Vitamin K antagonists that interfere with synthesis of factors II, VII, IX, and X.

A racemic mixture composed of S- warfarin which is 3-5 times as potent as R-warfarin as an anticoagulant, has a short half-life and is metabolized by cytochrome P-450 enzyme, CYP2C9,

Vitamin K dependent factors require gamma carboxylation of glutamate residues on the N terminus of polypeptides and vitamin K is a cofactor for carboxylase reaction.

Estimated 2 million patients currently use warfarin.

Patients achieve anticoagulation in the therapeutic range from 56 to 63% of the time.

Up to 36% of patients taking warfarin miss more than 20% of their doses.

Has a narrow therapeutic range and there are large variations in dose requirements from one patient to another.

Difficulties achieving optimal anticoagulation levels is due to slow onset of action of the drug, variable pharmacological effects, and food and drug interactions.

Selecting the initial dose of warfarin requires the incorporation of critical factors including: age, race, BSA, smoking status, diabetes, history of stroke, history of DVT or pulmonary embolus, target INR, and major interacting medications.

Crosses the placenta and is associated with adverse fetal effects, including a late fetal loss rate of 12%.

Half-life of 20-60 hours.

Oral anticoagulants can be continued for minimally invasive procedures including cataract surgery, trabeculectomy, vitreoretinal surgery, dental hygiene, simple extractions, restorations, endodontics and dental prosthetics.

Initiation of oral anticoagulation with doses between 5 and 10 mg for the first 1 or 2 days for most patients, with subsequent dosing based on the INR response.

There is wide  intra and interindividual  variability and small differences between beneficial and toxic therapeutic effects: the drug is classified as a narrow therapeutic index drug.

Several factors can alter the pharmacokinetics and pharmacodynamics of the drug and include: diet, multiple medications, concurrent illnesses, and alcohol use.

Obese individuals receiving warfarin have a 40% low risk of major bleeding compared with non-obese patients.

Meta-analysis reveals 44% of bleeding complications are associated with supratherapeutic INRs and 48% of thrombolic events occur with sub therapeutic readings (Oake N et al).

Patients with stable INR management have fewer anticoagulant related complications compared with individuals with less stable INR  control  (Witt DM).

The INR is the strongest and most robust predictor of the risk of thromboembolic and hemorrhagic events.

Warfarin  use in patients with atrial fibrillation with low underlying stroke risk receive minimal net benefit from such therapy ( Singer DE).

Before initiation of  therapy a medical history,  family history, medication history, social history, lifestyle, employment profile, level of understanding, health motivation and healthcare resources should be assessed.

G.I. bleeding affects an estimated 4.5% of patients treated with warfarin annually, and is associated with a significant increase in the risk of death.

Not resuming warfarin therapy in the 90 days following a G.I. bleed associated with an increased risk of thrombosis and death (Witt DM et al).

In a study of 442 patients resumption of warfarin after a G.I. bleed was associated with lower adjusted risk for thrombosis, and death, without significantly increasing the risk for recurrent GI bleeding (Witt DM et,al).

In the above study resumption of warfarin between days 1 and 7 following GI bleeding was associated with a higher risk of GI bleeding but a lower risk of thrombosis.

Clinical trials have not demonstrated increased thromboembolic risk associated with abrupt anticoagulant withdrawal (D’Agostino RB Jr.).

The use of warfarin may be  more risky than withholding treatment in patients with noncompliance, increased bleeding risk factors, history of falls, alcohol consumption, impaired memory and lack of  social support.

Education  of the patient is essential in the management of the patient on warfarin.

With the introduction of this agent frequent INR  assessments, at least 2 to 3 times per week, on necessary for dose titration.

Variants of cytochrome P450 2C9 (CYP2C9)  and vitamin K epoxide  reductase (VKORC1)  plays a role in therapeutic dosing,  determining their levels is not supported by routine use (Kangelaris KN et al).

It is suggested that for a target INR  range of 2.0 to 3.0 and optimum maintenance dose management strategy for warfarin would be to change dosage only   when the INR  is 1.7  or less or 3.3 or greater ( Wells PS  et al, Rose  AJ et al).

In managing maintenance doses of warfarin reductions greater than 20% should be avoided in most instances (Banet GA et al).

In elderly, debilitated, malnourished, in patients with congestive heart failure, in patients with liver disease, in those with recent major surgery, or in those taking medications that increases sensitivity to warfarin the use of 5 mg or less as starting doses are recommended.

Major hemorrhage for patients treated with warfarin for atrial fibrillation ranges from 1 to 7.4% per year (Wiedermann CJ et al, Levine MN et al).

A significant association exists between the intensity of anticoagulation and adverse clinical events, with an increased thrombotic risk at INR less than 2.0 and increased risk of bleeding when INR exceeds 4.0.

Comparing warfarin in atrial fibrillation in real world studies versus clinical trials reveals that in the real world there is a higher risk of major bleeding, ischemic stroke, and mortality (Murcia AF Project).

For patients on a stable dose of oral anticoagulation monitoring the INR should occur at intervals no longer than every 4 weeks.

INR recall intervals should be individualized based on control levels rather than fixed intervals: two to three month intervals in stable patients is reasonable.

When warfarin therapy is complicated by administration of drugs that interfere with its pharmacokinetic and pharmacodynamic properties increased INR monitoring frequency is employed for dose adjustments.

For patients with an INR above the therapeutic range, but <5, without significant bleeding, the dose should be lowered or omitted , monitored more frequently and resuming therapy at an adjusted dose when the INR is therapeutic

When the INR is minimally elevated above the therapeutic range, or associated with a factor or factors that transiently affect the INR, no dose reduction may be needed.

For patients with INRs 5 or greater but less than 9 without significant bleeding, omitting one or two doses is recommended, with more frequent monitoring with resumption of adjusted treatment when the INR is at a therapeutic level.

In patients with mild to moderately elevated INRs it is recommended that vitamin K be administered orally rather than subcutaneously.

After the first year of use the annual risk of major bleeding associated with vitamin K antagonists is 1-2% (Kearon C et al).

For patients with INRs 5 or greater but less than 9 with increased risk of bleeding an alternative management would be to give vitamin K 1-2.5 mg orally.

For patients with INR greater than 9 holding treatment and administering vitamin K 2.5-5 mg orally is suggested, with increased monitoring and further administration of vitamin K as needed.

For patients with an elevated INR with serious bleeding the warfarin should be held, vitamin K (10mg) should be administered by slow intravenous infusion and be supplemented by fresh frozen plasma, prothrombin complex concentrate or recombinant factor VIIa, depending upon the gravity of the bleeding.

In patients with life threatening hemorrhage such as CNS bleeding and an elevated INR warfarin should be withheld and fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa supplemented with intravenous vitamin K should be given until correction of the process.

In the presence of a mechanical heart valve, atrial fibrillation and moderate to high risk for thromboembolism it is recommended that bridging therapy with therapeutic doses of LMWH or unfractionated heparin be utilized during temporary inerruptiontion of vitamin K antagonist therapy.

In the presence of a mechanical heart valve, atrial fibrillation, and low risk for thromboembolism it is recommended that low dose LMWH bridging or no bridging be utilized during temporary interruption on of vitamin K antagonist therapy.

A meta-analysis of trials comparing warfarin with placebo in nonvalvular AF in stroke prevention demonstrated a significant reduction in in stroke and all cause mortality in patients treated with warfarin (Hart RG et al).

Patients with AF at highest risk of stroke, those wth previous stroke or TIA with nonvalvular AF derive the greatest risk reduction of stroke with warfarin compared with aspirin or no antithrombotic treatment (Hart RG et al).

Current use (2012) of warfarin in nonvalvular AF is associated with a low rate of residual stroke or systemic embolism of an estimated rate of 1.66 per year (Agarwal S et al).

Should be stopped 4-5 days prior to surgery to allow adequate normalization of the INR.

Self-monitoring of INR is superior to usual care with a 49% risk reduction of thrombembolic events (Heneghan C et al).

Self-monitoring of INR studies associated with bleeding rates similar to usual care groups, and no major effect on mortality (Heneghan C et al).

Should be resumed after surgery 12-24 hours, when adequate hemostasis exists.

In patients who require temporary cessation of treatment prior to surgery and the INR is still elevated at 1.5 or greater, a low dose of vitamin K 1-2 mg orally is suggested to normalized the INR.

In patients undergoing minor dental procedures warfarin should be continued around the time of the procedure and a prohemostatic agent should be co-administered.

In patients undergoing minor dermatologic procedures warfarin should be continued.

In patients undergoing cataract removal the drug can be continued.

Major bleeding complications occur in 2% of patients during the first three months of treatment.

Congenital anomalies occur in 6.4% of live births in which the fetus was exposed to warfarin through pregnancy, with rates of 10% to 12% reported in prospective studies where warfarin therapy continues beyond 6 weeks’ gestation.

Use in pregnancy results in the fetal warfarin syndrome manifested by birth defects with normal midfacial development, stippling of the epiphyses and mental retardation.

When a patients undergoes major surgery or surgery in which a body cavity is entered the bleeding risk is high and the patient should be off warfarin and have an INR of less than 1.5.

Bleeding risk increases with age, with patients older than 80 years having an odds ratio for a life-threatening bleeding event 4.5 compared with patients younger than 50 years.

In patients requiring reversal of anticoagulant effect for an urgent surgical or other invasive procedure it is recommended to five vitamin K 2.5-5.0 mg intravenously or orally, and for more immediately reversal fresh frozen plasma in addition to low dose intravenous or oral vitamin K.

Warfarin anticoagulation has been reversed with vitamin K1 to reinitiate synthesis of affected factors II, VII, IX, and X, along with proteins C and S and fresh frozen plasma to replete these factors more immediately.

Presently prothrombin complex concentrates have been approved for reversal management

After stopping treatment it takes 4 days for the INR to reach 1.5 or less the ratio felt to be safe for surgery.

Postoperative anticoagulation increases the rate of major bleeding by approximately 3%.

Multiple tooth extractions or other extensive dental surgeries should be done with an INR less than 1.5.

Restarting anticoagulation postoperatively may need to be delayed in patients undergoing neurosurgical procedures.

Acetominophen may increase the hypoprothrombinemic effect of warfarin.

When used with NSAIDs the INR must be monitored closely.

Fetal effects related to the dose and such changes are not seen with warfarin dose under 5 mg/day.

Induced skin necrosis can be preventive with preparative use of heparin or low-molecular weight heparin.

Prescribed for secondary thromboprophylaxis in patients with deep vein thrombophlebitis, pulmonary embolism, acute coronary syndromes, ischemic stroke, and peripheral arterial thrombosis.

Prescribed primarily for atrial fibrillation, after mechanical prosthetic heart valve placement, and for peripheral arterial bypass graft patency.

In atrial fibrillation initiation of warfarin without a parenteral anticoagulant is the standard treatment.

Prevents 64% of strokes in atrial fibrillation (Hart RG).

After stopping treatment there may be a physiologic rebound in clotting factors leading to a hypercoaguable state.

It is estimated that after stopping warfarin in a patient with atrial fibrillation for an operative procedure the risk of embolization is 0.012-.3% assuming the INR is subtherapeutic for 4-6 days.

The risk of thromboembolism with a history of recent venous thromboembolism when warfarin is stopped is about 40% in a 1 month interval after the initiation of warfarin and is 10% for those in their second or third month of anticoagulation.

It is advisable to postpone surgery following an acute venous thromboembolism for 3 months.

Doses must be adjusted for changes in patients’ weight, diet, comorbid conditions, and concomitant medication use.

Patients with functionally defective 2 and 3 allelic variants of cytochrome P-450 enzyme 2C9 require lower maintenance doses , longer time to stabilization and are higher risk for bleeding than are patients without these variants.

Cytochrome P-450 CYP2C9 is the enzyme primarily responsible for the metabolic clearance of the S-enantiomer of warfarin.

Warfarin has day by day variability which is partially determined by diet, comorbidities, interaction with other medications and genetic variations.

Carriers of reduced function polymorphisms of CYP2C9 have a decreased clearance of warfarin and require lower maintenance doses.

Carriers of VKORC1 have altered sensitivity to warfarin.

Patients with common genetic variants of CYP2C9 require lower dosage, a longer time to reaching stable dose, and greater hazards of overdosage with serious bleeding.

CYP2C9 genotype does not significantly affect the INR during the first week of treatment as does VKORC1.

Asians appear to be more sensitive than Caucasians to warfarin anticoagulation.

A risk of major bleeding during an 18 month period of 1.2-2.5% with extended thromboprophylaxis.

A gene encoding vitamin K epoxide reductase complex 1 (VKORC1) recycles reduced vitamin K, which is essential for post-translational gamma carboxylation of vitamin K dependent clotting factors II, VII, IX and X.

Mutations in VKORC1 gene can lead to warfarin resistance.

Genetic variation in VKORC1 modulates the early response to warfarin.

Patients carrying genetic variation in VKORC1 haplotype A have increased INR values in the first week of anticoagulation compared to patients who are non-A homozygotes.

KVORC1 haplotype predicts for time to first INR within the therapeutic range and the time to the first INR of more than 4.

In patients carrying two A alleles for VKORC1 the rate of reaching therapeutic and excess INR outcomes is approximately twice that of non-A homozygotes.

Genotype-guided dosing for warfarin leads to significantly faster time to therapeutic INR and maintenance dose compared with standard dosing protocols, as well as higher percent time at target INR over 3 months.

Common variants (termed *2 and *3) in CYP2C9, which encodes the enzyme responsible for inactivation of the active S-enantiomer of warfarin, resulting in slower elimination, and over-anticoagulation, unless doses are adjusted downward.

Molecular cloning studies in families with warfarin resistance identified mutations in VKORC1, which encodes a key vitamin K regulatory enzyme and is the primary protein target with which warfarin interacts to exert its anticoagulant effects.

Common VKORC1 promoter polymorphisms as determinants of warfarin dosage.

Three trials tested the utility of pharmacogenomically based algorithms in guiding warfarin therapy: the data show that an algorithm-based approach that includes pharmacogenetic information is either only marginally superior to or not superior to an algorithm that uses clinical information alone.

Over the INR range of 1.3-1.9 the mean factor levels of FII ranges from 31-65%, FV from 40-70% FVII from 22-60%.

Half of patients with intracerebral hemorrhage die within 30 days.

Associated intracerebral hemorrhages increased in incidence.

Approximately 18,000 cases of warfarin associated intracerebral hemorrhages occur annually.

Most intracerebral hemorrhages occur when the INR is in the therapeutic level.

The degree of INR prolongation at the time of intracerebral hemorrhage can predict for progressive hematoma enlargement, impaired function and mortality.

When the INR is greater than 3.0 intracerebral hemorrhage is associated with a fatal outcome in two thirds of cases.

Median age for patients with warfarin associated intracerebral hemorrhage in the 70’s.

The most significant complication of oral anticoagulation therapy is intracerebral hemorrhage.

Oral anticoagulants can induce a coagulopathy with large hematoma volumes associated with increased rates of hematoma enlargement that can contribute to higher mortality compared with ischemic stroke primary intracranial hemorrhage.

Among patients with oral anticoagulant associated intracranial hemorrhage reversal of INR to less than 1.3 within 4 hours and systolic blood pressure of less than 160 mmHg at 4 hours is associated with lower rates of hematoma enlargement, and resumption of such therapy is associated with lower risk of ischemic events (Kuramatsu JB et al).

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