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Warfarin and other VKAs: Dosing and adverse effects

Warfarin and other VKAs: Dosing and adverse effects
Literature review current through: Sep 2023.
This topic last updated: Jul 17, 2023.

INTRODUCTION — Warfarin and other vitamin K antagonists (VKAs, also called coumarins; eg, acenocoumarol, phenprocoumon, fluindione) have been available for decades and are used in various settings. Their use is challenging because their therapeutic range is narrow and dosing is affected by many factors including genetic variation, drug interactions, and diet. Bleeding risk is higher with warfarin than direct oral anticoagulants (DOACs). However, efficacy of warfarin is greater for certain indications including prosthetic heart valves and antiphospholipid syndrome.

Time spent outside the therapeutic range further increases the risk of bleeding and/or thromboembolic complications that the VKA was intended to prevent. Nevertheless, these agents have a large body of clinical experience and are highly effective in reducing the risk of venous and arterial thromboemboli in many settings.

The general principles underlying the clinical use of VKAs, including their complications and laboratory monitoring of the prothrombin time (PT) and international normalized ratio (INR), are reviewed here.

Separate topics review:

Interacting medications and medical conditions – (See "Biology of warfarin and modulators of INR control".)

Management of warfarin-associated bleeding or supratherapeutic INR – (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Reversal of anticoagulation in intracranial hemorrhage".)

INDICATIONS AND CONTRAINDICATIONS — Indications for VKAs are presented in separate topic reviews:

Atrial fibrillation – (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

Acute coronary syndrome – (See "Acute coronary syndrome: Oral anticoagulation in medically treated patients".)

Heart failure – (See "Antithrombotic therapy in patients with heart failure".)

Prosthetic heart valve – (See "Antithrombotic therapy for mechanical heart valves".)

Stroke – (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".)

Deep vein thrombosis – (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

Pulmonary embolism – (See "Venous thromboembolism: Initiation of anticoagulation".)

Antiphospholipid syndrome – (See "Management of antiphospholipid syndrome".)

Possible contraindications to the use of anticoagulants are listed in the table (table 1); however, this list is not intended to substitute for the judgement of the treating clinician, who can assess the risks and benefits for the individual patient.

ADVANTAGES AND DISADVANTAGES — VKAs have advantages and disadvantages compared with other anticoagulants, and the choice of agent depends on the clinical setting and patient factors. The table (table 2) summarizes advantages and disadvantages, which include the following:

Advantages:

Experience – There is a large body of clinical experience (including long-term use) and clinician familiarity with use.

Efficacy for selected indications – Efficacy of warfarin in greater than DOACs in patients with mechanical heart valves and some patients with antiphospholipid syndrome. (See "Antithrombotic therapy for mechanical heart valves" and "Management of antiphospholipid syndrome".)

AccessWarfarin is generally lower cost and wider availability.

Reversal – There is significant experience with reversing the anticoagulant effect of warfarin, if needed (eg, for serious bleeding), with vitamin K plus a source of factors II, VII, IX, and X (either Fresh Frozen Plasma [FFP] or prothrombin complex concentrates [PCCs]). However, there is no evidence that this translates to a lower case-fatality rate among patients who experience major anticoagulant-associated bleeding with DOACs. (See "Management of warfarin-associated bleeding or supratherapeutic INR".)

TitrationWarfarin carries the option and ability to increase the intensity of anticoagulation with appropriate monitoring when required such as in a subset of patients with antiphospholipid syndrome (APS) who truly "break through" conventional therapeutic range warfarin.

Monitoring effect and adherence – With warfarin, it is possible to ensure desired anticoagulant effect is achieved, even in patients with advanced kidney disease, patients at extremes of body weight, or patients taking medications that may interact with warfarin. In contrast, there is no routine monitoring for DOACs, and if adherence is low with a DOAC, the patient may not be adequately anticoagulated, but the medical team may not be aware of this.

Disadvantages:

Complication rates – Higher rates of thromboembolic and bleeding complications than direct oral anticoagulants (DOACs) in individuals with atrial fibrillation. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Risks and prevention of bleeding with oral anticoagulants", section on 'Drug class'.)

Increased bleeding risk with warfarin over DOACs is especially relevant for older adults, which impacts the choice of anticoagulant for many indications. (See 'Older adults' below.)

Associated costs and burdens – Requirement for frequent monitoring, with associated expenses and time requirements (although the ability to monitor international normalized ratio [INR] control may be an advantage for some individuals).

Dose changes – Dosing is affected by illness, changes in diet, and numerous interacting medications. (See "Biology of warfarin and modulators of INR control".)

WARFARIN ADMINISTRATION — The following principles apply to warfarin administration and are generally applicable to other VKAs as well.

Indications — Confirm that warfarin is the best choice for the patient. Major indications include mechanical heart valves and antiphospholipid syndrome (APS), especially high-risk APS. A direct oral anticoagulant (DOAC) is preferred for nonvalvular atrial fibrillation or venous thromboembolism (VTE), especially in older adults; older individuals may derive greater safety benefit from a DOAC, as long as cost barriers can be removed. (See 'Older adults' below.)

Some patients may take warfarin if they do not have access to a DOAC or if there are other reasons to avoid a DOAC such as concerns about adherence, absorption, kidney or liver function, or DOAC drug interactions.

Details and specific recommendations are discussed in separate topic reviews:

Prosthetic heart valves – (See "Antithrombotic therapy for mechanical heart valves" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair".)

Antiphospholipid syndrome – (See "Management of antiphospholipid syndrome".)

Atrial fibrillation – (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

Venous thromboembolism – (See "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management".)

Other indications – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Settings in which a heparin or vitamin K antagonist may be preferable'.)

Baseline testing — Prior to starting warfarin, it may be appropriate to obtain the following baseline testing, if not already done:

Baseline prothrombin time (PT) with international normalized ratio (INR) and baseline activated partial thromboplastin time (aPTT). We omit this testing unless there is a clinical reason to obtain it.

Complete blood count (CBC) including platelet count, to obtain a baseline and identify thrombocytopenia.

Liver function tests, to identify potential alterations of warfarin metabolism (or hemostasis).

Urine (or serum) pregnancy test for females of childbearing potential (due to risks of teratogenicity).

A decision can also be made regarding whether thrombophilia testing is indicated and when is the ideal time to perform it, taking into account the need for such testing and the potential effects of acute thrombosis and anticoagulant therapy on the results of such testing (table 3). (See "Screening for inherited thrombophilia in asymptomatic adults" and "Thrombophilia testing in children and adolescents" and 'Interference with thrombophilia testing' below.)

Coagulation testing may reveal an underlying thrombophilia such as the antiphospholipid syndrome (APS), which may artifactually increase the PT and/or aPTT, depending on the assay characteristics. Evaluation of abnormalities found upon baseline testing is presented separately. (See "Clinical use of coagulation tests" and "Approach to the patient with thrombocytosis" and "Diagnostic approach to thrombocytopenia in adults".)

We suggest not using pharmacogenetic testing (ie, genotyping for polymorphisms that affect warfarin or other VKA metabolism or the vitamin K-dependent coagulation factors) to guide initial dosing of the warfarin or other VKAs. Two meta-analyses of randomized trials (both involving approximately 3000 patients) found that dosing incorporating hepatic cytochrome P-450 2C9 (CYP2C9) or vitamin K epoxide reductase complex (VKORC1) genotype did not reduce rates of bleeding or thromboembolism [1,2].

The 2012 American College of Chest Physicians (ACCP) Guidelines also have recommended against the routine use of genotyping for guiding dosing of the VKAs, and the Centers for Medicare and Medicaid Services (CMS) announced a decision in 2009 to decline payment for warfarin genetic testing unless administered as part of a clinical trial comparing outcomes in tested and untested patients [3].

Details of the role of genetic variants in warfarin metabolism are presented separately. (See "Biology of warfarin and modulators of INR control", section on 'Genetic factors'.)

Initial dosing — For patients starting warfarin therapy, we suggest an initial daily dose of ≤5 mg, rather than higher doses or "loading" doses, unless the patient is known from previous experience to require higher doses.

The rationale for the avoidance of higher initial doses in most patients comes from several small randomized trials that compared initial doses of 5 versus 10 mg of warfarin, which found that higher doses generally did not result in more rapid therapeutic anticoagulation or improved outcomes, but these higher doses were more likely to lead to a supratherapeutic INR, which can increase the risk of bleeding [4-7]. Additionally, there is a theoretical concern that higher initial doses might cause more dramatic reductions in the anticoagulant factors, protein S and protein C, leading to a greater transient procoagulant state.

The initial warfarin dose is further individualized to take into account factors that may lead to excessive anticoagulation or increased risk of bleeding such as older age, variability in metabolism, and vitamin K dietary status [8-12]:

For an otherwise healthy adult, we generally use 5 mg daily on days 1 and 2.

For an adult who is frail, older (>70 to 80 years), malnourished, has liver or kidney disease or heart failure, or is receiving a medication known to increase warfarin sensitivity (eg, amiodarone), we use a lower dose (eg, 2.5 mg daily, 2.5 mg alternating with 5 mg).

Occasionally, a higher initial dose may be appropriate (eg, individual who was previously receiving warfarin anticoagulation and required a higher-than-average dose).

INR monitoring and appropriate dose adjustment is more important than the number of mgs in the starting dose. The initial dosing strategy presented here is similar to the 2011 British Committee for Standards in Hematology (BCSH), which states that there is no evidence to suggest a 10 mg initial dose is superior to a 5 mg initial dose, and lower doses may be appropriate in older adults [13]. A 2016 Cochrane review of randomized trials comparing an initial warfarin dose of 10 versus 5 mg (494 participants) found substantial heterogeneity and no major benefit of starting with 10 versus 5 mg, with individual trials coming to different conclusions about which starting dose resulted in a more rapid therapeutic INR and none of the trials demonstrating differences in bleeding or venous thromboembolism recurrence [14]. Our approach is more consistent with the 2008 ACCP guidelines, which recommend a starting dose of 5 to 10 mg daily, than the 2012 ACCP guidelines, which recommend a starting dose of 10 mg daily [3,15]. The BCSH and ACCP guidelines are updated regularly (available at https://b-s-h.org.uk/guidelines/guidelines/oral-anticoagulation-with-warfarin-4th-edition and http://journal.chestnet.org/guidelines).

INR-based initial dose adjustment — Typically, the PT with international normalized ratio (INR) is measured daily in hospitalized patients and starting on or around day 3 in healthy outpatients. Dosing on day 3 and subsequent days is based on the previous PT and INR results. An example of dose adjustments is provided in the table (table 4); however, this is not meant to replace a local/institutional algorithm.

Dosing calculations that incorporate additional clinical variables are sometimes used. The benefit of an automated dosing algorithm was demonstrated in a trial that randomly assigned 13,052 patients from 32 centers to one of two computer-assisted dosage programs (PARMA 5 or DAWN AC) versus dosage determined by the medical staff [16]. The time in target INR range was significantly improved by computer assistance as compared with medical staff dosage, with the greatest advantage being seen at those medical centers with fewer patient-years of experience. However, the overall number of adverse clinical events (eg, bleeding, thrombosis, death) was not significantly reduced (5.5 versus 6 events/100 patient-years for the computer-assisted and medical staff dosage groups, respectively; adjusted incidence rate ratio 0.90, 95% CI 0.80-1.02). An example of an automated dosing calculator is available at www.WarfarinDosing.org/Source/Home.aspx [17].

Importantly, the INR can increase within two to three days of the first warfarin dose, but full anticoagulation generally takes longer (in the range of five to seven days). During the first few days of warfarin therapy, prolongation of the PT/INR mainly reflects depression of factor VII, which has the shortest half-life (four to six hours); however, other vitamin K-dependent factors (eg, factors II [prothrombin], IX, and X) have longer half-lives and are not fully depleted for two to three days (figure 1). Thus, for patients with a very high thromboembolic risk, it may be necessary to overlap ("bridge") warfarin with another anticoagulant such as unfractionated or low molecular weight heparin during initiation of warfarin therapy. (See 'Transitioning between anticoagulants/bridging' below.)

Establishing a maintenance dose — Maintenance doses of warfarin vary significantly from patient to patient, ranging from <2 mg to ≥10 mg per day. Dosing is based on PT/INR readings (see 'Monitoring interval' below), with a goal INR that varies with the clinical setting. Typical INR goals are in the range of 2 to 3 in patients with atrial fibrillation or venous thromboembolism and somewhat higher in patients with mechanical heart valves. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Warfarin' and "Antithrombotic therapy for mechanical heart valves", section on 'Long-term anticoagulation'.)

No protocols for adjusting warfarin dosing have been uniformly accepted, and dose adjustment practices vary widely [3,5,7,15,18-22]. However, studies suggest that the use of algorithms improves time in the therapeutic range (TTR), an endpoint associated with a lower risk of thromboembolic events and bleeding [23-25]. As described in the ACCP guidelines, decision support through anticoagulation clinics and/or computerized warfarin calculation systems can improve prescribing practices, especially for inexperienced providers [3,15]. (See 'Outpatient management' below.)

Clinicians often tell patients to take warfarin in the evening, and this may be useful during initiation of therapy to allow same-day dose corrections to be made based on the INR result. However, a trial that randomly assigned 217 individuals taking warfarin for at least three months to take their dose in the morning or the evening found that switching to morning dosing did not have a statistically significant effect on the TTR [26]. Patients should take their dose at whichever time fosters the best adherence.

A reasonable approach to adjusting warfarin dosing is outlined in the warfarin dosing protocol used in patients with atrial fibrillation enrolled on the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial (table 5) [23]. Important aspects of this protocol include the following:

This protocol only applies to patients already taking warfarin and should not be used during the first week of therapy.

The interval for PT/INR monitoring depends on the stability of measured values, dose requirements, and clinical status.

The monitoring interval can be extended once a maintenance dose has been established and the PT/INR remains in the therapeutic range. (See 'Monitoring interval' below.)

More frequent monitoring (eg, once or twice weekly) is appropriate for patients with a PT/INR outside the therapeutic range. More frequent monitoring is also appropriate if changes occur that could alter warfarin absorption, metabolism, or anticoagulant effect (intercurrent illness, initiation of a new interacting medication, change in diet). (See "Biology of warfarin and modulators of INR control".)

The effect of dose changes may take up to three days to be reflected in the PT/INR. Thus, significant dose changes generally should be made only based on PT/INR results obtained at least two days after a previous dose adjustment.

For patients whose INR is only slightly outside the target range, repeat testing in a week without dose adjustment may be the best course of action. As an example, an observational study and modeling that predicted better INR control could be achieved by changing the dose when the INR is ≤1.7 or ≥3.3 (predicted TTR of 74 percent versus predicted TTR of 68 percent when changing the dose for INR ≤1.8 or ≥3.2) [27].

Additional interventions may be appropriate for patients with poor PT/INR control. (See 'Poor INR control/vitamin K supplementation' below.)

A post hoc analysis of 6022 patients in the RE-LY trial evaluated outcomes according to whether warfarin dose adjustments were consistent with the proposed algorithm [28]. As compared with patients taking warfarin who did not have algorithm-consistent dosing, patients who did have algorithm-consistent dosing spent more days with their PT/INR in the therapeutic range (13 versus 22 percent of days). The patients with algorithm-consistent dosing also experienced a lower incidence of stroke, embolism, or bleeding. While the use of the algorithm likely varied by center, the improvements in clinical outcomes did not appear to be due to other center variations in patient care since these outcomes did not differ among centers in patients in the original RE-LY trial who were assigned to treatment with dabigatran.

Factors that may affect individual maintenance dosing include nutritional status; vitamin K intake; hepatic, renal, and cardiac function; acute illnesses; medication adherence, drug-drug interactions (table 6), and genetic variation [29-32]. These factors are discussed in detail separately. (See "Biology of warfarin and modulators of INR control".)

Outpatient management — Outpatient management of warfarin may be supervised by hospital or community-based clinicians, anticoagulation clinics, or a self-management program. Monitoring used for this management may be performed at a laboratory or with a self-monitoring device (point-of-care device). (See 'Self-monitoring and self-management' below.)

A 2018 guideline from the American Society of Hematology recommended patient self-monitoring using a POC device and self-adjusted dosing over other approaches for those individuals who have demonstrated competence in self-testing and can afford the associated costs [33]. In general, management through an anticoagulation clinic or self-management is associated with better outcomes than individual clinician management in the community, as described below. The choice between these options will depend on clinician and patient resources and preferences. (See 'Anticoagulation clinics' below and 'Self-monitoring and self-management' below.)

Regardless of the management approach, studies have demonstrated that patient education and availability of a clinician to review medication changes and answer questions results in fewer bleeding complications, reduced hospitalization costs, and greater patient satisfaction. This was demonstrated in a prospective cohort study involving 2346 patients receiving warfarin who had 126 hospitalizations due to warfarin-related bleeding over a two-year follow-up period [34]. Compared with those who did not receive educational materials, those who did receive instruction had a reduced rate of bleeding (incidence rate ratio [IRR] 0.40, 95% CI 0.24-0.68). The likelihood of bleeding was increased in those who had four or more clinicians providing prescriptions (IRR 2.4, 95% CI 1.2-4.6).

Several studies have addressed the cost-effectiveness of various management approaches [35-42]. In general, the most cost-effective programs are those that reduce the number of emergency department visits and/or hospitalizations for hemorrhage or thromboembolism.

Anticoagulation clinics — Anticoagulation clinics are dedicated sites or services that provide testing and management of outpatient anticoagulation. Monitoring can be done with a point-of-care device on-site or through a laboratory. Dose changes can be managed by individuals with a variety of backgrounds including pharmacists, nurses, and physicians.

These clinics have the advantages of providing consistent provider interactions; opportunities to review patient medications, dietary changes, and clinical status; and ongoing patient education [43]. They can also provide routine reminders for upcoming and missed appointments, and documentation for PT/INR measurements and dose changes [44-46]. Often, algorithms or programs for calculating dose adjustments are used, which eliminates variability in dosing changes. Randomized trials have demonstrated that management of anticoagulation by hospital-based anticoagulation clinics is at least as good as routine hospital follow-up and marginally better than management directed by family physicians [47,48].

Examples of available data include the following:

A multicenter trial randomly assigned 10,421 patients to management using a new version of the PARMA 5 computer program versus manual dose change by experienced medical staff [49]. Overall number of major bleeds, thrombotic events, and death were similar in the two groups. The time in the therapeutic range (TTR) for the computer-assisted and manual approaches was 66 and 65 percent, respectively.

A systematic review and meta-analysis of randomized and nonrandomized trials compared management by a pharmacist-participated management program versus usual care in 728,377 individuals receiving warfarin [36]. Compared with usual care, pharmacist management was associated with a reduction in total bleeding (relative risk [RR] 0.51, 95% CI 0.28-0.94). However, major bleeding, thromboembolic events, and mortality were not significantly different.

A retrospective cohort study compared management by telephone versus face-to-face encounters in 234 patients receiving warfarin [50]. There were no significant differences in bleeding, thrombosis, emergency department visits, or hospital admissions between the groups.

A 2021 systematic review and meta-analysis involving over 8000 patients found that, compared to in-person management, telepharmacy management was associated with lower risks of any bleeding (RR 0.65, 95% CI 0.47-0.90) and hospitalization (RR 0.59, 95% CI 0.39-0.87) and no statistically significant difference in TTR, supratherapeutic INR, major or minor bleeding, or thromboembolic events [51].

Self-monitoring and self-management — Small portable devices are available for patients to measure their own degree of anticoagulation (eg, in-home measurement of PT/INR). When accompanied by appropriate education and training, along with consistent quality control, the majority of patients, including older adults, can effectively and safely adjust their anticoagulant dosing [52-59]. The PT/INR values obtained with these devices generally correlate well with laboratory measurements (figure 2).

Guidance from the BCSH suggests individuals using these devices should [42]:

Receive appropriate training and education in operating the monitor and managing warfarin dosing.

Should keep accurate records of PT/INR results and dose adjustments.

Should verify the accuracy of readings with standard laboratory testing at least every six months and if results are unexpectedly high or low or if there are concerns about storage conditions of the test strips.

Several systematic reviews and meta-analyses of randomized trials have concluded that appropriately trained patients who used self-monitoring and/or self-adjustment of VKA therapy had as good or better outcomes than those who used anticoagulation clinics or community-based management [40,60-63]. As an example, a 2016 meta-analysis of randomized trials compared self-monitoring and/or self-adjustment in 8950 individuals [63]. Compared with controls, individuals who used self-monitoring and/or self-adjusted dosing had the following outcomes over a follow-up period of 3 to 57 months.

Fewer thromboembolic events (RR 0.58, 95% CI 0.45-0.75)

No difference in major or minor bleeding events (RR 0.95, 95% CI 0.8-1.12 and RR 0.97, 95% CI 0.67-1.41, respectively)

A nonsignificant trend toward reduced mortality (RR 0.85, 95% CI 0.71-1.01)

The largest trial included in this meta-analysis, The Home INR Study (THINRS), randomly assigned 2922 patients using warfarin for a cardiac indication (atrial fibrillation, mechanical valve) to self-monitoring alone (without self-management) versus management in an anticoagulation clinic [64]. In this trial, clinical outcomes were similar, and the time to the first primary event (stroke, major bleeding episode, or death) was not significantly longer in the self-testing group than in the anticoagulation clinic-testing group (hazard ratio [HR] 0.88, 95% CI 0.75-1.04). The self-testing group had a small but significant improvement in the percent of time in the therapeutic range (TTR) for the PT/INR (absolute difference 3.8 percentage points) as well as small but significant improvements in patient satisfaction and quality of life.

Self-monitoring is not feasible for all patients and requires patient education and ability to use the device as well as an underlying institutional policy for providers of this service [40,61,65]. Approximately 80 percent of patients eligible for the THINRS trial (2931 of 3643) were able to demonstrate competency in using a home monitoring device [66]. Factors associated with inability to use the device included older age, prior stroke, impaired cognition, and reduced manual dexterity.

Some self-monitoring devices may give erroneous results in patients with an antiphospholipid antibody, as may some laboratory-based tests [67]. In this setting, the readings from the self-monitoring device should be compared with results of chromogenic testing of factor Xa activity. (See 'Interference with thrombophilia testing' below.)

Drug interactions — VKAs have numerous drug interactions that may warrant a change in therapy or increased PT/INR monitoring; these are discussed in detail separately. (See "Biology of warfarin and modulators of INR control", section on 'Drug interactions'.)

Warfarin resistance — The term "warfarin resistance" has been used by some clinicians for patients who require very high doses of warfarin to attain a therapeutic PT/INR. We prefer to avoid this term, as it implies a specific clinical entity, when in fact a variety of factors may impact warfarin dose requirements (eg, diet, metabolism, interacting medications).

A separate issue is a patient who has a thromboembolic event while receiving warfarin despite a therapeutic PT/INR. Management of such patients is discussed separately:

Recurrent venous thrombosis – (See "Venous thromboembolism: Anticoagulation after initial management" and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

Recurrent stroke – (See "Stroke in patients with atrial fibrillation", section on 'Anticoagulation failure'.)

There is no evidence that very large daily doses of warfarin confer additional toxicity or unanticipated side effects other than those listed below (see 'Complications' below), as long as the INR is in the therapeutic range.

Warfarin discontinuation — For patients discontinuing warfarin, the medication may be stopped abruptly; a taper is not required [3].

MONITORING (PT/INR) — Warfarin anticoagulation requires monitoring to determine the degree of anticoagulation and to guide dose adjustments to optimize the time in the therapeutic range, which is a surrogate for clinical outcomes.

For the vast majority of patients, monitoring is done using the prothrombin time with international normalized ratio (PT/INR), which reflects the degree of anticoagulation due to depletion of vitamin K-dependent coagulation.

The mechanism by which warfarin prolongs the PT/INR is discussed separately. (See "Biology of warfarin and modulators of INR control", section on 'Mechanism of action'.)

It is worth noting that the PT/INR in a patient on warfarin may not reflect the total anticoagulation status of the patient in certain settings:

First few days of warfarin initiation – (See 'Initial dosing' above and "Biology of warfarin and modulators of INR control", section on 'Biology'.)

Liver disease – (See "Hemostatic abnormalities in patients with liver disease", section on 'Laboratory abnormalities'.)

Baseline prolonged PT/INR (eg, lupus anticoagulant) – (See "Management of antiphospholipid syndrome", section on 'Anticoagulant monitoring'.)

Monitoring interval — The frequency of monitoring is determined by the stability of the PT/INR values over time and changes in clinical status.

Hospitalized patients generally have the PT/INR monitored daily because a variety of factors during hospitalization may affect warfarin absorption and/or metabolism.

Patients initiating anticoagulation with warfarin, or transitioning between warfarin and another anticoagulant, require frequent measurements (eg, daily, every other day, two to three times per week) in accordance with institutional protocols.

Those with a PT/INR outside the therapeutic range, or those with frequent dose adjustments or change in clinical status, require more frequent monitoring until the dose can be stabilized (eg, two or more times per week, or weekly).

Once the anticoagulant effect and patient's warfarin dose requirements have been stabilized for at least one to two weeks, the INR can be monitored less frequently, at intervals in the range of every two to four weeks [15,68]. Monitoring once every four weeks is often used.

Patients who have had repeatedly therapeutic, stable INRs may be monitored less frequently [69-71], and the 2012 American College of Chest Physician (ACCP) Guidelines and 2018 American Society of Hematology (ASH) Guidelines have suggested an INR testing frequency of up to 12 weeks for patients with consistently stable INRs [3,33]. However, we generally monitor more frequently than every 12 weeks in all but the most stable patients with clinical features similar to those in clinical trial populations.

Importantly, additional dose changes generally are not made until the patient has had a repeat PT/INR determination after two or more days at a new dose because changes in dose generally are not reflected immediately. (See 'Establishing a maintenance dose' above.)

Serial monitoring of the INR will detect many patients who are over-anticoagulated before they have had a bleeding episode. However, monitoring is not completely protective because there may be only a brief warning period during which a slightly elevated INR predicts for an imminent bleeding event. This was illustrated in a review of 32 patients with a warfarin-related hemorrhage in whom the mean INR at the time of bleeding was 5.9, but the mean INR at the most recent routine measurement, obtained an average of 12 days before the bleeding event, was 3.0 [72]. Additionally, many cases of warfarin-associated bleeding occur in the setting of a therapeutic INR. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk'.)

Importance of strict INR control — The intensity of anticoagulation correlates well with clinical outcomes. This has been demonstrated in various systematic reviews, meta-analyses, and other studies [24,73-76]. In a meta-analysis of 45 studies involving 71,065 individuals receiving a VKA, one-half of the thromboembolic events occurred when the international normalized ratio (INR) was below the therapeutic range, and 44 percent of hemorrhages occurred when the INR was above the therapeutic range [77]. This relationship is illustrated in the figures for patients with atrial fibrillation (figure 3) and other conditions (figure 4).

The quality of INR control is often assessed by determining the percentage of the time in the therapeutic range (TTR), a measure that can be estimated from a period of INR readings or calculated by an interpolation method. (See "Biology of warfarin and modulators of INR control", section on 'Overview of INR control'.)

In general, a TTR of 65 to 70 percent is considered to be good quality control [78,79]. A study in patients with atrial fibrillation found that adding warfarin to antiplatelet therapy led to improved outcomes when the TTR was >60 percent, but the benefit was lost with TTR approximately <60 percent [80].

The relative efficacy of various approaches for maximizing the TTR was addressed in a systematic review and meta-regression of 67 studies involving 50,208 patients followed for a total of 57,155 patient-years [81]. The PT/INR was in the therapeutic range an average of 64 percent of the time, and the rate varied with study setting:

Self-management – 72 percent

Randomized trials – 66 percent

Anticoagulation clinics – 66 percent

Community practices – 57 percent

Self-management, which yielded the highest percent of time spent within the therapeutic INR range, is not feasible in all situations but is often associated with a high TTR. This approach may be preferable for patients who place a high value on being able to control their testing and dosing. However, this approach is not feasible for all patients; it requires the capability to self-monitor and make dose adjustments, along with institutional policy, appropriately trained providers, and educational resources. (See 'Self-monitoring and self-management' above.)

As noted above, the time of day warfarin is taken does not appreciably affect the TTR once the individual's dose has been established. The time of day that would result in the best adherence should be used. (See 'Establishing a maintenance dose' above.)

Importantly, for patients with a suboptimal TTR, it is important to determine whether the variability in PT/INR measurements is due to factors such as diet or medication interactions, which might be improved by low-dose vitamin K supplementation (see 'Poor INR control/vitamin K supplementation' below) or by using a different oral anticoagulant; or to patient noncompliance, which may argue against the use of one of the direct oral anticoagulants because of their shorter half-lives and lack of validated monitoring. (See 'Advantages and disadvantages' above.)

Poor INR control/vitamin K supplementation — Two major factors that may lead to poor control of warfarin dosing and may be modified by relatively straightforward interventions are failure to take warfarin appropriately and very low dietary vitamin K intake/vitamin K deficiency.

Medication adherence – A variety of factors may reduce VKA adherence including confusion about dosing, delays in communication with the treating clinician, and challenges of taking a different dose on different days of the week (see "Biology of warfarin and modulators of INR control"). Patient education programs have been shown to improve the TTR in most settings, as discussed above. (See 'Outpatient management' above.)

Vitamin K status – In some cases, poor INR control may be due to low dietary vitamin K intake or vitamin K deficiency, both of which may make the patient especially sensitive to small day-to-day variations in vitamin K intake. Some populations may be at greater risk for vitamin K deficiency (eg, poor nutrition). Administration of a small daily dose of vitamin K has been tested in several studies and one published randomized trial [82]. A 2016 systematic review that included 15 studies (1838 patients) concluded that the use of daily vitamin K at a very small dose (range, 100 to 500 mcg daily) may be associated with a clinically relevant improvement in the TTR, but there is no clinically relevant benefit to using this approach in unselected populations receiving warfarin [83]. The dose must be sufficient to blunt large changes in the international normalized ratio (INR) but low enough that it does not interfere with anticoagulation. In the published trial, 70 patients with unexplained poor INR control were randomly assigned to receive 150 mcg of daily vitamin K or placebo for six months [84]. Compared with controls, individuals receiving low-dose vitamin K had less variability in PT/INR measurements and the increase in the TTR was greater (28 versus 15 percent). Additional studies also suggest that low-dose oral vitamin K, in the range of 100 to 200 mcg orally per day, may improve INR control [85]. This intervention may be appropriate for patients with suspected vitamin K deficiency for whom other interventions to improve anticoagulation status are ineffective, which may particularly apply to those with low dietary vitamin K intake (eg, older individuals with a limited diet or poor nutrition).

There are no low-dose oral formulations of vitamin K approved by the US Food and Drug Administration (FDA); however, several formulations are available from health food stores and pharmacies [86]. A pharmacist can help the patient locate a vitamin K1 oral 100 mcg supplement from a highly reliable, nationally known supplier that adheres to good manufacturing practices and standards.

In contrast to patients with poor INR control, for other patients receiving a VKA there is no evidence to support routine vitamin K supplementation [3].

Falsely elevated INRs — The most common cause of a falsely elevated international normalized ratio (INR) is the presence of heparin in the blood sample. This can be avoided by obtaining the needed blood sample from a peripheral vein rather than from indwelling central venous catheters, which might be contaminated with heparin.

Another common cause of a falsely elevated INR is inadequate filling of pediatric collection tubes, resulting in a higher than normal ratio of citrate anticoagulant to patient plasma. (See "Clinical use of coagulation tests", section on 'Sample collection and handling'.)

The presence of a lupus anticoagulant may also artificially prolong the PT/INR value. Approaches to monitoring warfarin in this setting are presented separately. (See "Management of antiphospholipid syndrome", section on 'Anticoagulant monitoring'.)

Other monitoring strategies (investigational) — The INR is based on the PT, and the PT is highly sensitive to the vitamin K-dependent factor with the shortest half-life (factor VII). Thus, minor fluctuations in factor VII levels can cause the PT and INR to shift in and out of range. However, the main mechanism of action of warfarin is likely to be via its effects on factors II and X.

A new strategy for warfarin monitoring has been proposed that depends on the levels of factor II and factor X rather than factor VII, referred to as the factor II and X prothrombin time (Fiix-PT; pronounced "fix-PT"); a corresponding Fiix-normalized ratio (Fiix-NR) can also be calculated [87]. In a comparison of thrombosis and bleeding rates in 2667 individuals stably anticoagulated with warfarin who had been managed based on the PT and INR, substitution of the Fiix-PT assay and Fiix-NR-based dose adjustments resulted in a lower thrombosis rate and a reduction in the number of laboratory tests and dose adjustments:

Thrombosis – Reduced from 2.8 percent to 1.2 percent per patient-year (p = 0.02)

Bleeding – Unchanged at 2.8 percent

Number of laboratory tests – Reduced from 17 to 13 per patient-year

Number of dose adjustments – Reduced from 5.0 to 3.3 per patient-year

The assay uses test plasma deficient in factors II and X and can be automated using diluted patient plasma samples. An editorialist noted that these real-world results confirm findings from an earlier small trial and suggested that implementation of the Fiix-PT and Fiix-NR should become a high priority [88].

TRANSITIONING BETWEEN ANTICOAGULANTS/BRIDGING — The goal when transitioning between anticoagulants is to maintain stable anticoagulation. Thus, when transitioning from another anticoagulant to a VKA, it is important to keep in mind that the full effect of the VKA does not occur for the first few days, despite prolongation of the prothrombin time/international normalized ratio (PT/INR) [89,90] (see 'Initial dosing' above). Likewise, when transitioning from warfarin to another anticoagulant, the resolution of warfarin effect may take several days.

The following approaches are reasonable when transitioning from another anticoagulant to warfarin or another VKA but do not substitute for clinical judgement regarding individual patient factors.

Heparin products/fondaparinux/argatroban to warfarin – The parenteral agent and the VKA are overlapped for at least five days, and for at least 24 hours or two consecutive days after the PT/INR has reached the therapeutic range [91].

Direct oral anticoagulants (DOACs [dabigatran; apixaban, edoxaban, rivaroxaban]) to warfarin – The anticoagulants are overlapped, since it takes several days for warfarin to become therapeutic (including two to three days after the INR reaches the target range). In cases of very high thromboembolic risk, a parenteral agent may be used during the transition from the DOAC to warfarin. The direct factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) also prolong the PT/INR, which may make monitoring during the transition more challenging; thus, it may be helpful to check the INR at the approximate trough of the DOAC dose. Specific instructions from the product information and society guidelines are discussed in a separate topic review. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.)

Warfarin to heparin/fondaparinux/argatroban – Start the parenteral agent when the INR is <2. (See "Perioperative management of patients receiving anticoagulants", section on 'Bridging anticoagulation'.)

Warfarin to a DOAC – Discontinue the VKA, monitor the PT/INR, and start the DOAC when the INR is below a certain threshold (between 2 and 3, with slight variations depending on the package information for each agent, as summarized in a separate topic review). In general, we think it is reasonable to discontinue VKA and initiate a DOAC when the INR is ≤2. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.)

One VKA to another VKA – When transitioning between VKAs, discontinue the old VKA and begin the new VKA at the next scheduled dose, assuming the PT/INR is in the therapeutic range. The PT/INR should also be monitored more frequently when substitution of one warfarin preparation for another has occurred in order to screen for differences in drug availability [92-94].

Aspects of anticoagulant discontinuation and initiation specific to individual clinical settings are discussed in detail separately:

Atrial fibrillation – (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Other reasons for switching agents' and "Atrial fibrillation in adults: Use of oral anticoagulants".)

Prosthetic heart valve – (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Planning for invasive procedures'.)

Venous thromboembolism – (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Switching anticoagulants during therapy'.)

Perioperative management – (See "Perioperative management of patients receiving anticoagulants".)

Gastrointestinal procedures – (See "Management of anticoagulants in patients undergoing endoscopic procedures".)

COUNSELING AND PATIENT EDUCATION

Dietary considerations — Warfarin efficacy is affected by changes in dietary vitamin K intake. Importantly, this should not be interpreted to mean that patients should eliminate vitamin K from the diet. Rather, patients must pay attention to their dietary vitamin K intake and attempt to maintain a relatively stable level of intake over time. (See "Biology of warfarin and modulators of INR control".)

Patients should be provided with information regarding the vitamin K content of foods and other sources (eg, vitamins) (table 7 and table 8) and advised to maintain a relatively consistent level of intake rather than told to avoid vitamin K-containing foods. (See "Biology of warfarin and modulators of INR control", section on 'Vitamin K intake'.)

The use of low-dose vitamin K supplementation in patients with poor international normalized ratio (INR) control is discussed above. (See 'Poor INR control/vitamin K supplementation' above.)

Alcohol and smoking — Patients taking warfarin are advised about the possibility of variable INR control with excessive alcohol intake or "binge" drinking; however, patients do not need to abstain from alcohol because they are taking warfarin. (See "Biology of warfarin and modulators of INR control", section on 'Tobacco, marijuana, and alcohol'.)

Tobacco may affect warfarin efficacy, especially smokeless tobacco, which has a high vitamin K content. Patient education regarding tobacco cessation is a component of routine medical care; the anticoagulation provider should be notified about changes in tobacco use as this may affect the INR. (See "Overview of smoking cessation management in adults".)

Sports participation — Use of an anticoagulant is associated with an increased risk of trauma-associated bleeding. Guidelines are not available to assist patients taking warfarin in determining which sports activities are to be avoided and which are acceptable. Patients who elect to participate in activities with a greater than average risk for blunt trauma should be aware that taking warfarin increases the likelihood that any given injury may be complicated by serious bleeding [95,96].

COMPLICATIONS

Bleeding — Factors that affect bleeding risk and an approach to the management of warfarin-associated bleeding or supratherapeutic international normalized ratio (INR) are presented in detail separately. (See "Risks and prevention of bleeding with oral anticoagulants" and "Management of warfarin-associated bleeding or supratherapeutic INR" and "Reversal of anticoagulation in intracranial hemorrhage".)

The safety benefit of a direct oral anticoagulant (DOAC) over warfarin may be greatest for older individuals, especially those with other risk factors for bleeding. (See 'Older adults' below.)

Skin necrosis — Skin necrosis has been reported in some patients within the first few days of receiving large doses of warfarin [97]. The skin lesions usually occur in areas with subcutaneous fat, including the extremities, breasts, trunk, or penis. Skin changes marginate over a period of hours from an initial central erythematous macule (picture 1 and picture 2 and picture 3). Biopsies demonstrate fibrin thrombi within cutaneous vessels and associated interstitial hemorrhage.

Skin necrosis appears to be mediated by the rapid reduction of protein C levels on the first day of therapy, which induces a transient hypercoagulable state. Approximately one-third of patients who develop these lesions have underlying hereditary protein C deficiency; however, among patients with protein C deficiency, skin necrosis is an infrequent complication of warfarin therapy [98].

In an individual with known protein C deficiency, approaches to anticoagulation include using a non-warfarin anticoagulant or providing a parenteral agent for the first few days of warfarin therapy until a stable PT/INR has been reached. Individuals without a diagnosis of protein C deficiency who are treated with warfarin for venous thromboembolism will receive another anticoagulant initially to achieve rapid anticoagulation for the acute event, whereas those with atrial fibrillation who are treated with warfarin prophylactically for stroke prevention generally are treated as an outpatient and do not receive another anticoagulant during the first few days of warfarin.

Case reports have also described skin necrosis or thrombosis at other sites in association with an acquired functional deficiency of protein C or protein S, heterozygous protein S deficiency, or the factor V Leiden mutation [99]. (See "Protein C deficiency", section on 'Warfarin-induced skin necrosis'.)

Teratogenicity during pregnancy — VKAs are known teratogens and are generally contraindicated during at least the first trimester of pregnancy. This subject is discussed in detail separately. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Warfarin teratogenicity'.)

Cholesterol embolization — Embolization of cholesterol crystals (cholesterol microembolism) is a rare complication of anticoagulation with warfarin. Typically, this occurs after several weeks of therapy and may present as a dark, purplish, mottled discoloration of the plantar and lateral surfaces of the lower extremities. This condition has been variously called "blue toe syndrome" or "purple toe syndrome" [100-102]. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)", section on 'Skin'.)

Vascular calcification — A number of studies have suggested that the chronic use of warfarin may lead to arterial calcification (eg, aortic valve, coronary arteries, femoral artery) [103-106]. As an example, in a series of 157 patients with atrial fibrillation who had calcium scans, coronary calcium scores increased significantly with the duration of VKA use, from a mean score of 53 in patients not receiving a VKA to a mean score of 236 in patients receiving a VKA for over five years [106]. The mechanism may involve inhibition of a vitamin K dependent matrix Gla protein. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid", section on 'Gla-containing proteins of mineralized tissue'.)

These observations notwithstanding, there is no evidence that warfarin increases the risk of clinical events that would be expected in patients with increased calcification of the arterial wall such as stroke, myocardial infarction, or peripheral vascular disease. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)

Nephropathy — Anticoagulant-related nephropathy (also called warfarin-related nephropathy) refers to acute kidney injury that occurs in the setting of excessive anticoagulation; its existence as a distinct entity is difficult to establish with certainty. The pathogenesis, risk factors, evaluation, and management are discussed in detail separately. (See "Anticoagulant-related nephropathy".)

Allergic reactions — Allergy to warfarin (which may be related to the dye in the tablet) is extremely rare although the frequency is unknown. Cross-allergy between coumarin derivatives has been described, but details are limited. In a case report, a single patient developed a maculopapular rash following treatment with three different coumarin derivatives [107].

The paucity of information concerning the safety of switching from one coumarin derivative to another because of an allergic reaction is such that the clinician will need to make clinical decisions on a case-by-case basis. The possibility that the patient is reacting to the dye in the tablet (rather than the coumarol moiety itself) should always be considered. In cases of suspected dye allergy, it may be prudent to use a dye-free tablet (such as a 10 mg dye-free warfarin tablet).

Interference with thrombophilia testing — Genetic testing for inherited thrombophilia (eg, prothrombin G20210A mutation, factor V Leiden mutation) can be performed during VKA use; however, it is not possible to reliably test protein S or protein C levels in a patient receiving a VKA, because these proteins are vitamin K-dependent (table 3). Some lupus anticoagulant assays will yield false positive results in patients receiving a VKA.

Importantly, these caveats for thrombophilia testing should not be interpreted to imply that this testing is performed routinely prior to warfarin initiation. Indications for thrombophilia testing are discussed separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Overview of the evaluation of stroke", section on 'Blood tests'.)

SPECIAL SITUATIONS

Conception/pregnancy — Warfarin is a known teratogen (see 'Teratogenicity during pregnancy' above). Strategies for anticoagulation of females receiving warfarin around the time of conception and in the setting of a prosthetic heart valve are presented separately. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Warfarin-associated bleeding' and "Management of antithrombotic therapy for a prosthetic heart valve during pregnancy".)

Surgery — Depending upon the type of surgery planned, anticoagulation with warfarin may have to be interrupted temporarily. This subject is discussed separately. (See "Perioperative management of patients receiving anticoagulants" and "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Planning for invasive procedures'.)

Rapid reversal of warfarin in patients who require urgent/emergent surgery is also discussed separately. (See "Perioperative management of patients receiving anticoagulants", section on 'Urgent/emergency invasive procedure'.)

Older adults — Bleeding risk and thrombotic risk both tend to increase with increasing age, but there is no upper age limit above which anticoagulation cannot be used [108,109]. Several studies have documented that appropriate anticoagulation has been prescribed at too low a dose or not prescribed at all to older individuals [110-113].

However, because bleeding risks increase with age, especially with warfarin, experts recommend that older individuals use a direct oral anticoagulant (DOAC) for most indications, including venous thromboembolism and atrial fibrillation. The safety benefit of a DOAC over warfarin may be especially relevant for older individuals with other risk factors for bleeding. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors for bleeding'.)

The 2023 updated Beers criteria from the American Geriatric Society (AGS) recommend that patients ≥65 years of age not initiate warfarin for venous thromboembolism (VTE) or nonvalvular atrial fibrillation unless there are contraindications to using a DOAC or substantial barriers to DOAC use [114]. According to these criteria, individuals ≥65 years who have been using warfarin long-term with well controlled INR (>70 percent of the time in the therapeutic range) without adverse effects may reasonably continue warfarin.

The following may be useful when prescribing warfarin to older individuals:

Age cutoff – There is no clear age cutoff that defines "older"; features of aging that increase bleeding risk in some individuals may not be relevant in others (eg, changes in diet, polypharmacy). The Beers criteria use ≥65 years to define an older adult [114].

Dosing – As a general rule, older individuals have increased sensitivity to the anticoagulant effect of warfarin at any given dose [115-118]. Thus, older individuals are likely to require a lower mean daily dose to maintain the international normalized ratio (INR) in the appropriate range. In one report, individuals ≥75 years needed less than one-half the daily warfarin dose of those <35 years for an equivalent INR [119]. A slightly lower warfarin starting dose (eg, 3 to 5 mg daily) is reasonable, and, as noted above, "loading" doses are to be avoided. (See 'Initial dosing' above.)

Drug interactions – Older individuals may be more likely to be prescribed multiple medications, sometimes from multiple providers. It is thus especially important to educate patients about the potential drug-drug interactions and to monitor the INR more closely (eg, once per week) when a new medication that may affect the INR is added. This is especially important for new antibiotics. (See "Biology of warfarin and modulators of INR control", section on 'Drug interactions'.)

Concomitant antiplatelet agents – Combined use of warfarin and antiplatelet agents may further increase bleeding risk by interfering with two mechanisms of hemostasis (platelets and coagulation factors). (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Concomitant antiplatelet medications'.)

This may be especially relevant in individuals with atrial fibrillation who develop an acute coronary syndrome. Appropriate use of triple antithrombotic therapy is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy" and "Acute coronary syndrome: Oral anticoagulation in medically treated patients".)

Shared decision-making – The increased risks of bleeding and thrombosis in older individuals highlight the need for patient education, understanding of the risks, and consideration of patient values and preferences. As an example, many clinicians are more concerned about the risk of fatal intracerebral bleeding, whereas many patients are more fearful of the chronic, devastating effects of a thrombotic stroke. For individuals with atrial fibrillation, the use of risk scores to estimate bleeding and thrombotic risk may be helpful in ensuring that the clinician and the patient have similar information about overall risks and modifiable risk factors. These risk scores are discussed in more detail separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants".)

Resumption after bleeding — Warfarin may be safely reinitiated in selected patients following a bleeding event. Considerations regarding whether and when to resume warfarin after bleeding are discussed separately.

After intracerebral hemorrhage (ICH) – (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Anticoagulation'.)

After an endoscopic procedure – (See "Management of anticoagulants in patients undergoing endoscopic procedures", section on 'Resuming anticoagulants after hemostasis'.)

After other bleeding – (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Resumption of anticoagulation after bleeding'.)

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 topics (see "Patient education: Warfarin (Beyond the Basics)" and "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Appropriate useVitamin K antagonists ([VKAs] eg, warfarin, acenocoumarol, phenprocoumon, fluindione) have a variety of indications for prophylaxis and treatment of thromboembolic disease, especially prosthetic heart valves and antiphospholipid syndrome. For most patients with venous thromboembolism (VTE) or atrial fibrillation, a direct oral anticoagulant (DOAC) is preferred. The improved safety profile of DOACs over warfarin is particularly relevant for individuals ≥65 years, especially those with other bleeding risk factors. However, there is a large body of experience with VKAs, and these agents may sometimes be preferred due to lower cost, extremes of body weight, severely impaired kidney or liver function, need to monitor adherence, or patient preference. (See 'Indications and contraindications' above and 'Advantages and disadvantages' above.)

Baseline testing – Prior to starting warfarin, patients should have a baseline complete blood count (CBC) with platelet count, prothrombin time (PT), partial thromboplastin time (aPTT), and creatinine. Liver function tests may be helpful in some patients, and females of childbearing potential should have a human chorionic gonadotropin (HCG) test. We suggest not using pharmacogenomic testing to guide warfarin dosing (Grade 2B). (See 'Baseline testing' above.)

Initial dosing – For most patients initiating warfarin therapy, we suggest an initial dose of ≤5 mg daily for the first two days rather than higher "loading" doses (Grade 2B). We generally use 5 mg for most healthy adults but might use a lower dose (eg, 2.5 mg daily, 5 mg alternating with 2.5 mg) for females older than 70, males older than 80, or those who are frail, malnourished, have liver or kidney disease, heart failure, or are receiving a medication known to increase warfarin sensitivity (table 6). An automated dosing calculator is available at www.WarfarinDosing.org/Source/Home.aspx. Dosing on subsequent days is guided by the PT/international normalized ratio (INR) value (table 4). (See 'Initial dosing' above.)

Maintenance dosing – Maintenance doses of warfarin vary significantly among patients; a reasonable approach to adjusting warfarin dosing is outlined in the table (table 5). In general, management through an anticoagulation clinic or self-management is associated with better outcomes than individual clinician management in the community. The choice between these options will depend on clinician and patient resources and preferences. (See 'Establishing a maintenance dose' above and 'Outpatient management' above.)

MonitoringWarfarin is monitored using the PT/INR, which correlates well with clinical outcomes. Monitoring intervals depend on the stability of previous measurements and changes in clinical status. (See 'Monitoring (PT/INR)' above.)

Improving efficacy – Patient education includes information about the effects of certain foods, smoking, and alcohol intake on INR control and how to minimize INR perturbations, as well as awareness about bleeding risk and pregnancy considerations. For patients with unexplained poor INR control, it is important to confirm that the VKA is being taken as prescribed and that the patient does not have vitamin K deficiency. (See 'Counseling and patient education' above and 'Poor INR control/vitamin K supplementation' above.)

Switching anticoagulants – It may be appropriate to overlap anticoagulants when changing from one agent to another to another, especially in patients with high thromboembolic risk. Recommendations for switching between oral anticoagulants are summarized above and discussed in more detail in a separate topic review. (See 'Transitioning between anticoagulants/bridging' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.)

Bleeding – Risk factors for VKA-associated bleeding and supratherapeutic INR, and recommendations for minimizing and managing these risks, are discussed in detail separately. (See "Risks and prevention of bleeding with oral anticoagulants" and "Management of warfarin-associated bleeding or supratherapeutic INR" and "Reversal of anticoagulation in intracranial hemorrhage".)

Other complications – Additional complications of VKAs include skin necrosis (typically in the setting of protein C deficiency), cholesterol embolization ("blue toe syndrome"), teratogenicity, vascular calcification, and allergic reactions. Warfarin can also interfere with some thrombophilia testing (table 3). (See 'Complications' above.)

Special situations – Management in individuals attempting conception, perioperative management, older individuals, and individuals with a bleeding episode are presented above and in separate linked topic reviews. (See 'Special situations' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Karen A Valentine, MD, PhD, who contributed to an earlier version of this topic review.

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Topic 1334 Version 112.0

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