Warfarin (AHFS 20:12.04)

Transcription

1 Chapter 24 Ann K. Wittkowsky Warfarin (AHFS 20:12.04) In 1939, Professor Karl Link at the University of Wisconsin, supported by a grant from the Wisconsin Alumni Research Foundation (WARF), isolated a coumarin derivative, dicumarol (bishydroxywarfarin), from spoiled sweet clover. This compound was found to be responsible for hemorrhagic deaths in cattle in the Midwestern U.S. and Western Canada for over a decade. A similar compound, warfarin, was later synthesized and marketed as a rodenticide. By 1955, this compound was commercially available as an anticoagulant. 1 Since then, warfarin has been established through clinical trials as a therapeutic agent for the prevention and treatment of venous and arterial thromboembolic disease. Unfortunately, a narrow therapeutic range and a vast array of drug, disease, and dietary interactions complicate safe use of warfarin. If not properly and respectfully used, this medication can lead to severe complications. The antithrombotic effect of warfarin is the result of its interference with the hepatic synthesis of vitamin K dependent clotting factors II, VII, IX and X. In addition, it interferes with the synthesis of the anticoagulant proteins C and S. In order for these clotting factors to become biologically active, glutamic acid residues at the NH2-terminal region of clotting factor precursors must undergo gamma-carboxylation. This process requires the presence of vitamin KH2, a reduced form of vitamin K. In the process of gamma-carboxylation, vitamin KH2 is oxidized to vitamin KO, an inactive form of vitamin K which is then converted to vitamin K by vitamin K epoxide reductase (VKOR) and then to vitamin KH2 by vitamin K1 reductase. This vitamin K hepatic recycling process assures a continuous supply of vitamin KH2 for clotting factor synthesis. 2 Warfarin inhibits VKOR and vitamin K1 reductase, resulting in accumulation of biologically inactive vitamin KO and thus a reduction in vitamin K dependent clotting factor synthesis. However, the biologic effects of warfarin are not apparent until the previously activated clotting factors are depleted. This depletion takes place according to the biologic half-life of each clotting factor (Table 24-1). 3 Thus, the full anticoagulant effect of warfarin does not occur for at least 3 7 days after beginning therapy or changing a dose. When warfarin therapy is discontinued, blood concentrations of the four vitamin K dependent clotting factors gradually return to pretreatment levels. Warfarin is monitored not by drug concentration measurements but by therapeutic response to the presence of the drug in serum. The prothrombin time (PT) or protime, expressed as an international normalized ratio (INR), describes the time to clot formation. The goal of warfarin therapy is to extend this time sufficiently to prevent pathologic clotting while minimizing the risk of hemorrhagic complications. An INR of 2 3 is suggested for most indications, although higher INRs may be necessary in other situations such as mechanical valve replacement. 2 The safety and effectiveness of warfarin therapy can by improved by thorough knowledge of the pharmacokinetic and pharmacodynamic factors that influence its anticoagulant effect. Table Elimination Half-Lives of Vitamin K Dependent Proteins Factor Half-Life II hr VII 4 6 hr IX hr X hr Protein C 8 hr Protein S 60 hr 351

2 352 Clinical Pharmacokinetics Usual Dosage Range in Absence of Clearance-Altering Factors Warfarin doses required to reach a therapeutic INR vary considerably among individuals. Although the average dose to reach an INR of 2 3 is 4 to 5 mg once daily, doses may range from as little as 0.5 mg daily to 20 mg or more. 4 Numerous factors influence dosing requirements, including goal INR, interacting medications, dietary vitamin K intake, alcohol use, underlying disease states, age, genetic factors, and others. A number of initiation and maintenance dosing strategies for adults and the elderly have been developed (see Dosing Strategies), all of which are based on assessment of INR response. Initiation therapy requires assessment of rate of increase in the INR after the first one to three doses of warfarin and until the INR reaches the lower limit of the therapeutic range, while maintenance therapy adjustments are based on an assessment of factors that may have led to changes in the INR. A weight-based loading protocol for infants and children has also been developed. 5 Infants and children appear to require lower warfarin doses than do adults. 6 A general description of dosing requirements is provided in Table Dosage Form Availability Warfarin is currently available in both oral tablet and injectable form. Coumadin is the proprietary form of warfarin. Each dose strength of Coumadin is readily recognizable by its color (Table 24-3), and all Coumadin tablets are scored. The 10-mg tablet contains no dye and can be used to differentiate warfarin allergy from dye allergy in patients who present with mild allergic reactions after initiation of warfarin therapy. Generic warfarin is available from many commercial sources. The various manufacturers of generic warfarin have generally continued the same color scheme for tablet size identifications, but there are a few color modifications as well as tablet shape and size changes. Practitioners should exercise appropriate caution when counseling patients based on color schemes of the doses. The U.S. Food and Drug Administration has given generic warfarin products an AB bioequivalence rating, meaning that the 90% confidence intervals of the rate and extent of absorption of the generic product are within Table Usual Dosage Ranges Age Initiation Dose Maintenance Dosage Infants 1 mo 1 yr 0.2 mg/kg/day for 1 4 days Average 0.33 mg/kg/day, based on INR response Young children (1 6 years) 0.2 mg/kg/day for 1 4 days Average 0.15 mg/kg/day, based on INR response Children (6 13 years) 0.2 mg/kg/day for 1 4 days Average 0.13 mg/kg/day, based on INR response Teenagers (13 18 years) 0.2 mg/kg/day for 1 4 days Average 0.09 mg/kg/day, based on INR response Adults (18 70 years) 5 10 mg once daily for 1 4 days 5 mg (range 1 20 mg) once daily, based on INR response Geriatrics (>70 years) mg once daily for 1 4 days 2.5 mg (range 1 20 mg) once daily, based on INR response. Often lower than for adults Table Coumadin Color Scheme Coumadin Dosage Size Color 1 mg Pink 2 mg Lavender 2.5 mg Green 3 mg Tan 4 mg Blue 5 mg Peach 6 mg Teal 7.5 mg Yellow 10 mg White

3 Warfarin % to 125% of the mean values of the innovator product. 7 Randomized controlled trials and observational studies have typically found no difference in stability of anticoagulant therapy or in the rate of adverse events when patients are switched from brand to generic warfarin Nonetheless, individual patients may experience changes in therapeutic response. Thus, patients should generally be treated with a single formulation of warfarin, and changes in product source should be considered when evaluating changes in therapeutic response. General Pharmacokinetic Information Warfarin is a racemic mixture of R and S enantiomers, optical isomers that differ significantly with respect to their pharmacokinetic and pharmacodynamic properties (Table 24-4) S-warfarin is more potent than R-warfarin, likely as a result of differences in receptor affinity to vitamin K reductase enzymes. 14,16,17 Absorption Warfarin is nearly 100% bioavailable (F = 1) when taken orally. 18 Both oral and intravenous formulations display similar pharmacokinetic characteristics. 19 The drug is rapidly and completely absorbed from the stomach and proximal small intestine with peak blood concentrations within 0.3 to 4 hr. 20 Food decreases the rate but not the extent of absorption. 21 Distribution Volume of distribution The volume of distribution (V) for racemic warfarin ranges from L/kg, similar to that of albumin. 22,23 The average V for both R and S warfarin is 0.15 L/kg. Protein binding Both R and S warfarin are highly (> 98%) bound to plasma proteins, primarily albumin. 24 Only the remaining free (unbound) concentration is pharmacologically active. The fraction of a given concentration that is unbound increases proportionately with decreasing plasma albumin concentrations and is accompanied by an increase in plasma clearance. 25,26 Stereoselective protein binding has been demonstrated, with a range of 98.9% to 100% for S warfarin compared to 98.7% to 99.9% for R-warfarin. 27 However, these differences are unlikely to be clinically significant. Elimination Warfarin displays stereoselective metabolism, involving both oxidation by cytochrome p450 enzymes in the liver parenchyma and reduction to diasteriomeric alcohols S-warfarin is approximately 90% oxidized, primarily by CYP2C9 to S-6-hydroxywarfarin and S-7-hydroxywarfarin formed in a 3:1 ratio, and to a lesser extent by CYP3A4 to S-4'-hydroxywarfarin and S-10-hdyroxywarfarin. R-warfarin is approximately 60% oxidized by CYP1A2 to R-6-hydroxywarfarin and R-7-hydroxywarfarin, by CYP3A4 to R-10-hydroxywarfarin and R-4'-hydroxywarfarin, and by CYP2C19 to R-8-hydroxywarfarin. These inactive oxidative metabolites and reduced alcohol derivatives of warfarin are eliminated by urinary excretion. Approximately 50% of a dose of racemic warfarin administered orally is recovered in the urine over 9 days, with recovery of 31% of S-warfarin metabolites and 19% of R-warfarin metabolites and only trace amounts of unchanged drug. 31 Table 24-4 shows clearance values for S- and R- warfarin. 14,34 A number of genetic variants of CYP2C9 have been identified.35 In comparison to patients who are homozygous for the wild-type allele (CYP2C9*1*1), patients with a heterozygous (CYP2C9*1*2, CYP2C9*1*3, CYP2C9*2*3) or homozygous (CYP2C9*2*2, CYP2C9*3*3) presentation of a variant allele display significant reductions in the metabolism of S-warfarin to 7-hydroxywarfarin. In in vivo studies, the clearance of S-warfarin is 8% to 42% lower in CYP2C9*1/*2 heterozygotes compared to the homozygous wild-type, and subject with the CYP2C9*1/*3 genotype have 38% to 63% lower clearance. Comparatively, heterozygous *2/*3 patients had 70% to 77% lower clearance, and homozygous *2*2 and *3/*3 patients had 68% lower and 38% to 91% lower clearance rates, respectively In response to reduced S-warfarin clearance, patients with variant expression of CYP2C9 have lower warfarin dosing requirements than patients with the wild-type allele Their risk of over-anticoagulation is higher

4 354 Clinical Pharmacokinetics during initiation therapy and during maintenance therapy, and they are more likely to experience bleeding complications of warfarin The genetic expression of VKORC1 also influences warfarin dosing requirements. A number of single nucleotide polymorphisms of VKORC1 have been shown to be associated with interindividual and interethnic warfarin dosing requirements. The most significant of these are 1173C>T in intron 1 (expressed as CC, CT, or TT) and 3730G>A (expressed as GG, GA, or AA) in the 3' untranslated region, as well as -1639G>A (expressed as AA, AG, or GG). 47 Initial work in 147 patients followed from initiation of warfarin therapy found that regardless of the presence of confounding variables, the mean adjusted daily dose of warfarin required to maintain a stable INR was higher (6.2 mg) among patients with the VKORC CC genotype than patients carrying the CT (4.8 mg) or the TT genotype (3.5 mg). 48 Subsequently, 10 common noncoding VKORC1 SNPs were identified, with 5 major haplotypes inferred in 368 patients (119 white, 96 of African descent, 120 of Asian descent), declaring a low-dose haplotype group (A) and a high-dose haplotype group (B). 49 The mean maintenance dose of warfarin for the 3 haplotype group combinations was 2.7 mg/d for A/A, 4.9 mg/d for A/B, and 6.2 mg/d for B/B. The A haplotype represents more warfarin sensitivity (i.e., less VKOR expressed), and the B haplotype represents less warfarin sensitivity. Asians had a higher proportion of group A haplotypes, and Africans had a higher proportion of group B haplotypes. Half-life and time to steady state The average elimination half-life of S warfarin is 29 hr and of R-warfarin is 45 hr ,23 Although it takes approximately five half-lives to reach steady state warfarin concentrations after initiation of therapy or dosage adjustments, therapeutic steady state is not achieved until the vitamin K-dependent clotting factors have also reached a new equilibrium. Dosing strategies Initiation dosing Because of wide variability in dosing requirements among patients, the initial dosing of warfarin therapy is based on the presence or absence of factors that may influence dosing requirement and on the INR response to initial doses. Large fixed loading doses (10 mg 15 mg daily for several days) and loading doses based on body weight (1.5 mg/kg), although once favored, are no longer recommended as they increase the risk of both over-anticoagulation and hemorrhage. 50,51 Instead, two general methods for initiation with moderate warfarin doses are used. These are the average daily dosing method and flexible initiation. Average daily dosing method. In an evaluation of over 2000 patients taking stable doses of warfarin for a variety of indications, the geometric mean dose was 4.57 mg daily, and the arithmetic mean dose was 5.13 mg daily.4 Patients who do not meet specific criteria that indicate either high or low sensitivity to the effects of warfarin can be initiated with a dose of 5 mg daily, with INR values checked within 3 5 days. Subsequent doses are based on Table Pharmacokinetic and Pharmacodynamic Characteristics of the Enantiomers of Warfarin R-warfarin S-warfarin Bioavailability 95% 100% 95% 100% Volume of distribution L/kg L/kg Protein binding 98.7% 99.9% 98.9% 100% Elimination half-life 45 hr (20 70 hr) 29 hr (18 52 hr) Hepatic metabolism 40% reduction 60% oxidation 10% reduction 90% oxidation 2C9>3A4 1A2>3A4>2C19 Clearance (single dose) L/hr/kg L/hr/kg Clearance (multiple dose) L/hr/kg L/hr/kg Stereospecific potency 1.0 (reference) R warfarin

5 Warfarin 355 the response to the INR and the INR is checked again in another 3 5 days. This pattern continues until the INR is above the lower limit of the therapeutic range, at which time a maintenance dose is selected based on the doses given to this point. Patients who are expected to be more sensitive to the effects of warfarin are described in Table In these patients, the average warfarin dosing requirement is likely to be reduced to 1 3 mg daily. Using the average daily dosing method, patients with any of these characteristics should be initiated with a lower dose (2.5 mg is often used), with subsequent dosing based on INR response as measured within 3 5 days. Several algorithms have been developed to assist with dosing decisions after the first few doses of warfarin have been administered. After four doses of warfarin 5 mg daily, the INR on day 5 was used to predict weekly warfarin maintenance doses in a scheme by Pengo et al. 52 Siguret et al. administered warfarin 4 mg daily for three doses and used the INR on day 4 to predict maintenance dose in elderly patients. 53 Comparatively, the INR on day 15 after 2 weeks of warfarin 2 mg daily was used to predict maintenance dose requirements in elderly patients in a scheme by Oates et al. 54 Two algorithms have been developed that use two INR values to predict warfarin maintenance dose. Tait et al. administered warfarin 5 mg daily for 4 days and used the INR on day 5 to select warfarin doses for days The subsequent INR on day 8 was then used to predict the maintenance dose. Kovacs et al. developed a similar algorithm using warfarin 10 mg daily for 2 days (Figure 24-1). 56 At day 3, the INR was used to guide dosing on days 3 and 4, and the INR on day 5 was used to guide the next 3 doses. In a study comparing this algorithm to a previously published 5 mg initiation algorithm, patients who received the 10 mg starting doses reached the therapeutic range more rapidly than those initiated with 5 mg starting doses, with no difference in the risk of major bleeding or overanticoagulation. 57 However, the patients in this study were relatively young and healthy outpatients with acute venous thrombosis. Warfarin initiation with 10 mg may lead to over anticoagulation and increased bleeding risk in older and less healthy patients with other indications for oral anticoagulation. 58 In addition, initiation with 10 mg can cause a rapid depletion of protein C, which may induce a relatively hypercoagulability. 59 Each of these algorithms differs not only in method used to achieve stable dosing, but also in validation sample size, population studied, time to achieve a therapeutic INR, risk of under- and over-anticoagulation during initiation therapy, and success in predicting the maintenance dose. None is a preferred method, but all demonstrate the importance of assessment of change in INR as a predictor of eventual warfarin maintenance dose requirement and the significance of evaluation of underlying factors that may influence warfarin dosing requirement in individual patients. Flexible initiation. Hospitalized patients who are available for daily INR testing may benefit from flexible initiation of warfarin. Several flexible initiation algorithms have been developed, each of which considers the rate of increase in the INR on a daily basis to inform daily warfarin dose and to predict the maintenance dosing requirements. The earliest nomogram by Fennerty et al. started with a 10-mg dose followed by daily INR and daily warfarin adjustments to reach a predicted maintenance dose by day This method was successfully applied in relatively young patients with thromboembolic disease (mean age 52) and in older patients with other indications for oral anticoagulation (mean age 66). 60,61 However, concerns about the use of 10-mg starting doses, particularly in the elderly, have persisted. Table Factors Likely to Increase Sensitivity to Warfarin Age >75 Clinical congestive heart failure Elevated baseline INR Clinical hyperthyroidism Fever End stage renal failure Diarrhea Malignancy Known CYP2C9 variant Following heart valve replacement Hypoalbuminemia Hepatic disease Malnutrition Decreased overall oral intake Drug-drug interactions

6 356 Clinical Pharmacokinetics Day-3 INR Days 3, 4 Dose (mg) Day-5 INR Days 5, 6, 7 Dose (mg) < , 15 < , 15, , 5, , > 3.5 0, 5, 5 0, 0, , 5 < , 7.5, 7.5 5, 5, , > , 2.5, 2.5 0, 2.5, , 2.5 < , 5, 5 2.5, 5, , > 3.5 0, 2.5, 0 0, 0, 2.5 >3.0 0, 0 < > , 2.5, , 0, 2.5 0, 2.5, 0 0, 0, 2.5 Figure Warfarin initiation dosing algorithm based on starting with 10-mg doses on days 1 and 2. Source: Reprinted with permission from Kovacs MJ, Anderson DA, Wells PS. Prospective assessment of a nomogram for the initiation of oral anticoagulant therapy for outpatient treatment of venous thromboembolism. Pathophysiol Haemost Thromb. 2002;32: A low-dose flexible initiation nomogram was associated with a lower risk of overanticoagulation in elderly patients (age >65) compared to a modification of the Fennerty nomogram. 62 More recently, an age-adjusted flexible warfarin initiation protocol was found to be superior to either the Fennerty nomogram or empiric dosing. 63 Further modifications of this age-adjusted flexible initiation protocol have since been published. 64 Crowther et al. compared flexible initiation nomograms that started with either 5 mg or 10 mg starting doses followed by daily INR determination and prediction of the maintenance dose by day 6. 65,66 These authors concluded that the 10 mg initiation was more likely to result in overanticoagulation on each day that INR was evaluated. These popular algorithms are presented in Table Initiation nomograms that incorporate genetic information Numerous algorithms that incorporate CYP2C9 and VKORC1 genetic information to predict warfarin dosing requirement have been published. In a homogenous, racially and ethnically diverse population, they explain only 37% to 55% of the variation in warfarin dose requirements. 67 During the first week of therapy, genotype alone accounts for 12% of therapeutic dose variability, but over the first several weeks of therapy becomes less relevant as INR and prior doses increasingly predict therapeutic dose, and genotype information. 68 In fact, much of the information provided by including genetic information in a dose-prediction model is captured by early INR response. 69 A systematic review of small clinical trials that compared genotype-based warfarin dosing to a non-genotype strategy found no statistically significant difference in bleeding rates, time within therapeutic range, or time to

7 Warfarin 357 Table Flexible Initiation Nomograms for Warfarin Day INR 5-mg Initiation Dose 10-mg Initiation Dose 1 5 mg 10 mg 2 < mg 7.5 mg 10 mg mg 2.5 mg mg mg > < mg 5 10 mg mg mg mg mg mg mg > < mg 10 mg mg mg mg 0 5 mg > < mg 10 mg mg mg mg 0 5 mg > < mg mg mg 5 10 mg mg mg > Source: Adapted with permission from Crowther MA, Harrison L, Hirsh J. Warfarin: less may be better. Ann Intern Med. 1997;127: achieve a stable warfarin dose. 70 Large scale, randomized controlled trials are underway to determine whether pharmacogenomic-based dosing will improve clinical outcomes. However, genotyping is unlikely to be costeffective in most patients. 71 Maintenance dosing Once a patient has reached the lower limit of the therapeutic range and is at relative steady state, maintenance dosing adjustments are frequently required to maintain the INR within the therapeutic range. Numerous factors influence the stability of therapy, including drug and disease state interactions, dietary vitamin K intake, alcohol use, activity, stress and many others. These factors and the INR must be evaluated regularly. The frequency of monitoring and assessment is described in Table Dosing adjustments are based on INR results and the presumed explanation for out of range INRs. For example, a transient cause of underanticoagulation, such as a missed dose, may be most appropriately managed by simply continuing the usual maintenance dose or giving a one-time booster dose (1.5 2 times the daily maintenance dose) to replace the missed dose. Comparatively, a more persistent cause of underanticoagulation such as the addition of an interacting enzyme inducer will require a more permanent dosing increase. Similarly, a transient cause of overanticoagulation such as acute illness may require holding a dose of warfarin without any change in the long-term maintenance dose. A more persistent cause of overanticoagulation such as addition of an interacting enzyme inhibitor will require a more permanent dosing reduction. When dosing adjustments are required, they are generally in the range of 5% to 20% of the daily dose, or 5% to 20% of the total weekly dose. 72 The tablet size(s) available to the patient and the patient s own concerns regarding same daily dosing (e.g., 4 mg daily or 28 mg weekly) or alternate-day dosing (2.5 mg Mondays, Wednesdays, and Fridays, and 5 mg on all other days, or 27.5 mg/wk) must also be considered. 73

8 358 Clinical Pharmacokinetics A maintenance dosing guideline for a patient with a goal INR of 2 3 is presented in Table However, it is imperative that the adjustments only be made in patients who have already reached the therapeutic range. The use of maintenance dosing adjustments (e.g., small 5% to 15% changes every 7 days rather than more aggressive initiation doses) during initiation therapy will significantly prolong the time to reach the lower limit of the therapeutic range. Therapeutic Range Many clinical trials evaluating the effectiveness and safety of warfarin have helped to establish specific INR ranges for the prevention and treatment of venous and arterial thromboembolism. The American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy meets every few years to summarize available literature and develop graded, evidence-based guidelines. 74 The therapeutic range for various indications, as recommended by the 8th ACCP Conference, are listed in Table Therapeutic Monitoring Warfarin therapy suppresses the vitamin K dependent clotting factors to different extents. In stable anticoagulated patients, factor II (mean activity 19%; range 9% to 54%) and factor X (mean activity 18%; range 9% to 45%) are suppressed to the greatest extent, compared to factor VII (mean activity 33%; range 16% to 57%) and factor IX (mean activity 48%; range 26% to 94%). 75 But despite considerable variability, mean activity of all clotting factors is highly predictive of INR. The intensity of warfarin therapy is monitored by evaluation of the prothrombin time (PT), expressed as the INR. 76 The PT is prolonged by deficiencies in plasma concentrations of clotting factors II, V, VII, and X. It is measured by adding both calcium and a tissue thromboplastin to plasma, which accelerates activation of the extrinsic pathway of the clotting cascade. Time to clot formation is read in seconds using various technologies. Thromboplastins are extracted from various tissue sources and prepared for use as commercial reagents. Because of lack of standardization among manufacturers of thromboplastins, each reagent is assigned an International Sensitivity Index (ISI) that describes its comparison to an international reference thromboplastin derived from human brain. The ISI is listed in the product information for each lot of thromboplastin. 77 The ISI is used to convert prothrombin time in seconds to the INR, using the formula: PT INR = PT patient mean normal ISI Table Frequency of INR Monitoring and Patient Assessment Initiation Therapy Flexible initiation method Average daily dosing method After hospital discharge First month of therapy Maintenance Therapy Dose held today in patient with significant overanticoagulation Dosage change today Dosage change made 2 weeks ago Routine follow-up of medically stable and reliable patients Routine follow-up of medically unstable or unreliable patients Daily through day 4, then within 3 5 days Every 3 5 days until INR > lower limit of therapeutic range, then within 1 week If stable, within 3 5 days; if unstable, within 1 3 days At least weekly In 1 2 days Within 1 2 weeks Within 2 4 weeks Every 4 6 weeks Every 1 2 weeks

9 Warfarin 359 Table Warfarin Dosing Adjustment Guidelines for INR Goal of 2 3 INR Dosage Adjustment Guidelines <1.5 Consider a booster dose of x daily maintenance dose Consider resumption of prior maintenance dose if factor causing decreased INR is transient [e.g.: missed warfarin dose(s)] If dosage adjustment needed, increase maintenance dose by 10% 20% Consider a booster dose of times daily maintenance dose Consider resumption of prior maintenance dose if factor causing decreased INR is considered [e.g.: missed warfarin dose(s)] If dosage adjustment needed, increase maintenance dose by 5% 15% No dosage adjustment may necessary if the last 2 INRs were in range, if there is no clear explanation for the INR to be out of range, and if in the judgment of the clinician, the INR does not represent an increased risk of thromboembolism for the patient Consider a booster dose of x daily maintenance dose Consider resumption of prior maintenance dose if factor causing decreased INR is transient [e.g.: missed warfarin dose(s)] If dosage adjustment needed, increase maintenance dose by 5% 10% 2 3 Desired range No dosage adjustment may necessary if the last two INRs were in range, if there is no clear explanation for the INR to be out of range, and if in the judgment of the clinician, the INR does no represent an increased risk of hemorrhage for the patient Consider continuation of prior maintenance dose if factor causing elevated INR is transient [e.g.: acute alcohol ingestion] If dosage adjustment needed, reduce maintenance dose by 5% 10% enance dose if factor cau Consider holding one dose Consider resumption of prior maintenance dose if factor causing elevated INR is transient [e.g.: acute alcohol ingestion] If dosage adjustment needed, decrease maintenance dose by 5% 15% > 4 Hold until INR < upper limit of therapeutic range Consider use of mini dose ( mg) oral vitamin K Consider resumption of prior maintenance dose if factor causing elevated INR is transient [e.g.: acute alcohol ingestion] If dosage adjustment needed, decrease maintenance dose by 5% 15% The mean normal PT is typically 12 seconds for most thromboplastin reagents and is measured by averaging the PT of non-anticoagulated subjects. The INR is the value that would have been obtained if the reference preparation had been used in the test. In this way, results obtained at different laboratories can be compared and results from different lots of the same manufacturer of thromboplastin can also be compared. Variations in thromboplastin sensitivity are due to differences in manufacturing, source, and method of preparation. More sensitive thromboplastins with ISI values close to 1.0 produces less rapid stimulation of factor X, resulting in greater prolongation of the PT for a given reduction in clotting factors. 78 Less sensitive thromboplastins activate residual factor X more rapidly and result in a less prolonged PT, despite a comparable reduction in clotting factors. ISI values range from 0.95 to 2.9, with a higher ISI number indicating a less sensitive reagent. Although manufacturers carefully calibrate the ISI values of their thromboplastins, they do not, in most cases, provide ISI values that are specific to the instrumentation that will be used to measure INR at individual

10 360 Clinical Pharmacokinetics Table Optimal Therapeutic Range by Indication Indication Target INR (Range) Atrial fibrillation 2.5 (2 3) Atrial flutter 2.5 (2 3) Cardioembolic stroke 2.5 (2 3) Left ventricular dysfunction 2.5 (2 3) Myocardial infarction 2.5 (2 3) Venous thromboembolism 2.5 (2 3) Valvular heart disease 2.5 (2 3) Valve replacement, bioprosthetic 2.5 (2 3) Valve replacement, mechanical Aortic, bileaflet 2.5 (2 3) Aortic, other 3 ( ) Mitral, all 3 ( ) laboratories. One means of overcoming this problem is the use of calibrating plasma provided by reagent manufacturers. 79 By using plasma samples with carefully calculated INR values, a laboratory can verify the correct ISI value for its system. Although PT is intended to be measured using plasma samples obtained by venipuncture, a number of point-of-care INR devices have been developed that use whole blood for rapid measurement of INR. 80 These test systems are used in anticoagulation clinics, physician offices, and hospital nursing units, and can be used for patient self-testing at home. 81 Pharmacodynamic Monitoring Patients treated with warfarin should be routinely monitored for signs and symptoms of the development, progression, or recurrence of venous or arterial thromboembolism. They should also be assessed regularly for the development of hemorrhagic complications to warfarin therapy. In addition, factors that influence the stability of the INR should be assessed on a regular basis. These include changes in dietary vitamin K intake, prescription and nonprescription medications and dietary supplements, underlying disease states, alcohol use, activity, the development of acute illness, and others. 2 Changes in any of these parameters can influence the intensity of anticoagulant therapy and increase the risk of hemorrhagic or thromboembolic complications. INR-related efficacy After initiation of warfarin therapy, initial elevations in the INR represent depletion of factor VII due to its short elimination half-life. 82 However, the antithrombotic effect of warfarin requires adequate depletion of factors II and X. 83 Since protein C also has a relatively short elimination half life, initial warfarin doses can induce a relative hypercoagulable state as the anticoagulant effect of protein C is depleted more rapidly than clotting factors II and X. 59 For these reasons, in addition to the known pharmacokinetic properties of warfarin, the antithrombotic effect of warfarin is delayed for 4 5 days after initiation. For treatment of acute venous thromboembolism, warfarin therapy must therefore be overlapped with heparin, a low molecular weight heparin, a direct thrombin inhibitor or an indirect factor Xa inhibitor during initiation therapy. 84 Current guidelines suggest that this overlap continue for a minimum of 5 days and until the INR is stable and above the lower limit of the therapeutic range. 85 The INR is designed for monitoring long-term anticoagulation therapy and is less valuable for patients during the induction phase of oral anticoagulant therapy. It is also less reliable for patients with significant liver dysfunction, hereditary factor deficiencies, or for screening for bleeding disorders. These conditions require evaluation of other measures of hemostasis.

11 Warfarin 361 The INR can be increased by the presence of heparin or low molecular weight heparin in the sample, as well as by direct thrombin inhibitors and indirect factor Xa inhibitors. 86,87 The INR is also influenced by hemolysis and elevated hematocrit. 88,89 Specimens must be handled differently by laboratory personnel in each of these situations. Antiphospholipid antibody (APA) syndrome is a condition associated with venous and arterial thromboembolism requiring chronic anticoagulation with warfarin and routine INR monitoring. 90 Since the INR is a phospholipid-dependent test, it may be invalid in patients with APA syndrome whether monitored by standard methodology or point-of-care testing. 91,92 In these patients an alternative monitoring strategy that is independent of phospholipids may be preferable. One option is the use of chromogenic factor X. 93 An INR of 2 3 is roughly equivalent to suppression of factor X to 25% of 45% of normal. Time spent within the therapeutic range (time-in-therapeutic range; TTR) is a measure of the quality of anticoagulant control and is a predictor of both the efficacy and the safety of oral anticoagulation. 94 Increased TTR is associated with a reduction in both thromboembolic complications and hemorrhage. TTR can be measured as the fraction of INRs in range, as a cross section of INRs on a given day, or by a linear interpolation method. 95 Each method has advantages and limitations, but all allow an overall examination of the quality of anticoagulation control. The fraction of INRs in range is commonly used as a quality assurance measure in anticoagulation clinics, while linear interpolation of TTR is frequently used in clinical trials to describe the quality of anticoagulation control. INRs below the therapeutic range are associated with an increased risk of thromboembolic events. The risk of stroke in patients with atrial fibrillation increases dramatically with INRs < Similarly, there is a steep increase in the risk of stroke at INRs < 2.5 in patients with mechanical heart valve replacement. 97 In patients with a first episode of idiopathic venous thromboembolism (VTE) treated for a minimum of 3 months, the risk of recurrent VTE in the 21 months following discontinuation of warfarin was lower in patients who spent more time within the therapeutic INR range of 2 3 and higher in patients who spent more time with an INR < Thus, the quality of oral anticoagulant control directly influences clinical outcomes. INRs below the therapeutic range occur frequently during long term oral anticoagulation and may be the result of various dosing issues (initiation therapy, withholding warfarin for invasive procedures, noncompliance, response to dosing adjustments), or of interactions (with drugs, disease states, diet, alcohol, etc.). 99 However, up to 30% of INRs < 2 cannot be explained despite extensive patient assessment. INR-related toxicity Bleeding is the primary adverse effect associated with warfarin. 100 Bleeding is typically referred to as either minor or major depending on the site of bleeding, its clinical consequences, and/or the interventions required for control. The risk of bleeding is dependent on the intensity of anticoagulation, underlying patient characteristics, concomitant use of drugs that impact hemostasis, and the length of anticoagulant therapy. Intensity of anticoagulation is a major determinant of the risk of major bleeding complications in patients taking warfarin. Outpatients taking warfarin who develop INRs > 6 are at a significantly greater risk of developing major bleeding within the next 2 weeks compared to patients with INRs within the therapeutic range of The risk of intracranial hemorrhage increases significantly when the INR is > 4. 97,102 Bleeding risk is also increased by variability in the INR, which is an indicator of poor management of warfarin therapy. 102,103 When warfarin therapy is managed in a designated anticoagulation clinic setting the risk of major bleeding can be minimized in comparison to warfarin management by routine medical care. 104,105 However, advanced age appears to increase the risk of warfarin-related intracranial hemorrhage, even when patients are managed by anticoagulation clinics. 106,107 Bleeding risk associated with warfarin therapy can be estimated by prediction methods that are based on the presence of risk factors for bleeding. One popular method assigns a point score (total 0 4 points) for the presence of age >65, history of stroke, history of gastrointestinal bleeding (1 point each) and any one of four other comorbid conditions (recent myocardial infarction, elevated serum creatinine >1.5 mg/dl, hematocrit <30% or diabetes) (1 point for any or all). 108 Application of this Bleeding Risk Index to warfarin patients managed in an anticoagulation clinic setting found that major bleeding occurred at a rate of 0.8%/patient-year in patients with a low risk score (0 points), 2.5%/patient-year in patients with an intermediate risk score (1 2 points), and 10.6%/patient yr in patient with a high risk score (3 4 points). 109

12 362 Clinical Pharmacokinetics Reversing INR-related toxicity Reversal of over-anticoagulation is accomplished by withholding warfarin, administering vitamin K, or administering blood products. 2 These strategies may be used alone or in combination, guided by the INR, the patient s bleeding risk and bleeding status, and the time needed for reversal. Blood products, such as fresh frozen plasma (FFP), act rapidly, have a short duration of effect, and are reserved for active bleeding. Prothrombin complex concentrates and recombinant factor VIIa have also been used to manage life-threatening warfarin induced bleeding. High dose vitamin K (10 mg by IV infusion) is often used in conjunction with blood products in patients who are bleeding. The onset of effect is relatively rapid and the duration of effect is prolonged, but can lead to extended warfarin resistance. Lower doses of vitamin K can be used to reverse over-anticoagulation when no bleeding is present. The oral route is preferred as subcutaneous administration can lead to a delay in onset of effect and both subcutaneous and intramuscular administration can lead to hematoma formation Vitamin K doses in the range of mg will reduce the INR back to within the therapeutic range within 24 hr without causing complete reversal or prolonged warfarin resistance. There are currently two formulations of vitamin K 1 available in the United States, a scored 5-mg tablet (Mephyton) and an injectable preparation available as a 2-mg/ml or 10-mg/ml aqueous dispersion (Aquamephyton) that can be administered orally. When more rapid reversal is needed (for example, prior to invasive procedures), the intravenous route can be used. Rapid IV administration of vitamin K has been associated with anaphylactic reactions, so a prolonged infusion in ml of diluent over minutes is necessary. 114 Current recommendations for reversal of over-anticoagulation are listed in Table Drug-Drug Interactions Warfarin is highly susceptible to interactions with prescription and non-prescription drugs as well as with herbal and other natural products. 115 Through a variety of mechanisms these interactions may elevate or reduce the INR, increasing the risk of hemorrhagic or thromboembolic complications, respectively. Pharmacokinetic interactions are those that influence the absorption, distribution, metabolism, or excretion of warfarin. Pharmacodynamic interactions influence response to warfarin without altering its pharmacokinetics. Clinically significant warfarin drug interactions are listed in Table Clinically significant interactions between warfarin and dietary supplements are listed in Table , The impact of drug interactions on INR, bleeding risk, or risk of thromboembolism may be seen when interacting drugs are initiated, discontinued, or when there is a change in dose. Patient susceptibility to drug interactions is highly variable, as is the magnitude of the response, the time of onset, and the duration of the interaction once the interacting drug is discontinued. 125 These variables are influenced by numerous underlying patient characteristics that may influence clotting factor synthesis and degradation, the pharmacokinetics and/ or pharmacodynamics of the interacting drug, and the pharmacokinetics and/or pharmacodynamics of the R and S enantiomers of warfarin. 126 Genetic expression of CYP2C9 influences warfarin dosing requirements and may also influence the risk and/or severity of warfarin drug interactions. 127 Table Current Recommendations for Reversal of Elevated INRs INR Strategy < 5 Lower dose or omit dose Omit one or two doses; or omit dose and give vitamin K ( mg orally). If more rapid reversal is required use <5 mg vitamin K orally. Repeat vitamin K (1 2 mg orally) if INR is still elevated at 24 hr. 9 Hold warfarin and give vitamin K (2.5 5 mg orally). Use additional vitamin K if necessary. Serious bleeding with high INR Hold warfarin and give vitamin K (10 mg slow IV infusion) supplemented with fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa. May repeat vitamin K every 12 hr if necessary. Life-threatening bleeding Hold warfarin and give fresh frozen plasma, prothrombin complex concentrates or recombinant factor VIIa supplemented with vitamin K (10 mg slow IV infusion). Repeat as necessary. (regardless of INR)

13 Warfarin 363 Table Clinically Significant Warfarin Drug Interactions Drugs/Drug Classes Effect on INR Mechanism vitamin K Decreased Increased synthesis of clotting factors methimazole Decreased Reduced catabolism of clotting factors propylthiouracil alcohol (chronic use) Decreased Induction of warfarin metabolism aminoglutethimide aprepitant Barbiturates bosentan carbamazepine dicloxacillin ethchlorvynol fosphenytoin a glutethimide griseofulvin mitotane nafcillin phenytoin a primidone Rifamycins Terbinafine cholestyramine Decreased Reduced absorption of warfarin colestipol sucralfate ascorbic acid Decreased Unexplained mechanisms azathioprine Corticosteroids a cyclosporin mercaptopurine Protease Inhibitors ribavirin Thyroid hormones Increased Increased catabolism of clotting factors chloral hydrate Increased Protein binding displacement Cephalosporins Increased Decreased synthesis of clotting factors vitamin E Aminoglycosides Increased Impaired vitamin K production by gut flora Tetracyclines

14 364 Clinical Pharmacokinetics Table (continued) Drugs/Drug Classes Effect on INR Mechanism acetaminophen Increased Inhibition of warfarin metabolism alcohol (acute use) allopurinol amiodarone Azole antifungals capecitabine celecoxib chloramphenicol cimetidine delavirdine disulfiram efavirenz Fluoroquinolone antibiotics fluorouracil fosphenytoin a ifosfamide isoniazid leflunomide Macrolide antibiotics metronidazole omeprazole orlistat phenytoin a propafenone quinidine quinine rofecoxib SSRIs Statins (not atorvastastin/ pravastatin) Sulfa antibiotics zafirlukast Direct thrombin inhibitors Increased response Additive anticoagulant heparin Low molecular weight heparins Thrombolytic agents acarbose Androgens carboplatin Unexplained mechanisms

15 Warfarin 365 Table (continued) Drugs/Drug Classes Effect on INR Mechanism clofibrate Corticosteroids a cyclophosphamide etoposide fenofibrate gefitinib gemcitabine gemfibrozil influenza virus vaccine isotretinoin mesalamine paclitaxel tamoxifen testosterone tolterodine tramadol trastuzumab aspirin/acetylated salicylates No effect Increased bleeding risk clopidogrel/ticlopidine Glycoprotein IIb/IIIa inhibitors Non steroidal anti-inflammatory drugs prasugrel Source: Adapted with permission from Wittkowsky AK. Drug interactions with oral anticoagulants. In: Colman RW, Marder VJ, Clowes AW, et al., eds. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; Interacting drugs are not often strictly contraindicated in patients taking warfarin, though appropriate therapeutic alternatives with little or no interaction potential should be used when possible. When non-interacting alternatives are not available or not appropriate, the interacting drugs can be used concurrently as long as the frequency of INR monitoring and the dosing of warfarin are adjusted appropriately. These interventions should be guided by the pharmacokinetic and pharmacodynamic characteristics of warfarin and of the interacting drug, known characteristics of the interaction in similar patients, the expected time course associated with the known or presumed mechanism of the interaction, and the underlying thromboembolic or hemorrhagic risk of the patient involved. For example, enzyme inhibition interactions typically occur rapidly, so the INR should be checked 2 3 days after the interacting agent is added to warfarin therapy. Enzyme induction interactions tend to occur more slowly, so the INR should be checked within the first week after addition of the interacting drug. However, no guidelines for drug interaction management exist, and appropriately so, since each case must be handled individually due to expected variability in response. Drug Disease State or Condition Interactions A number of disease states influence the therapeutic response to warfarin. The influence of these conditions should be considered during initiation of therapy when they may influence the starting dose of warfarin, as well as later in therapy when new onset, exacerbation, or improvement in these conditions may influence INR response and the maintenance dosing requirements for warfarin.

16 366 Clinical Pharmacokinetics Table Clinically Significant Interactions Between Warfarin and Dietary Supplements Supplements Effect Mechanism Chinese wolfberry Increased INR Inhibition of warfarin metabolism Cranberry juice Grapefruit juice Mango Danshen/methyl salicylate Increased INR Contain coumarin derivatives Dong quai Boldo/fenugreek Curbicin Increased INR Unknown Devil s claw Fish oil Glucosamine-chondroitin Melatonin Papaya extract Quilinggao Vitamin E Garlic Increased bleeding Inhibition of platelet aggregation Ginger Ginkgo Avocado Decreased INR Contain vitamin K/derivatives Coenzyme Q10 Foods high in vitamin K Green tea Some multivitamins Sushi containing seaweed St. John s wort Decreased INR Induction of CYP3A4 Ginseng Decreased INR Unknown Melatonin Soy Source: Adapted with permission from Wittkowsky AK. Drug interactions with oral anticoagulants. In: Colman RW, Marder VJ, Clowes AW, et al., eds. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; Advanced age Warfarin dosing requirements decline with advanced age. 128 There do not appear to be differences in the pharmacokinetics of warfarin in young versus elderly patients, however. 129 The elderly may have reduced availability of vitamin K stores and lower plasma concentrations of vitamin K dependent clotting factors, both of which could contribute to this observation. 129,130 Age may be the most important readily available predictor of warfarin dosing requirement. 131 Pregnancy and lactation Warfarin is a teratogen and is associated with congenital abnormalities such as stippled calcifications and nasal cartilage hypoplasia, particularly when exposure occurs during weeks 6 12 of pregancy. 132 Other abnormalities as well as fetal hemorrhage can occur throughout pregnancy. Accordingly, warfarin is considered contraindicated in pregnancy. Alternative anticoagulants such as heparin and low molecular weight heparin should be

17 Warfarin 367 used instead of warfarin in pregnant women. Warfarin is not excreted in breast milk and can be used safely post-partum by nursing mothers. 133 Alcoholism Acute alcohol ingestion can elevate the INR by inhibiting warfarin metabolism. 134 Patients who binge drink are at increased bleeding risk from overanticoagulation and from risk of falls. Conversely, chronic alcohol use is associated with CYP enzyme induction and causes higher warfarin dosing requirements in alcoholic patients. Patients taking warfarin should be encouraged to moderate their alcohol intake. Liver disease Hepatic disease is often accompanied by coagulopathy due to a reduction in clotting factor synthesis. 135 These patients may appear to be auto-anticoagulated with baseline elevated INRs. However, the degree of factor suppression in liver disease does not mimic that of patients treated with warfarin and thus these patients are not protected from thromboembolism. 136 Hepatic disease may reduce the clearance of warfarin. Renal disease and hemodialysis End stage renal disease is associated with reduced activity of CYP2C9, leading to lower warfarin dosing requirements. 137 Hypoalbuminemia associated with nephrotic syndrome increases the free fraction of warfarin, but there is also an associated increase in plasma clearance. 138 When INR is monitored in patients undergoing hemodialysis, blood draws should be taken from peripheral sites rather than from the dialysis graft as heparin can influence INR results. 139 It may also be necessary for the sample to be deheparinized with a heparin absorbent to eliminate any potential risk of contamination by heparin from the dialysis circuit. Congestive heart failure Exacerbations of heart failure can cause an increased responsiveness to warfarin and elevate the INR. 140 The likely mechanism of this effect is hepatic congestion leading to a reduction in warfarin metabolism. Cardiac valve replacement Patients commencing warfarin therapy after cardiac valve replacement appear to have increased response to warfarin. 141 This enhanced sensitivity diminishes over time and several weeks after surgery patients typically require higher doses than initially suspected. Hypoalbuminemia, age, diet, physical activity and reductions in clotting factor concentrations as a result of cardiopulmonary bypass all likely contribute to this phenomenon. Nutritional status Changes in dietary intake of vitamin K containing foods have a profound impact on warfarin dosing requirements and INR response. 124 Diets modified intentionally or as a result of disease, surgery, or other exogenous factors are likely to influence the therapeutic response to warfarin. Thyroid disease Hypothyroidism decreases the catabolism of clotting factors, leading to increased warfarin dosing requirements to maintain a therapeutic INR. 142 Conversely, hyperthyroidism increases sensitivity to warfarin. 143 Patient who start or stop thyroid replacement therapy or who undergo treatment for hyperthyroidism require careful INR monitoring and dosing adjustments to maintain safe and effective oral anticoagulation. Smoking and tobacco use status Constituents of cigarette smoke may induce cytochrome P450 enzymes, including CYP1A2, a minor contributor to the metabolism of R-warfarin. 144 Warfarin dosing requirements have been observed to decline after smoking cessation. 145 Chewing tobacco contains high quantities of vitamin K and can suppress INR response. 146