2 straight days. After that, the INR is checked 2 to 3 times a week for 1 - 2 weeks, then less often depending on the results.
- The target INR is 2 - 3 for most conditions (e.g. A fib, VTE), while a higher range (2.5 - 3.5) is recommended for certain mechanical heart valves. [12, 14]
- Patients should be made aware of how their diet can affect warfarin (see food and warfarin)
- A website is available that estimates a patient's therapeutic warfarin dose based on clinical factors and, if available, their CYP2C9 and VKORC1 genotypes. See warfarin dosing estimator and genetic testing for more.
- Monitoring therapy
- After the initiation period, INR testing can be reduced to once every 4 weeks. If INRs remain stable, the ACCP states that testing can be extended to once every 12 weeks.
- Recommendations for addressing out-of-range INRs are presented in the table below. See urgent reversal for guidelines on treating patients with life-threatening bleeding.
| Adjusting warfarin based on INR |
|---|
INR ≤ 0.5 below or above therapeutic range in previously stable patient
|
INR is above therapeutic range, but less than 5
|
INR is 5 - 9
|
INR is > 9
|
Need for surgery or dental extraction within 2 - 3 days
|
- REVERSING WARFARIN
- Urgent reversal
- The anticoagulant effect of warfarin can be reversed immediately by infusing blood products
- Prothrombin complex concentrate (PCC) is the preferred product, but fresh frozen plasma may be used if it is not available
- Prothrombin complex concentrate (PCC)
- PCC does not require thawing and blood group typing like FFP, so it can be administered more quickly. The volume of infusion for PCC is much less than FFP.
- PCC comes in 2 versions - 3-factor PCC (contains Factors II, IX, X) or 4-factor PCC (contains Factors II, VII, IX, X)
- A study in the Lancet compared fresh frozen plasma to 4-factor PCC in patients requiring urgent reversal of vitamin K antagonists. 4-factor PCC was superior to FFP in achieving hemostasis and rapid reversal of the INR. [PMID 25728933]
- Fresh Frozen Plasma (FFP) - traditional agent used. Requires thawing and blood typing. Volume infused can be large.
- activated Factor VII - less studied
- Professional recommendations
- The ACC publishes recommendations for managing bleeding in patients taking oral anticoagulants. Those guidelines are available at the link below.
- Vitamin K reversal
- The anticoagulant effect of warfarin can be reversed with vitamin K
- The liver must take the vitamin K and make clotting factors from it, so the effects are not immediate
- Vitamin K cannot be used for urgent reversal, but it can be used to treat high INRs in patients without life-threatening bleeding. See monitoring therapy for recommendations.
- Vitamin K can be given orally, subcutaneously, or intravenously. The time to effect varies by the route given.
- Intravenous vitamin K - INR will start to fall rapidly within 4 - 6 hours after administration
- Oral vitamin K - INR will start to fall 18 - 24 hours after administration
- Subcutaneous vitamin K - effect is unpredictable [20]
- STOPPING BEFORE PROCEDURES
- Overview
- Holding warfarin for 5 days will cause the INR to decrease to < 1.5 in 93% of patients [14]
- Professional recommendations
- WARFARIN + ANTIPLATELET THERAPY
- In some cases, patients will have indications for both anticoagulation and an antiplatelet drug (e.g. atrial fibrillation with CAD)
- Recommendations for treating these patients are covered at the links below
- FOOD AND WARFARIN
- Overview
- Warfarin works by inhibiting vitamin K, therefore, the anticoagulant effects of warfarin can be overcome by consuming vitamin K
- Vitamin K is primarily found in green, leafy vegetables
- Patients on warfarin should try to keep their dietary intake of green, leafy vegetables consistent. They should also check the labels on vitamins and supplements they are taking to see if they contain vitamin K.
- Large fluctuations in the consumption of vitamin K-containing foods will affect warfarin and INR levels
- The USDA has an online, searchable database that contains nutrient information including the vitamin K content of a large number of foods
- Foods high in vitamin K
- The estimated daily requirement of vitamin K for adults is 80 micrograms
- The average intake of vitamin K for most adults is 70 - 80 micrograms a day
- Patients on warfarin should try to keep their vitamin K intake consistent from day-to-day
- The table below list foods that are high in vitamin K. The vitamin K content of almost any food can be found in the USDA database.
- Patients on warfarin should try to keep their intake of these foods consistent
| Foods high in Vitamin K | |
|---|---|
| FOOD | Vitamin K (mcg) per 30 gram serving |
| Parsley, raw | 492 |
| Kale, cooked, boiled | 245 |
| Mustard greens, cooked, boiled | 177 |
| Spinach, cooked, boiled | 148 |
| Spinach, raw | 145 |
| Collards, cooked, boiled | 122 |
| Turnip greens, cooked, boiled | 110 |
| Swiss chard, cooked, boiled | 98 |
| Soybean oil | 55 |
| Green onions, raw | 47 |
| Brussels sprouts, cooked, boiled | 42 |
| Broccoli, cooked, boiled | 42 |
| Green leaf lettuce, raw | 38 |
| Romaine lettuce, raw | 31 |
| Broccoli, raw | 30 |
- WARFARIN RESISTANCE SYNDROME
- A small number of people who take warfarin require very large doses to achieve therapeutic INRs
- These people are thought to have a genetically inherited trait that causes reduced affinity of warfarin for its liver receptors [12]
- GENETIC TESTING
- Genetic variations in two enzymes can affect the activity of warfarin:
- CYP2C9 - involved in warfarin metabolism
- VKORC1 - vitamin K epoxide reductase complex 1 (the enzyme warfarin inhibits)
- Genetic testing and warfarin management
- Genetic testing is available which can detect variations in these enzymes. Results of these tests can then be used to guide warfarin dosing (see warfarindosing.org for more).
- Studies comparing the use of genetic testing to standard dosing have not found genetic testing to be cost-effective or beneficial
- A study published in 2013 compared two algorithms for dosing warfarin in the first 4 weeks of therapy. One algorithm incorporated results from genetic testing for CYP2C9 and VKORC1 alleles (genetic algorithm) and the other did not (control). The genetic algorithm was no better than the control algorithm for amount of time spent in the therapeutic INR range. [PMID 24251361]
- Professional recommendations
- The ACCP recommends against genetic testing in warfarin therapy [14]
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Overview
- A large number of case reports in the medical literature cite possible drug interactions with warfarin
- Unfortunately, these reports do not prove causality, and since a number of other factors (ex. medical conditions, diet, etc.) can alter the anticoagulant effect of warfarin, it is difficult to discern which cases are true drug interactions and which ones are not
- Anytime a patient on warfarin changes their concomitant medications, it is prudent to check for possible interactions. If a concern arises, then the INR should be checked more frequently during the initial medication change.
- Drug interactions
- Cholestyramine (Questran®) - Cholestyramine inhibits warfarin absorption and will decrease its effect. If taken concomitantly, warfarin should be taken 1 hour before, or 4 hours after cholestyramine
- Cytochrome P450 2C9 (CYP2C9) Inhibitors and Inducers - warfarin is a CYP2C9 sensitive substrate. CYP2C9 inducers may decrease exposure to warfarin and lower the INR, and CYP2C9 inhibitors may increase exposure to warfarin and increase the INR. Monitor closely when combining.
- Cytochrome P450 3A4 (CYP3A4) Inhibitors and Inducers - warfarin is a CYP3A4 substrate. CYP3A4 inducers may decrease exposure to warfarin and lower the INR, and CYP3A4 inhibitors may increase exposure to warfarin and increase the INR. Monitor closely when combining.
- Cytochrome P450 1A2 (CYP1A2) Inhibitors and Inducers - warfarin is a CYP1A2 substrate. CYP1A2 inducers may decrease exposure to warfarin and lower the INR, and CYP1A2 inhibitors may increase exposure to warfarin and increase the INR. Monitor closely when combining.
- Drugs that increase the risk of bleeding - drugs that inhibit coagulation may increase the risk of bleeding when taken with warfarin
- Drugs that may increase the risk of bleeding include:
- Anagrelide (Agrylin®)
- Aspirin
- Direct thrombin inhibitors (dabigatran)
- Factor Xa inhibitors (e.g. rivaroxaban, apixaban)
- Fish oil (e.g. Vascepa®)
- P2Y12 inhibitors (e.g. clopidogrel, ticagrelor, prasugrel)
- NSAIDs (e.g. ibuprofen, naproxen)
- SSRIs and SNRIs (e.g. fluoxetine, venlafaxine)
- Vorapaxar (Zontivity®)
- Mirtazapine (Remeron®) - may increase warfarin levels
- Orlistat (Xenical®, Alli®) - orlistat can inhibit vitamin K absorption which may potentiate the effects of warfarin. Patients who start orlistat while taking warfarin should have their INR levels monitored closely.
- Sulfonylureas (glimepiride, glipizide) - in an observational study, the combined use of warfarin with glimepiride or glipizide was associated with a higher risk of hypoglycemia in patients ≥ 65 years old. The mechanism behind this possible interaction is unclear. [16]
- Testosterone replacement therapies - may alter warfarin activity. Monitor INR more frequently when combining.
- Valproic acid - valproic acid may displace warfarin from protein-binding and increase its effect
- Vitamins/supplements - vitamins and supplements that contain vitamin K may alter the effects of warfarin
- Metabolism and clearance
- LONG TERM SAFETY
- Warfarin was approved for use in the U.S. in 1961
- It has been widely prescribed for decades
- Its side effects and benefits are well-known
- BIBLIOGRAPHY
- 1 - PMID 16908781
- 2 - PMID 19717844 - RE-LY study - dabigatran
- 3 - PMID 21830957 - ROCKET-AF study - rivaroxaban
- 4 - PMID 21870978 - ARISTOTLE - apixaban
- 5 - PMID 19966341 - RE-COVER study - dabigatran
- 6 - PMID 21128814 - EINSTEIN-DVT - rivaroxaban
- 7 - PMID 22449293 - EINSTEIN-PE - rivaroxaban
- 8 - PMID 22858728 - AHA GL on VTE
- 9 - PMID 22315257 - ACCP GL on VTE
- 10 - PMID Warfarin PI
- 11 - PMID 23184840 - CMAJ study
- 12 - PMID 12668507 - AHA guide to warfarin therapy
- 13 - PMID NIH fact sheet on warfarin - CLICK HERE
- 14 - PMID 22315259 - ACCP guide to warfarin therapy
- 15 - PMID 24682348 - AHA 2014 GL on A fib
- 16 - PMID 26643108 - Sulfonylureas and warfarin
- 17 - PMID 24251359 - ENGAGE TIMI-AF trial
- 18 - PMID 24251359 - ENGAGE TIMI-AF trial
- 19 - PMID 26867832 - ACCP 2016 VTE update
- 20 - PMID 29203195 - 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants