Warfarin has FDA approval for the prophylaxis and treatment of venous thrombosis and its complications such as a pulmonary embolus. This indication includes 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 after a patient's first MI.
Warfarin's anticoagulant effects help prevent clot formation and the extension of any current clots, but it has no direct effect on clot removal or reversing ischemic tissue damage. Warfarin exhibits its anticoagulation effects via the intrinsic and extrinsic pathways in the clotting cascade. This occurs by inhibiting the synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X) and the anticoagulant proteins C and S. Warfarin interferes with the synthesis of clotting factors by blocking the vitamin K oxidation-reduction cycle needed for the carboxylation of clotting factors. This ultimately lessens the amount of active vitamin K reserves available to act as a cofactor in the formation of glutamic acid residues within the aforementioned clotting factors.
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 is primarily metabolized by CYP 2C9, drug-drug interactions affecting this pathway may be more significant. Medications with a higher protein binding affinity than warfarin (e.g., aspirin) can displace warfarin creating more free warfarin within the blood stream.
Warfarin is an oral medication administered once daily. It can be taken at any time of day but is usually recommended to be taken in the afternoon or evening. By taking warfarin later in the day, healthcare providers are provided the opportunity to individualize a patient's dose based on the most current INR. An INR provides a standardized measurement of the prothrombin time (PT), which reflects how quickly a patient's blood clots via the extrinsic and common clotting pathways. The INR allows for 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. If a patient has an INR of 2.0 to 3.0, it takes his or her blood 2 to 3 times longer to clot than someone not taking an anticoagulant. Most patients have a goal INR of 2.0 to 3.0, but there are some indications such as a mechanical heart valve in the mitral position that requires an INR goal of 2.5 to 3.5. 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. In regards to 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.
Signs and symptoms of bleeding should be monitored upon initiation of warfarin since this is the most common adverse effect. Rare yet severe adverse effects include tissue necrosis, calciphylaxis, and 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 and can result in vascular calcification and cutaneous necrosis. 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 should be considered in patients with severe adverse effects unless the risk outweighs the benefit of taking an anticoagulant.
There are multiple medications and herbal products that can potentiate or inhibit the effects of warfarin. Any medication 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 when there is not a specific drug-drug interaction. Drug-drug interactions are numerous and usually lead to an increase in PT/INR levels unless the concomitant medication is a CYP P450 inducer such as rifampin.
Antimicrobial agents are one of the most common medication classes that can interact with warfarin. There are multiple proposed theories including eradication of gut bacteria that produce vitamin K2, which would result in less antagonism of warfarin. Some antimicrobials directly interfere with the metabolism of warfarin due to CYP inhibition including metronidazole, trimethoprim-sulfamethoxazole, fluoroquinolones, isoniazid, and fluconazole. Amiodarone 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. With any increase in thyroid function, there is potential for an increase in the PT/INR of a patient taking warfarin due to the increased catabolism of vitamin K-dependent clotting factors. 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. Fibric acid derivatives have been associated with potentiating the effects of warfarin through metabolism inhibition although the mechanism(s) are not fully understood. Both phenytoin and alcohol can lead to increases or decreases in PT/INR levels. Upon initiation of phenytoin, PT/INR levels typically increase due to the displacement of warfarin from protein binding sites. Long-term phenytoin use with warfarin can lead to a decrease in PT/INR levels since it is a CYP inducer. Acutely, drinking more alcohol will inhibit the metabolism of warfarin, but chronic use of alcohol without liver failure can induce liver enzymes and result in a lower PT/INR. Ongoing alcohol use is a concern for risk of gastrointestinal bleeding in individuals who are and are not taking warfarin.
Since there is limited standardization of herbal products, it is difficult to demonstrate when clinically significant drug-herbal interactions exist with warfarin. American ginseng has led to a decrease in PT/INR for individuals concomitantly taking warfarin in a small randomized, controlled study. Green tea has been associated with inhibiting the effects of warfarin due to its high amount of vitamin K. The aforementioned drug-drug and drug-herbal interactions are some of the more commonly encountered ones, but a drug information source always should be referenced when determining a potential interaction with warfarin. Although not discussed in this review, it should be noted that drug-food and drug-disease interactions may occur and should be considered as a possible cause of INR variation in addition to drug-drug and drug-herbal interactions, non-adherence, etc.
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 when 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. Patients with malignant hypertension should not use warfarin due to the risk of hemorrhagic stroke with extremely high blood pressure. Although most contraindications with warfarin are in regards to bleeding potential, non-adherence is considered a contraindication as well. Potential drug-drug interactions should be evaluated based on the clinical risk and benefit of the medications.
The laboratory parameter used to determine if warfarin is in an appropriate therapeutic range is the prothrombin time (PT)/INR. The PT is the number of seconds it takes the blood to clot, and the INR provides a mechanism for standardizing the PT measurement depending on the thromboplastin reagent used by a laboratory. During warfarin therapy, a blood sample is taken to determine a PT/INR. Once a patient is in the maintenance phase of therapy, a PT/INR typically is collected at least every four weeks. If a patient's PT/INR becomes supratherapeutic or subtherapeutic, another PT/INR level will need to be collected within 1 to 7 days, depending on the original PT/INR, to ensure the patient's level has returned to the therapeutic range. A PT/INR also may be collected when starting, discontinuing, or changing doses of medications that are known to interact with warfarin, therefore, affecting the PT/INR level.
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 and PT/INR levels 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 should be monitored to help avoid potential adverse effects related to supratherapeutic or subtherapeutic PT/INR levels.
Warfarin toxicity may be determined by signs and symptoms of bleeding prior to the determination of a supratherapeutic PT/INR level. Bleeding risk rises steeply once the INR is greater than 5.0. There are multiple treatment options for a patient depending on the patient's clinical presentation and PT/INR. The first step to treating a patient is to discontinue warfarin. Then, vitamin K1 may be administered orally, subcutaneously, or intravenously. Oral vitamin K is preferred unless a patient has major bleeding or an extremely elevated PT/INR, and then intravenous vitamin K is recommended. Subcutaneous vitamin K1 should be reserved for select patients since vitamin K is a fat-soluble vitamin and is erratically absorbed from the subcutaneous tissue. Oral vitamin K can take up to 24 hours to fully reverse warfarin-induced coagulopathy, whereas intravenous vitamin K can often reverse coagulopathy within 4-6 hours.
If more rapid reversal is desired, fresh frozen plasma (FFP) can be administered, though administration often takes several hours to administer. If emergent reversal is desired, prothrombin complex concentrates (PCCs) can be rapidly administered with full reversal of coagulopathy within 15-30 minutes.
Management of drug-drug interactions related to warfarin and its sequelae should involve an interdisciplinary approach involving laboratory technicians, nurses, pharmacists, and physicians. The first step in managing these interactions often comes at the time of warfarin initiation. Physicians should work closely with pharmacists to avoid prescribing medications that have interactions with warfarin. If these medications are absolutely necessary, adjustment of the patient's dose of warfarin is strongly recommended with close followup and monitoring early in the treatment regimen. The patient should also be educated 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 all often required to quickly obtain and administer appropriate reversal agents and appropriately monitor a response to therapy. Only by working together can healthcare providers minimize drug-drug interactions and rapidly treat those that could not have been prevented.
|||Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines., Kearon C,Akl EA,Comerota AJ,Prandoni P,Bounameaux H,Goldhaber SZ,Nelson ME,Wells PS,Gould MK,Dentali F,Crowther M,Kahn SR,, Chest, 2012 Feb [PubMed PMID: 22315268]|
|||Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines., You JJ,Singer DE,Howard PA,Lane DA,Eckman MH,Fang MC,Hylek EM,Schulman S,Go AS,Hughes M,Spencer FA,Manning WJ,Halperin JL,Lip GY,, Chest, 2012 Feb [PubMed PMID: 22315271]|
|||Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines., Lansberg MG,O'Donnell MJ,Khatri P,Lang ES,Nguyen-Huynh MN,Schwartz NE,Sonnenberg FA,Schulman S,Vandvik PO,Spencer FA,Alonso-Coello P,Guyatt GH,Akl EA,, Chest, 2012 Feb [PubMed PMID: 22315273]|
|||Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines., Whitlock RP,Sun JC,Fremes SE,Rubens FD,Teoh KH,, Chest, 2012 Feb [PubMed PMID: 22315272]|
|||Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines., Ageno W,Gallus AS,Wittkowsky A,Crowther M,Hylek EM,Palareti G,, Chest, 2012 Feb [PubMed PMID: 22315269]|
|||Old and new oral anticoagulants: Food, herbal medicines and drug interactions., Di Minno A,Frigerio B,Spadarella G,Ravani A,Sansaro D,Amato M,Kitzmiller JP,Pepi M,Tremoli E,Baldassarre D,, Blood reviews, 2017 Feb 5 [PubMed PMID: 28196633]|
|||Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines., Holbrook A,Schulman S,Witt DM,Vandvik PO,Fish J,Kovacs MJ,Svensson PJ,Veenstra DL,Crowther M,Guyatt GH,, Chest, 2012 Feb [PubMed PMID: 22315259]|
|||Rapidly progressive nonuremic calciphylaxis in the setting of warfarin., Bae GH,Nambudiri VE,Bach DQ,Danziger J,Faulkner-Jones B,McMahon C,Huang SJ,, The American journal of medicine, 2015 Oct [PubMed PMID: 26164564]|
|||Vazquez SR, Drug-drug interactions in an era of multiple anticoagulants: a focus on clinically relevant drug interactions. Hematology. American Society of Hematology. Education Program. 2018 Nov 30; [PubMed PMID: 30504330]|
|||Onysko M,Holcomb N,Hornecker J, Antibiotic interactions: Answers to 4 common questions. The Journal of family practice. 2016 Jul; [PubMed PMID: 27565097]|
|||Edwin SB,Jennings DL,Kalus JS, An evaluation of the early pharmacodynamic response after simultaneous initiation of warfarin and amiodarone. Journal of clinical pharmacology. 2010 Jun [PubMed PMID: 20081064]|
|||Lu Y,Won KA,Nelson BJ,Qi D,Rausch DJ,Asinger RW, Characteristics of the amiodarone-warfarin interaction during long-term follow-up. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2008 May 15 [PubMed PMID: 18463344]|
|||Tomisti L,Del Re M,Bartalena L,Tanda ML,Pucci A,Pambianco F,Danesi R,Braverman LE,Martino E,Bogazzi F, Effects of amiodarone, thyroid hormones and CYP2C9 and VKORC1 polymorphisms on warfarin metabolism: a review of the literature. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2013 Nov-Dec [PubMed PMID: 23807523]|
|||Bucerius J,Joe AY,Palmedo H,Reinhardt MJ,Biersack HJ, Impact of short-term hypothyroidism on systemic anticoagulation in patients with thyroid cancer and coumarin therapy. Thyroid : official journal of the American Thyroid Association. 2006 Apr [PubMed PMID: 16646683]|
|||Gastrointestinal bleeding and intracranial hemorrhage in concomitant users of warfarin and antihyperlipidemics., Leonard CE,Brensinger CM,Bilker WB,Kimmel SE,Han X,Nam YH,Gagne JJ,Mangaali MJ,Hennessy S,, International journal of cardiology, 2017 Feb 1 [PubMed PMID: 27888753]|
|||Alcohol and medication interactions., Weathermon R,Crabb DW,, Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism, 1999 [PubMed PMID: 10890797]|
|||Review on mechanisms and interactions in concomitant use of herbs and warfarin therapy., Leite PM,Martins MA,Castilho RO,, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2016 Oct [PubMed PMID: 27470545]|
|||Shalansky S,Lynd L,Richardson K,Ingaszewski A,Kerr C, Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis. Pharmacotherapy. 2007 Sep [PubMed PMID: 17723077]|
|||Brief communication: American ginseng reduces warfarin's effect in healthy patients: a randomized, controlled Trial., Yuan CS,Wei G,Dey L,Karrison T,Nahlik L,Maleckar S,Kasza K,Ang-Lee M,Moss J,, Annals of internal medicine, 2004 Jul 6 [PubMed PMID: 15238367]|
|||Werba JP,Misaka S,Giroli MG,Yamada S,Cavalca V,Kawabe K,Squellerio I,Laguzzi F,Onoue S,Veglia F,Myasoedova V,Takeuchi K,Adachi E,Inui N,Tremoli E,Watanabe H, Overview of green tea interaction with cardiovascular drugs. Current pharmaceutical design. 2015 [PubMed PMID: 25312732]|
|||Werba JP,Misaka S,Giroli MG,Shimomura K,Amato M,Simonelli N,Vigo L,Tremoli E, Update of green tea interactions with cardiovascular drugs and putative mechanisms. Journal of food and drug analysis. 2018 Apr; [PubMed PMID: 29703388]|
|||R Sousa A,Barreira R,Santos E, Low-dose warfarin maternal anticoagulation and fetal warfarin syndrome. BMJ case reports. 2018 Apr 7 [PubMed PMID: 29627779]|
|||Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis., Dezee KJ,Shimeall WT,Douglas KM,Shumway NM,O'malley PG,, Archives of internal medicine, 2006 Feb 27 [PubMed PMID: 16505257]|