Version October 2024
INTRODUCTION — Warfarin and other vitamin K antagonists (VKAs, also called coumarins; eg, acenocoumarol, phenprocoumon, fluindione) are used in a variety of clinical settings. Use of VKAs is challenging because their therapeutic range is narrow and dosing is affected by many factors including drug interactions, diet, and genetic variation in warfarin and vitamin K metabolism. Time spent with a prothrombin time/international normalized ratio (PT/INR) above the therapeutic range increases the risk of bleeding, and time spent below the therapeutic range increases the risk of thromboembolic complications.
This topic review discusses the biology, mechanism of action, and factors that modulate INR control during anticoagulation with a VKA.
Warfarin administration, and management of warfarin-associated bleeding and supratherapeutic INR, are discussed in detail separately. (See "Warfarin and other VKAs: Dosing and adverse effects" and "Management of warfarin-associated bleeding or supratherapeutic INR" and "Reversal of anticoagulation in intracranial hemorrhage".)
BIOLOGY
Mechanism of action — Warfarin and related vitamin K antagonists (VKAs) block the function of the vitamin K epoxide reductase complex in the liver, leading to depletion of the reduced form of vitamin K that serves as a cofactor for gamma carboxylation of vitamin K-dependent coagulation factors [1]. The epoxide reductase is needed to recycle vitamin K between reduced and epoxide forms. Without gamma carboxylation, the vitamin K-dependent factors, including factors II (prothrombin), VII, IX, and X, are immunologically detectable, but they cannot function because they cannot adequately bind calcium and phospholipid membranes needed for their hemostatic function [2]. (See "Vitamin K-dependent clotting factors: Gamma carboxylation and functions of Gla".)
Gamma carboxylation of glutamic acid residues occurs at the time of protein synthesis; it does not affect the structure or function of existing proteins. Thus, the ultimate anticoagulant effect of VKAs is delayed until the previously synthesized, functional clotting factors are cleared from the circulation. Depletion of both factor X and factor II (prothrombin) is important for clinical efficacy, and factor II has the longest half-life of the vitamin K-dependent factors (approximately three days) [3,4]. Thus, the desired anticoagulant effect of a VKA does not occur for at least three days after drug initiation despite prolongation of the prothrombin time (PT) at earlier time points. The initial prolongation of the PT is due primarily to depletion of factor VII, which has a short half-life (four to six hours) (figure 1) [5]. (See 'PT/INR prolongation' below.)
VKAs also inhibit vitamin K-dependent gamma carboxylation of the anticoagulant factors protein S and protein C, which inhibit activated factors VIII and V. Thus, warfarin has a transient procoagulant effect during the first day or two of use. This is rarely of clinical significance, with the possible exception of patients who receive "loading doses" of warfarin (especially those with inherited protein C deficiency) who may (rarely) develop warfarin-induced skin necrosis [6]. (See "Protein C deficiency", section on 'Warfarin-induced skin necrosis'.)
Administration of large doses of vitamin K1 can render patients resistant to warfarin for up to a week or more. The vitamin K accumulates in the liver and bypasses the need for vitamin K recycling by the epoxide reductase [2].
PT/INR prolongation — At therapeutic levels of anticoagulation, VKAs prolong the PT, which reflects the extrinsic pathway of coagulation in vitro (figure 2). Most laboratories and portable devices report the results of the PT along with an INR, a parameter that allows comparison of PT values from different institutions. PT readings from different institutions cannot be accurately compared, because different laboratories often use different assay reagents that could produce different PT readings for the same plasma sample. The INR standardizes the PT value to an international reference thromboplastin standard. The three reference standards in use are thromboplastin made from recombinant human tissue factor reconstituted into phospholipid vesicles, or thromboplastin from rabbit or bovine (cow) origin [7,8]. (See "Clinical use of coagulation tests", section on 'Prothrombin time (PT) and INR'.)
The initial prolongation of the PT/INR during the first one to three days of warfarin initiation does not reflect full anticoagulation, because only the factor with the shortest half-life (factor VII, half-life four to six hours) is initially depleted (table 1); other functional vitamin K-dependent factors with longer half-lives (eg, prothrombin, half-life approximately three days) continue to circulate [5] (see 'Mechanism of action' above). The full anticoagulant effect of a VKA generally occurs within approximately one week after the initiation of therapy and results in equilibrium levels of functional factors II, IX, and X at approximately 10 to 35 percent of normal [3].
The clinical implications of the delay in full anticoagulation were demonstrated in a trial that compared treatment with a VKA alone or a VKA overlapped with intravenous heparin in patients with an acute proximal deep vein thrombosis (DVT) [9]. The trial was terminated early (after accrual of 120 patients) due to an excess of symptomatic thromboembolic events in the VKA alone group. This delay in full anticoagulation despite prolongation of the PT/INR during initial therapy provides the rationale for overlapping another anticoagulant such as a parenteral agent with a VKA during the initial days of therapy (so called "bridging") in patients with an especially high thromboembolic risk. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Transitioning between anticoagulants/bridging' and "Management of heparin-induced thrombocytopenia", section on 'Transition to warfarin or other outpatient anticoagulant' and "Perioperative management of patients receiving anticoagulants", section on 'Limited indications for bridging' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Patients at low risk of bleeding'.)
For patients who are stably anticoagulated with a VKA, the percentage of time in the therapeutic range (TTR) is often used as a measure of the quality of anticoagulation control. At a conference on anticoagulation, approximately three-quarters of the 250 participants reported using a TTR measure as a quality indicator for their anticoagulation services [10]. TTR can be calculated using a variety of methods (eg, linear interpolation between INR values; percent of INRs in range, cross section of in-range INRs at a single time point) [11]. The TTR reported depends on the method of calculation as well as the INR range considered "therapeutic." A TTR of 65 to 70 percent is considered to be a reasonable and achievable degree of INR control in most settings [10,11]. The effect of various practice settings on TTR and the correlation between INR control and clinical outcomes are discussed separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Importance of strict INR control'.)
At levels of therapeutic anticoagulation, VKAs typically cause only mild prolongation (or do not prolong) the activated partial thromboplastin time (aPTT), and they do not prolong the anti-factor Xa activity level, a test typically used to measure the effect of heparin or direct oral factor Xa inhibitors (table 2). (See "Clinical use of coagulation tests", section on 'Patient on anticoagulant'.)
VKA metabolism — VKAs are absorbed via the gastrointestinal tract, circulate bound to albumin, and accumulate in the liver. Warfarin reaches maximal blood concentrations approximately 90 minutes after oral administration; only the non-protein-bound fraction is biologically active.
Commercially available warfarin and acenocoumarol are racemic mixtures of S and R enantiomers. S-warfarin is more potent than R-warfarin. S-warfarin is metabolized primarily by the hepatic cytochrome P-450 2C9 isoform (CYP2C9); R-warfarin also undergoes a small degree of hepatic metabolism by other P-450 cytochromes (eg, 1A2, 3A4) and is excreted in the urine [12]. Thus, the overall anticoagulant effect of warfarin is more likely to be influenced by CYP2C9 genotype and CYP2C9 drug interactions (eg, medications, over-the-counter herbal remedies) than by CYP1A2/CYP3A4 genotype or other drug interactions [13]. However, the relative importance of the S versus the R enantiomer may vary among patients depending on patient comorbidities, medications, and genetic factors (see 'Comorbidities' below and 'Drug interactions' below and 'Genetic factors' below). Phenprocoumon is also metabolized by CYP2C9, but levels appear to be less influenced by CYP2C9 genotype.
Tecarfarin (ATI-5923) is a VKA in development that is not affected by the CYP2C9 system; it is metabolized by esterases rather than CYPs [14]. Accordingly, it is not susceptible to many of the genetic and medication effects common to the other VKAs. However, in a 2016 trial that randomly assigned 607 individuals who required anticoagulation to receive tecarfarin or warfarin, the TTR was similar between the two drugs, even in patients who were receiving CYP2C9-interacting drugs, suggesting that this potential benefit may not be clinically relevant [15].
VKAs differ in their half-lives:
●Warfarin – 36 to 42 hours (slightly less than two days) [5,13]
●Acenocoumarol – 8 to 11 hours [13]
●Phenprocoumon – three to five days or longer [13,16]
●Fluindione – 69 hours (slightly less than three days) [17]
A variety of environmental and genetic factors further influence the absorption, pharmacokinetics, and pharmacodynamics of the VKAs, leading to great inter- and intra-patient variability in anticoagulant response. (See 'Drug interactions' below and 'Comorbidities' below and 'Genetic factors' below.)
Teratogenicity — Warfarin is a teratogen. Evidence regarding the specific embryopathic events and their mechanisms are presented separately. (See "Vitamin K-dependent clotting factors: Gamma carboxylation and functions of Gla" and "Use of anticoagulants during pregnancy and postpartum", section on 'Warfarin teratogenicity'.)
However, warfarin is not detected in human breast milk. Breastfeeding is reasonable as long as the infant is monitored for bruising and bleeding [18,19].
OVERVIEW OF INR CONTROL
Summary of factors that affect INR control — A variety of factors influence warfarin dose requirement, including genetic and environmental influences. Patients receiving warfarin should attempt to keep dietary vitamin K intake relatively constant over time to minimize the risk of under- or over-anticoagulation (eg, subtherapeutic INR with increased vitamin K intake or supratherapeutic INR with decreased vitamin K intake). More frequent monitoring of the prothrombin time (PT)/INR is used to guide VKA dose modifications in the presence of interacting medications to reduce the risk of over- or under-anticoagulation. An advantage of warfarin is that the INR can be monitored and the warfarin dose can be adjusted to account for changes in diet or other medications. (See 'Risk factors for supratherapeutic INR' below and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.)
Factors that affect the dose-response relationship between warfarin dose and INR include the following [1,12,20-24]:
●Nutritional status, including vitamin K intake
●Medication adherence
●Genetic variation
●Drug interactions
●Smoking and alcohol use
●Kidney, liver, and cardiac function
●Hypermetabolic states
These are discussed in more detail in the sections below.
Risk factors for supratherapeutic INR — Patients treated with warfarin frequently become excessively anticoagulated, even those who have been stable for many months. The most common causes of a supratherapeutic INR are interactions between warfarin and other drugs, diet, or superimposed conditions (eg, liver disease, malabsorption) that may interfere with warfarin ingestion, absorption, or metabolism. Many of these risk factors are modifiable and/or could be accompanied by more intensive monitoring.
Major classes of modifiable factors include the following:
●Patient comorbidities (eg, heart failure)
●Acute illnesses (eg, infections, gastrointestinal illnesses)
●Medication interactions (eg, antimicrobials [antibiotics, antifungals], acetaminophen [if taken at larger-than-recommended daily doses], nonsteroidal antiinflammatory drugs [NSAIDs]) (see 'Drug interactions' below)
●Large day-to-day variations in vitamin K intake
●Errors in dosing (eg, patient taking wrong dose or wrong tablet strength, or taking extra doses inadvertently)
Comorbidities should be managed appropriately, and acute illnesses should be addressed promptly. Patients should be advised to discuss any new medication or supplement with their clinician, and clinicians are advised to evaluate potentially important interactions when introducing a new medication. If interacting drugs must be used, INR monitoring frequency should be increased.
Evidence for the contribution of various medical conditions to supratherapeutic INR values was reviewed in a prospective cohort study with a nested case-control design from among 17,056 outpatients treated with vitamin K antagonists in a regional Red Cross anticoagulation clinic over a two-year period [25]. Multivariate analysis identified the following comorbidities associated with an INR ≥6:
●Diarrhea – Odds ratio (OR) 12.8
●Fever – OR 2.9
●Relapsed (incident) congestive heart failure – OR 3.0
●Stable (prevalent) impaired liver function – OR 2.8
●Stable (prevalent) congestive heart failure – OR 1.6
Companion analyses from the same cohort evaluated the effects of potentially interacting medications and dietary and lifestyle factors [26,27]. Importantly, while it is useful to pay close attention to dietary intake of vitamin K (table 3), the goal is to maintain a moderate constant level of intake rather than to eliminate vitamin K from the diet.
In addition to these modifiable risk factors, fixed patient characteristics including female sex, increased age, and previous INR instability or hemorrhage have been associated with a greater sensitivity to warfarin and/or an increased risk of bleeding [2,28-31]. Factors that increase bleeding risk independent of effects on INR should also be minimized when possible. (See "Risks and prevention of bleeding with oral anticoagulants".)
DIETARY FACTORS
Vitamin K intake — Individuals anticoagulated with warfarin generally are sensitive to fluctuations in vitamin K intake, and adequate INR control requires close attention to the amount of vitamin K ingested from dietary and other sources [32]. Vitamin K bypasses the target enzyme of the vitamin K antagonists (VKAs), the vitamin K epoxide reductase; thus, large variations in dietary vitamin K may result in INR instability. (See 'Mechanism of action' above.)
The goal of monitoring vitamin K intake is to maintain a moderate, constant level of intake rather than to eliminate vitamin K from the diet. Specific guidance from anticoagulation clinics may vary, but a general principle is that maintaining a consistent level of vitamin K intake should not interfere with a nutritious diet.
Patients taking warfarin may wish to be familiar with possible sources of vitamin K (to avoid inconsistency). For example, one-half cup of spinach contains >500 mcg of vitamin K. Other vegetables high in vitamin K include other greens (eg, beet, collard, mustard, turnip, kale) and Brussels sprouts (table 3). In contrast, most lettuces and other green vegetables have moderate or low vitamin K content (eg, <100 mcg per one-cup serving).
Additional sources of significant amounts of vitamin K include multivitamins, calcium supplements, nutritional and vitamin-fortified drinks, and some herbal products [33-35]. Individuals receiving a VKA must closely check the ingredients of any over-the-counter supplement and avoid inadvertent ingestion of high vitamin K doses from these products.
Several small studies have demonstrated the relationship between vitamin K intake and INR control. As examples:
●In a prospective cohort of 147 adults receiving long-term VKA therapy, those with good INR control, defined as time in the therapeutic range of ≥66 percent, had more regular, less variable day-to-day vitamin K intake (median range, 1.76 versus 2.73 mcg/kg/day) [36].
●In a prospective cohort of 1157 individuals chosen for stable anticoagulation control at baseline (defined as four consecutive INR readings in the therapeutic range), 335 (29 percent) subsequently had a subtherapeutic INR [37]. Daily vitamin K intake in 63 of these individuals was assessed by a food frequency questionnaire and categorized as low, normal, or high (<100 mcg, 100 to 300 mcg, or >300 mcg, respectively). There was a trend towards an inverse relationship between good INR control and daily vitamin K intake, with a slightly greater likelihood of therapeutic INR in those with high vitamin K intake and a slightly lower likelihood of therapeutic INR in those with low intake, although neither reached statistical significance.
●In a retrospective review that evaluated dietary vitamin K intake in 26 individuals who had stable INR control, defined as no change in warfarin dose over six months and standard deviation of INR <0.5, compared with 26 individuals who had unstable control, there was a correlation between stable control and a higher mean daily vitamin K intake (76 versus 29 mcg) [38]. Dietary fat intake was also evaluated because vitamin K is fat soluble, and this did not correlate with INR control.
Administration of low daily doses of vitamin K (eg, 100 to 200 mcg daily) may be tried in selected patients with unexplained INR variation, although high-quality evidence to suggest this will be effective for all (or most) patients is lacking. This practice and evidence to support it are discussed separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Poor INR control/vitamin K supplementation'.)
Intestinal microflora produce vitamin K2, and one of the ways antibiotics contribute to variability in the prothrombin time (PT)/INR is by reducing intestinal vitamin K synthesis [39]. (See 'Antibacterial and antifungal drugs' below.)
Other dietary factors — In general, patients are advised to consume a healthy diet, and they should not avoid fruits and vegetables for fear of altering the INR, with the exception of regulating vitamin K intake as discussed in the preceding section. (See "Healthy diet in adults".)
Cranberry juice and grapefruit juice have very low vitamin K content but have been reported to affect VKA anticoagulation in some studies, and some anticoagulation clinics advise patients to limit their intake to one or two servings (or less) per day [40-45].
Caffeine-containing beverages generally are not observed to have major effects on INR control, although cases of individuals consuming large quantities of coffee products (eg, liters per day) associated with inappropriately low INR have been reported [46].
Alcohol in low or moderate amounts (eg, one or two servings per day) is unlikely to have major effects on the INR, and regular use is less likely to alter metabolism than erratic use (eg, binge drinking). Contributions of excess alcohol intake are presented below. (See 'Tobacco, marijuana, and alcohol' below.)
Weight-loss diets may lead to alterations in warfarin dose requirements due to changes in vitamin K intake or warfarin metabolism; individuals on weight-loss diets generally should have more frequent testing of the INR.
Overall nutritional status — Individuals who are severely malnourished may be more sensitive to warfarin. Severe vitamin K deficiency may occur, but this is uncommon in the absence of a broad-spectrum antibiotic, especially in outpatients.
MEDICATION ADHERENCE — Medication adherence for vitamin K antagonists (VKAs) can be challenging due to the need for frequent monitoring and dose adjustments, dietary restrictions, medication interactions, and, in some cases, use of different medication doses on different days to achieve the optimal weekly intake.
Interventions to improve medication adherence include patient education and counseling and availability of a clinician to answer questions regarding dose adjustments and medication interactions. These are facilitated by the use of an anticoagulation clinic. Additional patients are able to improve adherence using INR self-monitoring and warfarin self-management approaches that incorporate pill boxes, dosing calendars, smartphone applications, and dosing algorithms. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Outpatient management'.)
Reducing the number of medications prescribed may be helpful, if this can be done safely. In a review of anticoagulation control in a cohort of over 100,000 patients, receipt of 16 or more medications resulted in a 5 percent reduction in INR control compared with seven or fewer medications [47].
For individuals with decreased medication adherence, it is important to determine the reasons and contributing factors. Some factors such as difficulty maintaining stable daily dietary vitamin K intake may be improved with use of a direct-acting oral anticoagulant (DOAC) in the appropriate clinical setting. However, other factors such as inability to take the medication at the correct daily dose and frequency may not be improved with the use of a DOAC, especially since the ability to monitor adherence with a DOAC is not readily available.
Impaired cognition, depressed mood, and inadequate health literacy also have been implicated in warfarin instability, especially in older patients [48]. Warfarin overdose, either intentional (eg, suicide attempt) or unintentional (eg, toddler) has been reported, with a mean peak INR of approximately 6 [49].
DRUG INTERACTIONS
Summary of drug interactions — A large number of drugs interact with vitamin K antagonists (VKAs) by a variety of mechanisms, and additional interacting drugs continue to be introduced (table 4) [50]. Determining clinically important drug interactions that prolong the prothrombin time (PT) and international normalized ratio (INR) is challenging. With some drugs, the evidence substantiating claims is very limited; in other cases, the evidence is strong but the magnitude of effect is small [12].
Patients should be advised to discuss any new medication or over-the-counter supplement with the clinician managing their anticoagulation, and clinicians are advised to confirm whether a clinically important drug-drug interaction has been reported when introducing a new medication in a patient anticoagulated with a VKA. Resources for this are available in the drug interactions program and through various other websites.
Medications interact with VKAs by the following mechanisms [39,51-53]:
●Prolonged PT/INR:
•Altered intestinal flora, with reduced intestinal vitamin K synthesis – Antimicrobials, especially cotrimoxazole, metronidazole, macrolides, and fluoroquinolones
•Inhibition of hepatic CYP2C9, with reduced warfarin metabolism – Many agents (eg, fluconazole, voriconazole, metronidazole, amiodarone, and sulfamethoxazole)
•Interruption of vitamin K recycling – Acetaminophen
•Displacement of warfarin from albumin – Any medication that binds albumin; however, this effect is usually minor
●Increased bleeding risk independent of PT/INR:
•Injury to gastrointestinal mucosa – Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs)
•Interference with platelet function – Anti-platelet drugs, including aspirin, NSAIDs, dipyridamole, clopidogrel, prasugrel, and ticagrelor
•Other (incompletely characterized) – Gingko biloba, dong quai, fenugreek, chamomile
●Reduced anticoagulation:
•Induction hepatic CYP2C9, with increased warfarin metabolism – Rifampin, carbamazepine, phenytoin, primidone
•Bypass warfarin effect via large amounts of vitamin K – Some vitamin and calcium supplements
•Incompletely characterized – St. John's wort
The tables list common VKA interacting medications (table 4) and herbal products (table 5), and details of some common interactions are discussed in more detail in the following sections.
Information regarding the COVID-19 therapy nirmatrelvir-ritonavir (Paxlovid) is limited. One small study suggested an initial decrease in INR in approximately one-half of treated patients, although changes in warfarin dosing were not required [54].
Medication interactions should be minimized when possible. Individuals with high fever or severe intercurrent illness are likely to require additional evaluation and monitoring for the potential effect of the illness itself on their anticoagulant (see 'Intercurrent illness' below). If an interacting medication is introduced, the PT/INR should be monitored more frequently to allow VKA dose adjustments as needed. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Other medications'.)
There is evidence to suggest that individuals with a personal history of venous thromboembolism (VTE) can use estrogen in combination with warfarin and expect a reasonably low risk of VTE recurrence. A study of 1888 females who were receiving an anticoagulant after an initial VTE episode did not find an association between recurrent VTE risk and the use of hormonal therapy [55]. A levonorgestrel-releasing intrauterine device is thought to be relatively safe. (See "Contraception: Counseling and selection", section on 'Special populations' and "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD' and "Menopausal hormone therapy: Benefits and risks".)
Common drug interaction examples
Aspirin/NSAIDs — Use of aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), or other antiplatelet agents such as clopidogrel or dipyridamole increases the risk of bleeding in patients treated with VKAs [51,56-60]. Thus, for patients for whom other interventions are available, these medications are avoided for routine management of minor pain or fever. Patients anticoagulated with warfarin generally are advised not to use aspirin for primary prevention of cardiovascular disease. In patients who have a history of acute coronary syndrome (but also require warfarin for other reasons), the risks and benefits of adding aspirin or other antiplatelet medications must be individualized. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)
For those who do require an NSAID, use of a COX-2 selective agent may lead to fewer bleeding complications as these agents do not interfere with platelet function. (See "Overview of COX-2 selective NSAIDs", section on 'Lack of platelet inhibition and use during anticoagulation'.)
The lower bleeding risk with COX-2 selective NSAIDs was demonstrated in a nested case-control study of patients in the Netherlands taking phenprocoumon or acenocoumarol along with NSAIDs. Over a two-year period there were 1491 bleeding episodes, 15 percent of which involved the use of NSAIDs [57]. On multiple regression analysis, there was a significantly increased risk for bleeding in the following settings:
●Use of a nonselective versus a COX-2 selective NSAID – odds ratio (OR) 3.1
●NSAID use for >1 month (versus ≤1 month) – OR 3.0
●Last INR >4.0 (versus ≤4.0) – OR 1.9
There are multiple potential mechanisms by which antiplatelet agents can increase bleeding risk, including gastrointestinal toxicity, interference with normal platelet function, and increases in INR [56-59]. This subject is discussed separately. (See "Nonselective NSAIDs: Overview of adverse effects" and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk' and "NSAIDs (including aspirin): Pharmacology and mechanism of action", section on 'Cyclooxygenase inhibition'.)
Acetaminophen — Acetaminophen can theoretically interfere with warfarin anticoagulation, especially at higher doses (eg, >2 to 3 grams daily for more than two to three days). Greater doses or durations have been demonstrated to increase the PT/INR in some patients. We instruct patients that if they will use ≥2 g/day of acetaminophen for at least three consecutive days, their INR should be tested three to five days after the first acetaminophen dose [53]. However, it is important to note that acetaminophen taken at recommended doses is generally much safer for pain than nonsteroidal antiinflammatory drugs (NSAIDs) in individuals receiving warfarin.
The mechanism(s) by which acetaminophen prolongs the PT/INR are incompletely understood and are thought to involve changes in warfarin potency rather than warfarin metabolism (eg, pharmacodynamic rather than pharmacokinetic effects) [53,61]. The main role appears to be interruption of vitamin K recycling between reduced and oxidized forms (see 'Mechanism of action' above) by acetaminophen metabolites or oxidative stress [53,62].
Evidence for prolongation of the PT/INR by acetaminophen comes from observational data and small randomized trials [53]:
●Several small randomized trials, each involving fewer than 50 patients, have compared the effect of acetaminophen (2 to 4 grams per day) with placebo [63-66]. These have found increases in the INR associated with acetaminophen use (mean increase, approximately 1.0; mean maximum INR, approximately 3.5).
●In a case-control study that compared 93 outpatients receiving warfarin who had INR >6.0 with 196 controls receiving warfarin with a therapeutic INR, those with an INR >6.0 were more likely to have received acetaminophen [67]. The highest dose category (≥9100 mg of acetaminophen per week, equivalent to four 325 mg tablets per day) was associated with a 10-fold increase in the likelihood of INR >6.0 (16 versus 3 percent; adjusted odds ratio [OR] 10.0 [95% CI 2.6-37.9]). Lower weekly doses had smaller effects, and weekly doses <2.2 grams did not increase the odds of an INR >6.0.
Antibacterial and antifungal drugs — A variety of antibiotics affect warfarin metabolism, especially metronidazole and macrolides (eg, erythromycin, clarithromycin), as well as antifungal agents (fluconazole, voriconazole) (table 4) [50,68]. Even topical agents (eg, topical econazole or bifonazole) have been reported to alter metabolism [69]. Most agents lead to PT/INR prolongation; however, some (eg, dicloxacillin, nafcillin, rifampin) decrease warfarin effect [70]. It may be prudent to substitute alternative antibiotics when available and equally efficacious; when one of these antibiotics must be administered, more intensive warfarin monitoring generally is needed.
The mechanisms by which these agents alter anticoagulation include disruption of intestinal microflora, inhibition (or less commonly, induction) of hepatic CYP2C9 or other cytochrome P-450 isoforms, and other changes (eg, changes in diet). Importantly, the underlying infection may also affect anticoagulation status through effects on metabolism, reduced oral intake, diarrhea, or other mechanisms. (See 'Intercurrent illness' below.)
Evidence for the role of various agents comes from a variety of observational studies. As examples:
●A retrospective cohort study evaluated the effect of antibiotic use in 5857 individuals receiving warfarin and an antibiotic for an upper respiratory infection who had an INR 5.0 versus 570 controls who had an upper respiratory infection but did not receive an antibiotic and 5579 controls who did not have an upper respiratory infection (all assessments were based on prescriptions filled during the study period) [68]. The percentage of patients with an INR >5.0 was highest in the patients receiving an antibiotic (3.2 versus 2.6 percent in controls with an upper respiratory infection and 2.2 percent in controls without an infection). Antimicrobials most frequently implicated in a supratherapeutic INR included metronidazole, moxifloxacin, trimethoprim-sulfamethoxazole, and levofloxacin. Clinically relevant bleeding and thromboembolism were infrequent and similar across all groups.
●A population-based study evaluated the relationship between INR and antibiotic use in 1124 patients receiving acenocoumarol or phenprocoumon [28]. Of these, 351 (31 percent) had an INR >6.0. The risks of over-anticoagulation was greatest with trimethoprim-sulfamethoxazole (adjusted relative risk [RR] 20.1; 95% CI 10.7-37.9), clarithromycin (RR 79), norfloxacin (RR 45), amoxicillin (RR 32), doxycycline (RR 32), and vancomycin (RR 18). The increases in INR above the therapeutic range often occurred within the first three days of antibiotic usage.
●A case-control study evaluated the relationship between upper gastrointestinal (GI) bleeding and antibiotics commonly used to treat urinary tract infections in patients receiving warfarin [71]. Of 134,637 patients in a database, there were 2151 cases of upper GI bleeding (1.6 percent). Compared with controls, those with upper GI bleeding were more likely to have received cotrimoxazole (adjusted OR 2.84; 95% CI 2.33-6.33) or ciprofloxacin (adjusted OR 1.94; 95% CI 1.28-2.95). In contrast, there was no significant association with use of amoxicillin, ampicillin, nitrofurantoin, or norfloxacin.
Anti-ulcer medications — Anti-ulcer medications, including H2-receptor blockers, proton pump inhibitors (PPIs), and sucralfate may potentially affect warfarin anticoagulation, although this is not a major cause of INR variability in our practice. We generally do not discourage patients from using these drugs, especially if they are at high risk of gastrointestinal bleeding.
A discussion about use of these medications to reduce bleeding risk is presented separately. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Gastric protection'.)
Sucralfate may decrease absorption of vitamin K antagonists. If it must be given, the vitamin K antagonist should be given at least two hours before or at least six hours after sucralfate.
TOBACCO, MARIJUANA, AND ALCOHOL — Tobacco and excess alcohol use have well described adverse health effects, some of which are associated with increased thromboembolic risk that may have prompted the vitamin K antagonist (VKA) administration in the first place. (See "Cardiovascular risk of smoking and benefits of smoking cessation" and "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment", section on 'Adverse consequences'.)
In addition, tobacco, marijuana, and excess alcohol may alter the anticoagulant effect of VKAs, as illustrated by the following:
●Smokeless tobacco – Smokeless tobacco use is especially prevalent in India and Southeast Asia [72]. There are limited data on the effects on anticoagulation, but a case report has raised the concern that smokeless tobacco has a high vitamin K content, which could dramatically affect warfarin anticoagulation [73]. This effect is likely to be more significant than the induction of hepatic cytochromes that is seen with smoking tobacco.
●Smoking
•Tobacco – The effect of chronic cigarette smoking on warfarin metabolism was evaluated in a systematic review and that included 13 studies (prospective and retrospective series) involving over 3000 patients [74]. A meta-analysis of the studies that evaluated warfarin dose requirement found that smoking increased the dose requirement by 12 percent, corresponding to a requirement of 2.26 additional mg of warfarin per week. However, two studies that evaluated the effect of chronic smoking on INR control found equivalent control in smokers and non-smokers.
The mechanisms by which cigarette smoking interacts with warfarin metabolism is by causing enhanced drug clearance through induction of hepatic cytochrome P-450 activity (eg, CYP1A1, CYP1A2, CYP2E1) by polycyclic aromatic hydrocarbons in cigarette smoke [74]. Nicotine itself (eg, in nicotine replacement products, electronic cigarettes) is not thought to alter warfarin metabolism [75,76].
•Marijuana – Components of marijuana are potent inhibitors of CYP2C9 activity. Case reports and systematic reviews suggest that marijuana smoking or consumption of other products (cannabidiol [CBD] oil, tetrahydrocannabinol [THC], medical cannabis or cannabinoids) can increase the INR [77-82]. Individuals taking a VKA should be counseled about these effects, and the possibility of interference may be discussed in individuals with high INRs or INR variability. Warfarin dose adjustments may be required in some cases. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Cannabis and cannabinoids'.)
Cases in which marijuana has been mixed with a superwarfarin compound (brodifacoum) have also been reported [83]. This subject is discussed separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Superwarfarin poisoning'.)
●Excess alcohol – The interaction between excess alcohol use and warfarin anticoagulation was evaluated in a case-control study that compared alcohol use in 265 individuals receiving warfarin who had major bleeding with 305 controls from the same cohort receiving warfarin who did not have major bleeding [84]. The risk of major bleeding was increased with moderate to severe alcohol use and with heavy episodic drinking (odds ratio [OR] 2.10; 95% CI 1.08-4.07 and OR 2.36; 95% CI 1.24-4.50, respectively).
Mechanisms by which alcohol use interacts with warfarin anticoagulation are many, and the contribution of various factors depends greatly on the amount of intake and the severity of associated liver disease. Excess alcohol consumption may interfere with warfarin metabolism. Severe liver disease may also be associated with coagulopathy, thrombocytopenia, and/or gastrointestinal varices, all of which increase bleeding risk independent of effects on warfarin metabolism. (See "Hemostatic abnormalities in patients with liver disease".)
We counsel patients to discontinue smoking and chewing tobacco for health reasons and to avoid excess or erratic alcohol use. (See "Overview of smoking cessation management in adults" and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Counseling and patient education'.)
Individuals who alter their tobacco use should inform their anticoagulation provider so that potential changes in the INR may be anticipated and appropriate testing and dose changes instituted. Those participating in a smoking cessation program may benefit from more frequent INR monitoring because they may require warfarin dose reduction. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring interval'.)
COMORBIDITIES — The major comorbidities that affect anticoagulation control are liver disease, kidney dysfunction, and heart failure. In addition, other comorbidities such as metastatic cancer, diabetes, or uncontrolled hyperthyroidism may also play a role [2]. None of these comorbidities is a contraindication to vitamin K antagonist (VKA) use; in fact, many increase thromboembolic risk. In our experience, patients with severe chronic kidney or liver disease are at increased risk for erratic INR results as well as for hemorrhagic complications. Closer attention to monitoring and dose adjustments is often indicated in these settings and, in some cases, the risks of anticoagulant therapy may outweigh the potential benefit.
Liver, kidney, heart, and thyroid disease
●Liver – The liver is the predominant site of warfarin metabolism. It is also the source of the majority of coagulation factors. Thus, liver disease can affect warfarin dosage, INR control, and coagulation in general. Importantly, individuals with severe liver disease are not "auto-anticoagulated," because they often have a combination of abnormalities that both impair hemostasis and increase thrombotic risk. For patients with significant liver disease who need anticoagulation, low molecular weight heparin is often a more practical alternative than warfarin. (See "Hemostatic abnormalities in patients with liver disease" and "Heparin and LMW heparin: Dosing and adverse effects".)
●Kidney – Warfarin undergoes partial excretion in the kidney. Patients with kidney disease can receive warfarin, and management is generally similar to the population without impaired kidney function; however, dose requirement may be lower. This was illustrated in a cohort of 980 participants in a pair of prospective cohort studies that analyzed the effect of a variety of factors on warfarin dosing [85]. Decreasing kidney function correlated with a lower warfarin dose requirement, with dose reductions of approximately 10 and 20 percent in those with moderate and severely impaired kidney function. Severely impaired kidney function is an independent risk factor for adverse outcomes (both bleeding and thrombosis) in patients who take warfarin; the net benefit of vitamin K antagonists in patients with advanced kidney disease is being increasingly scrutinized. A 2015 meta-analysis of warfarin use in dialysis-dependent individuals with atrial fibrillation found no reduction of mortality with warfarin use (hazard ratio [HR] 1.03; 95% CI 0.96-1.11) [86].
●Heart – Heart failure has been shown to interfere with INR stabilization. As an example, in a database of 15,276 individuals with atrial fibrillation, INR stabilization could not be achieved in 3809 (25 percent) [87]. Heart failure was associated with a lower likelihood of INR stabilization (odds ratio [OR] 0.78; 95% CI 0.70-0.87). In a case-control study that included 533 individuals with stable INR control and 2555 comparator patients, INR control was better in individuals without heart failure (OR 2.08; 95% CI 1.36-3.17) [29]. Other studies have observed similar correlations between heart failure and reduced INR control [88].
Discussions of antithrombotic therapy in patients with heart failure or atrial fibrillation, including indications, choice of agent(s), risks, benefits, and other management details, are presented separately. (See "Antithrombotic therapy in patients with heart failure" and "Atrial fibrillation in adults: Use of oral anticoagulants".)
●Thyroid – Thyroid disease has been reported to affect INR control, especially amiodarone-induced thyrotoxicosis, which can occur with 10 to 15 percent of individuals taking amiodarone [89]. This effect is independent from the known effect of amiodarone on warfarin metabolism, which also may increase the INR (table 4).
Hyperthyroidism unrelated to amiodarone can also potentiate the effect of warfarin, leading to increased bleeding risk and increased INR; conversely, hypothyroidism can blunt the warfarin response and decrease the INR [89]. The purported mechanisms involve clearing of clotting factors (more rapid clearance in hyperthyroidism potentiating warfarin effect; reduced clearance in hypothyroidism diminishing warfarin effect).
These associations may warrant closer monitoring in individuals receiving warfarin, especially during initiation of warfarin or treatment of the underlying comorbidity.
Intercurrent illness — Acute illnesses may alter anticoagulation through effects on vitamin K intake, VKA metabolism, and medication interactions, especially infections and gastrointestinal illnesses [68]. We generally monitor the INR more frequently in any patient with an infection requiring antibiotic therapy, with the monitoring interval individualized according to the type and severity of illness, oral intake, need for added medications, and any other relevant factors. Patients hospitalized for an acute illness generally have monitoring of the prothrombin time (PT)/INR on a daily or every-other-day basis.
The impact of an acute illness on INR control was demonstrated in a case-control study that compared 93 outpatients receiving warfarin who had INR >6.0 with 196 controls receiving warfarin who did not have an INR >6.0 [67]. Those with an INR >6.0 were more likely to have had a recent diarrheal illness (odds ratio [OR] 3.5; 95% CI 1.4-8.6) or to have decreased oral intake (OR 2.6; 95% CI 2.2-30).
The effect of hospitalization on INR control was illustrated in a retrospective cohort study using a laboratory database that included 5380 patients on warfarin. During a one-year period, 951 (17 percent) were hospitalized [90]. All measures of anticoagulation control changed in the peri-hospitalization period, with an INR above the therapeutic range more likely before hospitalization and an INR below the therapeutic range more likely after discharge.
GENETIC FACTORS — Genetic polymorphisms have been implicated in altered sensitivity to warfarin and other vitamin K antagonists (VKAs); however, we do not advocate routine genetic testing prior to VKA administration as randomized trials have shown that this practice does not affect patient-important outcomes. Results of these trials are presented separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Baseline testing'.)
The major genes involved in VKA sensitivity are vitamin K epoxide reductase, subunit 1 (VKORC1), the drug target; and hepatic cytochrome P450 2C9 isoform (CYP2C9), which metabolizes the drug to an inactive form [91-97].
●VKORC1 – The vitamin K epoxide reductase complex recycles vitamin K to produce the reduced form that serves as a cofactor in gamma carboxylation of vitamin K-dependent coagulation factors. VKORC1 encodes a subunit of this complex. A number of polymorphisms in VKORC1 have been demonstrated to affect dose requirements of warfarin and other VKAs [92,98-103]. (See 'Mechanism of action' above and "Vitamin K-dependent clotting factors: Gamma carboxylation and functions of Gla", section on 'Vitamin K recycling by VKOR'.)
●CYP2C9 – Cytochrome P450 2C9 is the primary hepatic enzyme responsible for metabolic clearance of warfarin and acenocoumarol [98,104-110]. Genetic variation in the CYP2C9 gene has been demonstrated to affect warfarin and acenocoumarol dose requirements, although to a lesser degree than VKORC1 variants in some studies [94,98,108-116]. Anticoagulation with phenprocoumon, which has a longer half-life, may be less affected by CYP2C9 polymorphisms than warfarin or acenocoumarol [13]. (See 'VKA metabolism' above and "Overview of pharmacogenomics", section on 'CYP isoenzymes and drug metabolism'.)
Case reports have identified mutations in other genes (eg, CYP4F2, the gene encoding the cytochrome P450 4F2 isoform; and folylpolyglutamate synthase [FPGS], which encodes an enzyme involved in folate metabolism) that lead to more dramatic effects on VKA dose requirements; these are extremely rare [117-119].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)" and "Patient education: Prothrombin time and INR (PT/INR) (The Basics)")
●Beyond the Basics topic (see "Patient education: Warfarin (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Biology – Warfarin and related vitamin K antagonists ([VKAs], acenocoumarol, phenprocoumon, fluindione) block vitamin K epoxide reductase in the liver, leading to reduced gamma carboxylation of vitamin K-dependent factors (II [prothrombin], VII, IX, and X). Full anticoagulation requires depletion of factor X and factor II activities to approximately 20 percent. This may take up to three days, and initial prolongation of the prothrombin time (PT) and international normalized ratio (INR) does not reflect full anticoagulation. This is the basis for overlapping ("bridging") with another anticoagulant (generally unfractionated or low molecular weight [LMW] heparin) in individuals at high thromboembolic risk. VKAs are primarily metabolized in the liver by hepatic P-450 2C9. Half-lives of VKAs differ substantially. (See 'Biology' above.)
●Diet – Warfarin anticoagulation is sensitive to fluctuations in vitamin K intake, and INR control requires close attention to vitamin K in the diet and supplements (table 3). The goal is to maintain a moderate, constant level of intake rather than to eliminate vitamin K. (See 'Dietary factors' above.)
●Adherence – Medication adherence for VKAs can be challenging, and interventions to improve adherence (eg, patient education, availability of a clinician to answer questions regarding dose adjustments and medication interactions) are facilitated by the use of an anticoagulation clinic and/or self-management approaches. (See 'Medication adherence' above.)
●Drug interactions – Many drugs (table 4), over-the-counter medications, and herbal remedies (table 5) interact with VKAs. Most increase bleeding risk. Patients should be advised to discuss any new medication or supplement with their clinician, and clinicians are advised to evaluate potentially important interactions when introducing a new medication. Interactions are avoided or minimized when possible; if interacting drugs must be used, monitoring frequency should be increased. (See 'Drug interactions' above.)
●Smoking and alcohol – Smoking and alcohol may alter the effect of VKAs. We counsel patients to discontinue smoking for health reasons and to avoid excess or erratic alcohol use. Individuals participating in smoking cessation programs may benefit from more frequent INR monitoring. (See 'Tobacco, marijuana, and alcohol' above.)
●Comorbidities – Chronic kidney or liver dysfunction, heart failure, and thyroid disease may impact INR control and VKA dose requirements. Acute illnesses, especially infections, gastrointestinal illnesses, and illnesses requiring hospitalization, may alter time in the therapeutic range and warrant closer attention to monitoring and dose adjustments. (See 'Comorbidities' above and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring interval'.)
●Genetic variation – Genetic polymorphisms have been implicated in altered sensitivity to warfarin and other VKAs, including polymorphisms in genes such as VKORC1, which encodes a subunit of the vitamin K epoxide reductase complex, and CYP2C9, which encodes a hepatic cytochrome. However, genetic testing has been shown not to improve INR control, and we do not advocate routine genetic testing prior to VKA administration. (See 'Genetic factors' above.)
ACKNOWLEDGMENT — UpToDate acknowledges Karen A Valentine, MD, PhD, who contributed to earlier versions of this topic review.
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