Outpatient anticoagulant therapy

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Outpatient Anticoagulant TherapyJACK E. ANSELL, MD

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The coumarin-type oral anticoagulants have been in use formore than 70 years and are well-established weapons in thearmamentarium against thrombotic disease.1 Their discoveryevolved from investigations into a hemorrhagic disease of cattleoccurring early in the twentieth century attributed to the con-sumption of spoiled sweet clover. Karl P. Link,2 a biochemist atthe University of Wisconsin, eventually isolated the responsibleagent in spoiled sweet clover, dicumarol (3-3′-methyl-bis-4-hydroxycoumarin), which quickly entered the clinical arena

through work at the Mayo Clinic in 1941. Link subsequentlysynthesized a related compound (warfarin), initially popular-ized as a rodenticide in the late 1940s, that entered clinicalpractice in the 1950s and quickly became the major oral anti-coagulant in clinical use. Little has changed in the formulationof the coumarin-type oral anticoagulants or vitamin K antago-nists (VKAs). They have remained critically important drugs inthe primary and secondary prevention of thromboembolism.In the last 20 years, the use of oral anticoagulants has grownconsiderably, commensurate with the increased understandingof the important role of thromboembolism in cardiovasculardisorders. Now, for the first time, a new class of oral anticoagu-lants has been developed that can best be characterized astarget- or factor-specific oral anticoagulants. These agents are

targeted to bind to and neutralize a specific coagulation factor.These drugs have favorable pharmacokinetic attributes, andemerging phase 3 trials show that they are effective and safecompared with standard therapy. This chapter reviews both theVKAs and the new target-specific oral anticoagulants.

Vitamin K Antagonists

MECHANISM OF ACTION

Vitamin K is an essential cofactor in the posttranslationalγ -carboxylation of several glutamic acid residues in the vitaminK–dependent coagulation factors II, VII, IX, and X (Fig. 39-1),as well as protein C and protein S.3-5 In the absence of γ -

carboxylation, these proteins are unable to bind calcium andphospholipid, and depending on the level of carboxylation, theymanifest a reduced coagulant (i.e., enzymatic) potential. War-farin produces its anticoagulant effect by interfering with thecyclic interconversion and regeneration of reduced vitamin Kfrom its 2,3-epoxide (vitamin K epoxide).3-5 Warfarin exerts thiseffect by inhibiting an enzyme, vitamin K epoxide reductasecomplex 1 (VKORC1), responsible for this interconversion (seeFig. 39-1).6 Dietary vitamin K enters the body in a partiallyreduced state, bypassing the warfarin-sensitive reductase andreplenishing fully reduced vitamin K stores in the presence ofwarfarin therapy.

PHARMACOKINETICS AND PHARMACODYNAMICS

Because of its excellent bioavailability and favorable pharmaco-kinetics, warfarin is the most commonly used oral anticoagu-lant in North America. It is highly water soluble and rapidlyabsorbed from the gastrointestinal (GI) tract after oral inges-tion.7,8 Peak absorption occurs in 60 to 90 minutes. Food maydelay the rate of absorption but is said not to reduce the extentof absorption.

Warfarin is a racemic mixture of stereoisomers known as theR and S forms; the two have distinctive metabolic pathways,half-lives, and potencies. Racemic warfarin has an averageplasma half-life of 36 to 42 hours, with a range of 15 to 60 hours.Variability in warfarin half-life due to natural differences inmetabolism, disease- and/or drug-induced alterations in meta-bolic fate, or the sensitivity of the VKORC1 enzyme to warfarinaccount for the marked variations in an individual’s initialresponse to, and maintenance requirement for, warfarin. The Senantiomer of warfarin (five times more potent than the Renantiomer) is metabolized primarily by the CYP 2C9 enzymeof the cytochrome P-450 (CYP450) system.9 A number ofgenetic polymorphisms (single-nucleotide polymorphisms, orSNPs) in this enzyme lead to a reduced activity of the enzyme

and may influence both the dosage required to achieve a thera-peutic level and the bleeding risk with warfarin therapy.10-14 Specifically, the CYP2C9*2 and CYP2C9*3 alleles are associatedwith lower dosage requirements and higher bleeding complica-tion rates compared with the wild-type CYP2C9*1.8,10-14 Theprevalence of these polymorphisms varies in populations asindicated in Table 39-1.

A number of SNPs have been discovered in the VKORC1 gene that lead to varying sensitivities of the enzyme to warfarininhibition and have been shown to have a major impact onthe pharmacodynamics of warfarin.15,16 A combination ofSNPs leads to various haplotypes of the gene and gene product.Some of these haplotypes result in an enzyme that is sensitiveto warfarin inhibition so that a lower dosage of warfarin is

required, whereas others are more resistant, so that a higherdosage (and maintenance dosage) of warfarin is neededto achieve a therapeutic international normalized ratio(INR).15,17-20 The prevalence of these haplotypes varies in dif-ferent populations as indicated in Table 39-1. A combinationof genetic alterations in either the CYP2C9 or VKORC1 geneshas been shown to account for as much as 20% to 50% of thevariability in warfarin maintenance dosing.14,17,19 The effect ofwarfarin also varies inversely with the amount of vitamin Kabsorbed (from the diet and from metabolic byproductsof GI bacteria) and varies directly with the amount of warfarinabsorbed or available to exert its anticoagulant effect.


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39 Outpatient Anticoagulant Therapy 69

Figure 39-1 Reduced vitamin K is oxidized in the posttranslationalmodification of prothrombin (and other vitamin K–dependentcoagulation factors), introducing carboxyl groups to severalglutamic acid moieties in the prothrombin polypeptide and formingγ -carboxyglutamic acid. The oxidized form of vitamin K is recycledafter a reduction mediated by VKORC (vitamin K epoxide reductasecomplex). VKORC is the target enzyme inhibited by the S isomer ofwarfarin. S-warfarin is the active portion of warfarin, whereas the Risomer has little effect. S-warfarin is metabolized by the cytochromeP-450 (CYP450) oxidase enzyme 2C9.

Prothrombin precursor

Glutamic acid

C

CH2

CH2

COOH

Reduced vitamin K

Vitamin K epoxide reductase

Warfarin

CYP1A1CYP1A2CYP3A4

CYP2C9

Oxidized vitamin K

“Carboxylase”CO2

O2

CO2

Prothrombin

γ -Carboxy-glutamic acid

C

OO

CH2

CH

COOHHOOC

S-w ar f a r i n R - w a r fari

n

HC

HN

HC

HN

CYP2C9 POLYMORPHISM*

CYP2C9 * 1 (%)

CYP2C9 * 2 (%)

CYP2C9 * 3 (%)

Whites 79-89 8-19 6-10Native Canadians 91 3 6African Americans 98 1.5-3.6 0.5-1.5Asians 95-98 0 1.7-5

TABLE 39-1

Frequency of Genetic Polymorphisms of CYP2C9 and VKORC1 in Different Ethnic Groups

VKORC1 HAPLOTYPE†

H1H2(%) H8H9(%)

European Americans 37 58African Americans 14 49Asian Americans 89 10

From Takahashi H, Echizen H: Pharmacogenetics of warfarinelimination and its clinical implications. Clin Pharmacokinet 40:587–603, 2001; and Rieder MJ, Reiner AP, Gage BF, et al: Effectof VKORC1 haplotypes on transcriptional regulation and warfarindose. N Engl J Med 352:2285–2293, 2005.

*CYP2C9*1 is the wild type (i.e., common genotype) and CYP2C9*2 and CYP2C9*3 are polymorphisms associated with reducedfunctional capacity to metabolize the S enantiomer of warfarin.

†H1H2 and H8H9 are different haplotypes (combinations ofpolymorphisms) that are associated with either greater sensitivity(H1H2) or less sensitivity (H8H9) to warfarin inhibition.

WARFARIN AND DRUG INTERACTIONS

Drug interactions commonly occur by affecting the pharmacokinetic or pharmacodynamic behavior of warfarin.7,21 Druinteractions may interfere with GI absorption of warfariresulting in a reduction in plasma levels, or interfere with thmetabolism of warfarin leading to a reduction or increase iclearance and, consequently, higher or lower plasma warfarilevels. The latter effects may be stereospecific in that only onof the enantiomers may be affected or it may be nonspecific ithat both enantiomers may be affected. Interference in thmetabolism of the S enantiomer, usually through effects on thP-450 cytochrome system (CYP 2C9 enzyme), is more commoand has a greater potential for enhancing the intensity of antcoagulation because the S enantiomer is several times morpotent than the R enantiomer. Drugs may also decrease plasmwarfarin levels by enhancing the metabolic clearance of racemwarfarin.

The pharmacodynamics of warfarin may also be alterewhen drugs interfere with other aspects of hemostasis ovitamin K1 homeostasis. Third-generation cephalosporins containing an N -methylthiotetrazole side chain are an example i

that they interfere with the regeneration of reduced vitamiK1 from the 2,3-epoxide form. Some drugs or disease state(liver disease, hyperthyroidism) can alter the metabolism ocoagulation factors, inhibit coagulation factor interactions bother mechanisms (heparin), or inhibit other aspects of hemostasis (aspirin effect on platelet function) and lead to a greaterisk of bleeding. In general, such interactions are most problematic when interacting drugs are added to or deleted from patient’s regimen, or a dose change is made. Once a patient haachieved stability on warfarin and an interacting medicatiothere should be little problem in maintaining stability of warfarin dosing.

Assessing the literature for warfarin-drug interactions problematic because of the poor quality of the reports. Ho

brook and colleagues

22

performed a systematic review of wafarin and food interactions and found serious problems in threporting of potential interactions. They reviewed 187 separatreports of interactions involving 120 drugs or foods and founthat no report met their quality criteria as an excellent studyThere were 33 small randomized controlled trials of fair or gooquality. There were 148 reports that were rated as poor qualitand 130 of these were case reports (96% single case reportsTable 39-2 summarizes these interactions and categorizes themby level of cause and effect on INR.

A new problem of recent development is the widespread usof dietary supplements and herbal preparations.23,24 Unlike druproducts, dietary supplements are not tested before marketinfor safety, efficacy, dosing requirements, or interactions wit

other medications. They are not required to meet quality standards for labeling, nor are they required to meet U.S. Pharmacopeia standards for tablet content uniformity (see Chapter 32Consequently, patients may be exposed to different ingredienas well as different doses of those ingredients in similar producproduced by different manufacturers and in different batchefrom the same manufacturer. There are a growing number ocase reports describing interactions between warfarin andietary supplements, but virtually none of these interactionhas been systematically substantiated. Because of the uncetainty that exists, it is wise for patients taking warfarin to avoithe use of dietary supplements or, at least, to be carefull


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700 PART 6 Special Issues

Highly Probable Probable Possible Highly Improbable

POTENTIATION OF WARFARIN EFFECT

Antiinfectives CiprofloxacinCotrimoxazoleErythromycinFluconazoleIsoniazid (600 mg daily)MetronidazoleMiconazole oral gelMiconazole vaginal

suppositories Voriconazole

Amoxicillin/clavulanateAzithromycinClarithromycinItraconazoleLevofloxacinRitonavir Tetracycline

AmoxicillinAmoxicillinTranexamic rinseChloramphenicolGatifloxacinMiconazole topical gelNalidixic acidNorfloxacinOfloxacinSaquinavir Terbinafine

CefamandoleCefazolinSulfisoxazole

Cardiovascular drugs AmiodaroneClofibrateDiltiazemFenofibratePropafenoneSulfinpyrazone (biphasic

with later inhibition)

AspirinFluvastatinQuinidineRopiniroleSimvastatin

Amiodarone-inducedtoxicosis

DisopyramideGemfibrozilMetolazone

BezafibrateHeparin

Analgesics,antiinflammatories,and immunologics

PhenylbutazonePiroxicam

AcetaminophenAspirinCelecoxibDextropropoxypheneInterferonTramadol

CelecoxibIndomethacinLeflunomidePropoxypheneRofecoxibSulindacTolmetinTopical salicylates

LevamisoleMethylprednisoloneNabumetone

CNS drugs Alcohol (if concomitant liverdisease)

CitalopramEntacapone Sertraline

DisulfiramChoral hydrateFluvoxamine Phenytoin

(biphasic with laterinhibition

Felbamate FluoxetineDiazepamQuetiapine

GI drugs and foods CimetidineFish oilMangoOmeprazole

Grapefruit juice Orlistat

Herbal supplements Boldo-fenugreekQuilinggao

DanshenDong quaiLycium barbarum L.PC-SPES

DanshenMethyl salicylate

Other drugs Anabolic steroidsZileuton

FluorouracilGemcitabineLevamisole/fluorouracilPaclitaxelTamoxifenTolterodine

AcarboseCyclophosphamideMethotrexateFluorouracilCarubicinDanazolIfosphamideTrastuzumab

EtoposideCarboplatinLevonorgestrel

INHIBITION OF WARFARIN EFFECT

Antiinfectives GriseofulvinNafcillinRibavirinRifampin

DicloxacillinRitonavir

Terbinafine CloxacillinNafcillinDicloxacillinTeicoplanin

Cardiovascular drugs Cholestyramine Bosentan Telmisartan FurosemideAnalgesics,

antiinflammatories,and immunologics

Mesalamine Azathioprine Sulfasalazine

CNS drugs BarbituratesCarbamazepine

Chlordiazepoxide Propofol

GI drugs and foods High vitamin K–contentfoods/enteral feeds

Avocado (large amounts)

Soy milkSucralfate

Sushi containing seaweed

Herbal supplements Ginseng Green teaOther drugs Mercaptopurine Chelation therapy

Influenza vaccineMultivitamin supplement

CyclosporineEtretinate

Adapted from Holbrook AM, Pereira JA, Labiris R, et al: Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 165:1095–1106, 2005.

CNS, Central nervous system; GI, gastrointestinal; PC-SPES, a proprietary product consisting of eight Chinese herbals.

TABLE 39-2 Clinically Significant Interactions with Warfarin by Level of Causation and Drug Group


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observed when beginning or stopping a supplement. For alisting of various drug interactions or reported herbal interac-tions, the reader is referred elsewhere.21

THERAPEUTIC RANGE AND MONITORINGOF WARFARIN

The concept of a safe and effective therapeutic range evolvedlargely as a consequence of trial and error and clinical empiri-cism in the 1940s and 1950s.1 A prothrombin time (PT) ratioof 2.0 to 2.5 or 3.0, measured using a human brain throm-boplastin reagent sensitive to a reduction in the vitaminK–dependent coagulation factors, was believed to represent thistherapeutic range. However, less sensitive rabbit brain throm-boplastin reagents came into use in the 1950s and 1960s, whichresulted in the need for a higher average warfarin dose toachieve the same prolongation of the PT.25 Hull and coworkers26 demonstrated the consequences of this situation in a study of

patients with deep vein thrombosis (DVT) treated with warfa-rin by documenting a higher incidence of bleeding in thosemonitored using the less sensitive rabbit brain thromboplastin,but no increase in recurrent thromboembolism in those moni-tored using the more sensitive reagent, when PTs for bothgroups were maintained in a similar therapeutic range.

To correct for differences in thromboplastin sensitivity, theWorld Health Organization recommended the use of an inter-national standard PT.27 All thromboplastins are equilibratedagainst a sensitive international reference thromboplastin, andthe equilibration factor (the International Sensitivity Index, orISI) is used to convert PT ratios (patient PT divided by themean of the normal range) to an international ratio (theINR). The INR is essentially the PT ratio one would obtain if

the international reference thromboplastin had been used tomeasure the PT. Box 39-1 demonstrates how a local PT ratiois converted to an INR, a calculation that is now performedautomatically by laboratory instrumentation. By converting allPT ratios to INRs one can interpret a patient’s PT result regard-less of where the test is performed and then follow the guide-lines of international consensus groups for therapeuticeffectiveness as outlined in Table 39-3.28 Use of the INRdoes not eliminate all discrepancies in PT reporting,29 but itsignificantly improves evaluation of PT results compared withusing raw seconds or the PT ratio when monitoring patientstaking warfarin.

INR, International normalized ratio, a comparative rating of PT ratiosfor individuals with stable therapeutic anticoagulation; ISI, Inter-national Sensitivity Index, a comparative rating of differentthromboplastins.

Box 39-1 USE OF THE ISI TO CALCULATE AN INR

To convert a prothrombin time (PT) ratio to an INR equivalent:INR = (PT ratio)x , where x = ISIExample:PT = 17.9 secMean of normal range = 12.2ISI of thromboplastin = 2.3

Then:17.9 ÷ 12.2 = 1.47 PT ratio

1.472.3 = 2.4 INR

Indication Target INR (Range)

Prophylaxis of venous thrombosis 2.5 (2.0-3.0)Treatment of venous thrombosis 2.5 (2.0-3.0)Treatment of pulmonary embolism 2.5 (2.0-3.0)Prevention of systemic embolism Atrial fibrillation 2.5 (2.0-3.0)

Recurrent systemic embolism 2.5 (2.0-3.0) After myocardial infarction* 3.0 (2.5-3.5)Bioprosthetic heart valves (M or Ao

position)†2.5 (2.0-3.0)

Mechanical prosthetic heart valves Bileaflet valve in Ao position 2.5 (2.0-3.0) Bileaflet or tilting valve in M position 3.0 (2.5-3.5) Mechanical valve + atrial fibrillation (any

position)3.0 (2.5-3.5)

Mechanical valve + additional riskfactors

3.0 (2.5-3.5) + aspirin(81 mg daily)

From Hirsh J, Dalen JE, Anderson DR, et al: Oral anticoagulants:mechanism of action, clinical effectiveness, and optimal therapeutirange. Chest 119(Suppl):8S–21S, 220S–227S, 2001, with permission

*For prevention of recurrent MR, an INR of 3.0 (2.5-3.5) isrecommended.

†For St. Jude or CarboMedics bileaflet or Medtronic-Hall tilting-diskvalve.

TABLE 39-3

Indications for Oral Anticoagulation andRecommended Intensity of Treatment

Ao, Aaortic valve; INR, international normalized ratio; M, mitral valve

PRACTICAL ASPECTS OF WARFARINMANAGEMENT

Initiation and Maintenance Dosing

The administration of a large loading dose of warfarin to initate therapy (30 mg to 60 mg was used in the 1960s) is of historcal interest only. It induces a rapid, but excessive, reduction ifactor VII activity, predisposing patients to hemorrhage in th

first few days of therapy, and it fails to achieve a more rapidecline of the other vitamin K–dependent coagulation factor(II, IX, and X).30,31 Therapy is properly initiated using an averagmaintenance dosage (about 5 mg daily) for the first 2 or days.31 When an immediate effect is required, such as in thtreatment of acute venous thrombosis, heparin should be giveconcurrently with warfarin for at least 5 days. Warfarin treatment should overlap with heparin therapy for a period of 4 t5 days because it takes that long to lower those vitamiK–dependent coagulation factors with longer half-lives. Heparis usually discontinued when the INR has been in the therapeutic range on two measurements taken at least 24 hours apart. initiation of treatment is not urgent (e.g., in chronic stable atrifibrillation [AF]), warfarin can be commenced out of hospit

at an anticipated maintenance dosage of about 5 mg dailywhich usually achieves a therapeutic anticoagulant effect iabout 5 days, although a stable INR may take longer to achievTwo studies showed that using an initial 10-mg dose of warfariin outpatients achieved a therapeutic INR more rapidly thausing a 5-mg dose without producing a higher rate of excessivanticoagulation.32,33 Using a 10-mg starting dose for outpatienis currently recommended by the latest American College oChest Physicians (ACCP) Evidence-Based Clinical PracticGuidelines.34 The fear of creating a hypercoagulable state ipatients with unrecognized protein C deficiency who are nosimultaneously given heparin has not been substantiated i


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Outpatient management of warfarin therapy should aim forsimplicity and clarity to avoid patient confusion, poor compli-ance, and dosing errors that may result in complications.1 It isrecommended that a limited number of warfarin tablet strengthsbe used in clinical practice and that patients clearly understandthe various dosing patterns that are used, such as alternate-daydoses or dosing levels based on days of the week.1 One mustalso be aware that several different warfarin products are onthe market, which can lead to confusion for the patient. Thereare generic preparations sold as warfarin, brand preparationssold as Coumadin, and branded generics sold under a differentname (e.g., Jantoven). Patients may be given two differentpreparations and be taking both, not knowing that they are thesame drug.

Management of Nontherapeutic InternationalNormalized Ratios

Patients receiving long-term warfarin therapy often have unex-pected fluctuations in dose response that require careful man-agement. These may be due to inaccuracy in PT testing, changesin vitamin K intake (increased or decreased vitamin K in thediet), changes in vitamin K or warfarin absorption (GI factors

or drug effects), changes in warfarin metabolism (liver diseaseor drug effects), changes in vitamin K–dependent coagulationfactor synthesis or metabolism (liver disease, drug effects, wors-ening right-sided heart failure with increasing hepatic conges-tion, other medical conditions), or patient compliance issues(surreptitious self-medication, missed doses, miscommunica-tion about dose adjustment, and so on).

A nontherapeutic (e.g., elevated) INR can be managed bybriefly discontinuing warfarin, administering vitamin K, orinfusing fresh frozen plasma (FFP) or a factor concentrate.42 The choice is based largely on the severity of the clinical situa-tion (e.g., degree of elevation of the INR, presence of severebleeding). Assuming an ongoing normal food intake and rea-sonable hepatic function, when warfarin administration is

interrupted, it takes about 4 to 5 days for the INR to return tothe normal range in patients whose INR is between 2.0 and3.0.43 The INR will return to normal more quickly in patientsrequiring a larger daily maintenance dose than in those requir-ing a lower daily maintenance dose. After treatment with oralvitamin K, the INR declines substantially within 24 hours.Because the absolute daily risk of bleeding is low even when theINR is excessively prolonged, many physicians manage patientswith INR values of 4.0 to 9.0 by simply holding warfarin andmonitoring more frequently,44 unless the patient is at a higherrisk of bleeding or bleeding has already developed. Vitamin Kcan be administered by the intravenous, subcutaneous, or oralroute. Intravenous injection may be associated with anaphylac-tic reactions in rare cases, but it does lead to reversal of the

INR more quickly than oral or subcutaneous administrationof vitamin K.45 The response to subcutaneous vitamin K maybe unpredictable and sometimes delayed.46 Recent studiesconfirm earlier reports that oral administration is predictablyeffective, more so than subcutaneous administration, and hasthe advantages of safety and convenience over parenteral routes.Ideally, vitamin K should be administered in a dose that willquickly lower the INR into a safe, but not subtherapeutic, rangewithout causing resistance when warfarin is reinstated.47-49 Highdoses of vitamin K, although effective, may lower the INR morethan is necessary and lead to warfarin resistance persisting forup to 1 week.

patients with AF. However, in patients with a known protein Cdeficiency or other thrombophilic state, it would be prudent tobegin heparin before, or at the same time as, warfarin. A startingdose lower than 5 mg might be appropriate in the elderly, inpatients with impaired nutrition or liver disease, and in patientsat high risk of bleeding. The physician should be aware of vari-ables that influence the response to anticoagulation in theelderly. The dosage required to maintain a therapeutic range inpatients older than 60 years of age has been shown to decreasewith increasing age,35 and older patients are more likely to haveother variables that might influence INR stability or the riskof bleeding, such as a greater number of other medical condi-tions or concurrent drug use.35 Consequently, it is advisable tomonitor treatment more carefully in older patients to maximizetheir time in the therapeutic range.36

Estimation of the maintenance dose is often based on obser-vations of the INR response following administration of a fixeddose of warfarin over an interval of a few days. An individualwho rapidly achieves a high therapeutic INR (above 1.5) aftertwo doses of warfarin is likely to require a low maintenancedose. The opposite holds for a patient who show little elevationof the INR (below 1.5) after two doses. It is now known that a

major determinate influencing a patient’s response to initialand maintenance dosing is the patient’s genotype for the prin-cipal enzyme that metabolizes warfarin (CYP 2C9) and thetarget enzyme through which warfarin mediates its effect(VKORC1).10-20 Polymorphisms in the genes for these enzymesaccount for almost 50% of the variability in dosing require-ments. They are also associated with a higher rate of bleedingevents. Access to rapid-turnaround genetic testing is onlynow becoming possible to make pharmacogenetic dosing prac-tical. Several large randomized trials are in progress, and onerecently completed trial showed a higher percentage of time inthe therapeutic range (69%) with pharmacogenetic dosing thanwith standard dosing (58%) at 1 month, and fewer critical INRvalues (INR of ≤1.5 or ≥4.0) with pharmacogenetic dosing

(4.5% versus 9.4%, respectively; P


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In the presence of significant bleeding, the INR must bereversed immediately. This can be done by replacing the vitaminK–dependent factors using FFP. At least 15 to 30 mL/kg of FFPshould be given to have a significant impact on factor replenish-ment.50,51 The amount used should depend on the degree towhich the INR is out of range and the severity of the bleeding.In the average 70-kg person, this equates to 4 to 8 units of FFP,which may take up to 6 to 24 hours to order, thaw, and infuse,and in some patients may put an undue stress on the heart. Inaddition, the half-lives of the individual vitamin K–dependentfactors govern the durability of any response. More FFP mightbe required. In a patient with life-threatening bleeding, espe-cially intracranial hemorrhage, maximal factor replacementmust be achieved in the shortest interval possible. This can beaccomplished by using factor concentrates that have high factorconcentrations in a small volume.52 Prothrombin complex con-centrates (PCCs), containing the vitamin K–dependent factors,have traditionally been used.53 Studies have also shown thatrecombinant factor VIIa (rFVIIa) can reverse the coagulopathyand associated bleeding induced by warfarin, as well as othercoagulopathies.54,55 Given the expense of these agents, oneshould use the lowest effective dose to control the bleeding.

PCCs are often dosed in a range of 25 to 50 IU/kg, but thespecific dose will depend on body weight, degree of INR pro-longation, and desired level of correction. The same consider-ations are relevant for the dosing of rFVIIa, although the rangeof dosing reported empirically ranges from approximately20 g/kg to more than 100 g/kg. Both PCCs and rFVIIa havethe potential to induce a prothrombotic state, and thromboem-bolism has occurred as a result of such therapy.56,57 Table 39-4 outlines the 2008 ACCP recommendations for managingpatients receiving coumarin anticoagulants who need the INRlowered because of actual or potential bleeding.42 These recom-mendations have not significantly changed in the most recentguidelines.34

The decision to provide coverage to a patient who comes to

one’s office with a subtherapeutic INR is similar to a bridgingdecision. If the thrombogenic risk is so high (such as within thefirst week or two of treating new DVTs and/or pulmonaryembolisms [PEs]) that even a few days at a subtherapeutic levelplaces the patient at high risk, then treating the patient with lowmolecular weight heparin (LMWH) for a few days until a thera-peutic INR is achieved with higher doses of warfarin is appro-priate. In most cases, this intervention is not needed,34 andsimply raising the dose of warfarin is sufficient to reestablish atherapeutic range in a few days.

Management of Oral Anticoagulation duringInvasive Procedures

Clinicians are often confronted with the challenge of managing

anticoagulation in individuals requiring noncardiac surgery orother invasive procedures, especially individuals with prostheticheart valves who are currently taking warfarin (Chapters 37 and47). There is a paucity of critical studies examining the alterna-tive choices for anticoagulation (called bridging therapy ) in thissetting. Physicians must assess the risk of bleeding from a pro-cedure if anticoagulation is continued versus the risk of throm-bosis if anticoagulation is discontinued, as well as therisk of bleeding from an alternative rapidly acting anticoagulantand the cost of alternative anticoagulation options. Recentreviews have addressed the management of these patientsand the options available,58 and the ACCP has made formal

recommendations.59 Historically, full-dose intravenous unfrationated heparin (UFH) has been the standard therapy fopatients who need full anticoagulant protection that is readireversible before a procedure. Its major drawbacks are the complexity and cost associated with intravenous heparin therapand hospitalization. LMWH offers another, less complex altenative because it requires no monitoring and can be given ahome.60-66 LMWH has been shown to produce therapeutic leveof anticoagulation more rapidly than UFH and to provide

Condition Description

INR above therapeuticrange but


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Study No. of Patients Bridging RegimenPostoperative

Follow-up (weeks)Major Bleeding

(95% CI) Thrombosis

Turpie65 174 Enoxaparin 1 mg/kg BID 4 2.3% (0.06%-5.7%) 0.6%Kovacs62 224 Dalteparin 200 IU/kg QD 4 6.7% (4.1%-108%) 3.6% (1.8%-6.9%)Dunn64a 260 Enoxaparin 1.5 mg/kg QD 2 3.5% (1.6%-6.5%) 1.5%Spyropoulos64 668 Enoxaparin/dalteparin 1 mg/kg BID 4 3.3% (2.0%-5.1%) 0.9%

Douketis63 650 Dalteparin 100 IU/kg BID 1 0.9% (0.4%-2.0%) 0.3%

BID, Twice daily; CI, confidence interval; QD, daily.

TABLE 39-5

Recent Studies of the Use of Low Molecular Weight Heparin as Alternative (Bridging) Therapy in PatientsReceiving Warfarin Who Require Invasive Procedures

Risk of Thromboembolism or Bleeding Example Recommendation or Suggestion*

Low risk of thromboembolism offanticoagulants

Bileaflet mechanical aortic valvewithout AF; AF with low CHADS2 score; VTE > 12 mo ago

Stop warfarin approximately 5 days before procedure;allow the INR to return to normal; no need to bridgewith rapidly acting anticoagulant; resume warfarinafter procedure.

Intermediate risk of thromboembolismoff anticoagulants

Bileaflet mechanical aortic valve withother risk factors such as AF, prior

stroke, heart failure, hypertension; VTE 3-12 mo ago

Approach is based on individual patient and surgery-related factors. For instance, one might use a

prophylactic dose of LMWH rather than a full dose.

High risk of thromboembolism offanticoagulants

Mechanical mitral valve; old-style aorticvalve; AF with high CHADS2 score(5 or 6); recent (


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score of Fang and coworkers.88 All of these scoring systemincorporate many common risk factors, including age, historof bleeding, renal insufficiency, anemia, hypertension, an

others. None of them, however, is so specific that other factocan be ignored, and in deciding the risk of bleeding in an indvidual patient many factors need to be taken into considerationincluding the living environment, other comorbid conditionpatient compliance, and others. Table 39-7 summarizes thebleeding risk indices.

Anticoagulation Management Services

Adoption of a coordinated and focused approach to the management of therapy through the use of specialized program(anticoagulation clinics) significantly improves clinical oucomes by improving therapeutic control and time in ththerapeutic range, lessening the frequency of hemorrhage othrombosis, and decreasing the use of medical resources, whic

leads to more cost-effective therapy. These programs are characterized by the presence of a knowledgeable provider whosprimary responsibility is to manage therapy, an organizesystem of follow-up, rapid and reliable INR monitoring, angood patient communication and education.89,90

Most patients receiving long-term oral anticoagulant theraptoday are treated by their personal physicians (characterized a“usual care”) along with all the other patients in the physicianpractice without an organized program of management, education, or follow-up.91 Studies indicate a rate of major hemorhage of at least 7% to 8% per patient-year of therapy.42 Theris a similar rate of recurrent or de novo thromboembolismso that the overall serious adverse event rate is at least 15%per patient-year of therapy. These adverse events are generall

a consequence of suboptimal therapeutic control, with hemorhage or thrombosis occurring as a consequence of excessivor subtherapeutic anticoagulation. These outcomes can bcontrasted to the rates identified in studies of care delivereby an anticoagulation management service (anticoagulatioclinic),42,92-96 which indicate a more than 50% reduction in botmajor hemorrhage and thrombosis compared with usual carA few studies also suggest a significant cost benefit to coordnated care compared with usual care because of a reduction iadverse events and reduced use of hospital services. Anticoagulation care administered as described earlier was first recommended by the ACCP consensus guidelines in 2008.42

Dental procedures represent a particularly common inter-vention in patients taking anticoagulants. A recent comprehen-sive review of the subject indicated that, in most cases, no

change in the intensity of anticoagulation is needed.

59,69

Whenthere is a need to control local bleeding, tranexamic acid orε-aminocaproic acid mouthwash has been used successfullywithout interruption of anticoagulant therapy.59,70,71

Diagnostic Evaluation of Bleeding

When bleeding occurs, especially from the GI or urinary tract,it is important to consider the possibility of a serious underlyingoccult lesion as the source of bleeding. A number of descriptivestudies indicate that the chance of finding such a lesion isapproximately 5% to 25%, which supports the need for furtherinvestigation in such cases.72-75 The significance of hematuria ina patient taking warfarin is less clear. There is a low prevalenceof microscopic hematuria in patients not taking anticoagulants,

and the likelihood of finding an underlying malignancy appearsto be less.76-79

PREDICTING AND MANAGING THE RISKSOF ORAL ANTICOAGULANT THERAPY

Over the last 20 years, several developments have improved thesafety and efficacy of oral anticoagulation. These include defin-ing the optimal intensity of therapy by well-designed random-ized trials and standardizing the reporting of PTs using the INR,which have led to more appropriate and standardized therapy.Identification of the risk factors associated with bleeding hasalso advanced. Time in the therapeutic range is an importantmeasure of the quality of anticoagulation care, and a strong

relationship exists between time in the therapeutic rangeand either bleeding or thrombosis rates as demonstrated byCannegieter and colleagues,80 Hylek and coworkers,81,82 andothers.83,84 In addition to time in the therapeutic range, anumber of patient characteristics serve as risk factors for bleed-ing. Knowing these risk factors for an individual patient beforeinitiating anticoagulant therapy or deciding to extend therapyis an essential aspect of care and balancing risk and benefit. Anumber of risk indexes have been developed to help the clini-cian. These include the Bleeding Risk Index of Beyth and col-leagues,85 the HEMORR 2HAGES index of Gage and coworkers,

86 the HAS-BLED score of Pisters and colleagus,87 and the ATRIA

OBI HEMORR2HAGES HAS-BLED ATRIA

Age ≥ 65 yr 1 Abnormal renal/liver function 1 Hypertension 1 Anemia 3Prior stroke 1 Alcohol abuse 1 Abnormal renal/liver

function1/2 Severe renal disease 3

Prior gastrointestinal bleeding 1 Cancer 1 Stroke 1 Age ≥ 75 yr 2Recent myocardial infarction,

diabetes, hematocrit 1.5 mg/dL

1-4 Age > 75 1 Bleeding 1 Any prior bleed 1Reduced platelet count or

function

1 Labile INR 1 Hypertension 1

Elderly (>65 yr) 1Rebleeding risk 1 Drugs or alcohol 12Hypertension 1Anemia 1Genetic factors 1Fall risk 1Stroke 1

Low risk 0 ≤1


9/19


PATIENT SELF-TESTING AND PATIENTSELF-MANAGEMENT

As a result of technologic advances in INR measurement, thereis a potential for further simplifying and improving anticoagu-lation management by point-of-care (POC) testing.97 POCtesting allows PT to be determined from a finger-stick sampleof whole blood and consequently opens the possibility forpatient self-testing. Portability of instrumentation means thatINR measurement devices are no longer confined to the physi-cian’s office, a private laboratory, or a nearby hospital, but canbe moved into the patient’s home or even taken with the patientwhen traveling. Standardization of reagents and instruments, aswell as reliance on the INR, further reduce the inaccuraciesassociated with the use of multiple reagents and laboratories.Instrumentation for PT monitoring is discussed in depth inChapter 40.

These POC instruments have been tested in a number ofdifferent clinical settings, and their accuracy and precision areconsidered to be more than adequate for the monitoring of oralanticoagulant therapy in both adults and children.98 It is pos-sible that this new model of care is significantly more reliable

and consistent than the variable and haphazard PT monitoringoften employed in the usual care of many patients takingoral anticoagulants.99 Use of these instruments is particularlyrational for patients receiving prolonged or indefinite antico-agulant therapy. Patients who self-test can call their physiciansand obtain instructions for warfarin dose adjustment, andselected patients can manage their own warfarin dosing afterproper training.

Many studies have demonstrated the ability of patients toperform self-testing and to obtain an accurate result. One of thelargest trials recently completed, the THINRS trial,100 randomlyassigned nearly 3000 patients with atrial fibrillation or mechan-ical prosthetic valves either to perform self-testing or to receivestandard anticoagulation clinic management. Importantly, 80%

of patients were shown to be able to perform self-testing. Dosemanagement in the self-testing group was performed by theanticoagulation clinic. Although there were no significant dif-ferences in the incidence of thrombosis or major bleeding,the self-management group had a significantly higher propor-tion of time in the therapeutic range and a significantly higherlevel of patient satisfaction and quality of life. A recent CochraneCollaborative review 101 also found an improved quality of lifein patients who monitored their INRs at home as well a signifi-cant decrease in thromboembolic events (risk ratio [RR], 0.50;95% confidence interval [CI], 0.36 to 0.69) and all-causemortality (RR, 0.64; 95% CI, 0.46 to 0.89). Patients who per-formed self-testing, but not dose management, also showed asignificant reduction in major bleeding (RR, 0.56; 95% CI, 0.35

to 0.91), whereas those who also managed their own dose didnot. Finally, a meta-analysis of individual patient data from 11trials encompassing 6417 individuals and 12,800 person-yearsof follow-up found similar results of a significant reduction inthromboembolism in the self-monitoring group (hazard ratio[HR] 0.51; 95% CI, 0.31 to 0.85) but no reduction in majorhemorrhage (HR, 0.82; 95% CI, 0.74 to 1.06) or death (HR,0.82; 95% CI, 0.62 to 1.09).102

Based on the foregoing, POC PT monitoring offers thepotential to improve the risk : benefit profile of anticoagulanttherapy; to increase patient satisfaction, patient involvement,and possibly patient compliance; and, by reducing the labor

intensity of physician management, to encourage the morewidespread use of warfarin. The cost effectiveness of suchtherapy needs to be studied.

Target-Specific Oral Anticoagulants

LIMITATIONS OF WARFARIN

Warfarin is a safe and effective oral anticoagulant if a therapeu-tic INR is properly maintained. In practice, however, it isdifficult to manage warfarin therapy because its therapeuticlevel is affected by many factors, including diet, other medica-tions, illnesses, and genetics. Although warfarin prevents64% of strokes in a controlled research setting,103 its clinicaleffectiveness averages 35%,104 and only 50% of patients main-tain a therapeutic INR during therapy.105 Warfarin’s narrowtherapeutic range predisposes to many adverse events fromboth underanticoagulation (resulting in thrombus formation)and overanticoagulation (leading to hemorrhage). To ensurethat a therapeutic INR is achieved, frequent monitoring isrequired that may be inconvenient for patients and physiciansand costly for the health care system. Specialized anticoagula-

tion clinics are needed to address the complexity of managingwarfarin therapy. An additional drawback of warfarin is its slowonset and offset of action. It takes 72 to 96 hours to becomeeffective and requires overlap with a rapidly acting parenteralanticoagulant or bridging therapy until a therapeutic INR isachieved. Its slow offset, with an effective half-life of approxi-mately 40 hours, makes it difficult to manage before procedures.Safety concerns and therapeutic complexity lead many physi-cians to underuse warfarin, prescribing it to only two thirds ofappropriate candidates.104

New oral anticoagulants in development are free of many ofwarfarin’s drawbacks and offer a convenient alternative to war-farin. The drugs that are furthest along in development targeteither thrombin or factor Xa. When inhibited, these coagulation

factors, due to their central locations in the common coagula-tion pathway, block both the intrinsic and extrinsic pathways(Fig. 39-2). These small molecules directly block either factorXa or thrombin (factor IIa) at their catalytic pocket. Novelagents promise to be more convenient and possibly safer thanwarfarin because they are given in fixed dosages, have a predict-able anticoagulant effect, do not require monitoring, have fewor minimal interactions with drugs or diet, and have a rapidonset of action that eliminates the need for parenteral antico-agulation. Several landmark studies are now available on thedirect thrombin inhibitor dabigatran and the two factor Xainhibitors rivaroxaban and apixaban that have led the approvalof these agents in the United States for an increasing numberof indications.

DABIGATRAN

Dabigatran etexilate (Pradaxa) is a direct thrombin inhibitoradministered once or twice daily. It is an oral prodrug that israpidly converted by a serum esterase to dabigatran, a potent,direct, competitive thrombin inhibitor. Dabigatran has a 2-hour onset, 14- to 17-hour half-life, and 6.5% bioavailability.106 Eighty percent of dabigatran is excreted via the kidneyunchanged, and renal function is an important determinant oftherapy. Dabigatran’s serum concentration may be influencedby drugs that inhibit or induce the P-glycoprotein transporter,


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Long-Term Anticoagulation Therapy (RE-LY) phase 3 trial.1

This prospective noninferiority trial involved 18,113 patienwith atrial fibrillation and at least one additional risk factor fostroke (CHADS2 score ≥ 1). Patients were treated with dabigatran (blinded dosages of 150 mg twice daily or 110 mg twicdaily) or open-label warfarin (to a target INR of 2.5) and werfollowed for a period of 2 years. Results of the trial are summarized in Table 39-12. In brief, dabigatran (150 mg twicdaily) was superior to warfarin in reducing stroke or systemembolism but noninferior with regard to incidence of majobleeding. The lower dosage of 110 mg twice daily was noninferior for the primary outcome but was superior to warfarin witregard to major bleeding. Either dabigatran dosages signifi

cantly reduced the rate of intracranial hemorrhage, but Gbleeding was greater with dabigatran than with warfarin anmore patients taking dabigatran complained of dyspepsia. Myocardial infarction also occurred more frequently with dabigatran, but the difference was not significant.

DIRECT FACTOR Xa INHIBITORS

Oral inhibitors of factor Xa bind to the active site of factoXa and block its interaction with prothrombin. Numeroufactor Xa inhibitors are in clinical development, with rivaoxaban (Xarelto) and apixaban (Eliquis) being in the moadvanced stages.

Rivaroxaban

Rivaroxaban is a selective factor Xa inhibitor administereonce or twice daily.106 It has an onset of action of 2.5 to hours and a half-life of 5 to 9 hours, and is partially eliminateby the kidney (approximately 66%) with the remainder metabolized by CY P450 enzyme 3A4. Its elimination may bimpaired if it is given with strong CYP 3A4 inhibitors (e.gketoconazole, ritonavir). Table 39-8 summarizes rivaroxabanproperties.

Rivaroxaban has been studied for use in VTE preventiofollowing orthopedic surgery, and the results of four majophase 3 orthopedic trials are summarized in Table 39-9.115-1

but most interactions are of minor significance. Table 39-8 reviews dabigatran’s properties.

Dabigatran has undergone extensive phase 3 testing in majororthopedic surgery.107-110 Results of these studies are summa-rized in Table 39-9. Dabigatran (150 mg and 220 mg) andenoxaparin (40 mg daily initiated preoperatively and then oncedaily) were equally effective in preventing venous thromboem-bolism (VTE) with no increased bleeding risk.107-109 The NorthAmerican enoxaparin regimen (30 mg twice daily beginningpostoperatively) used in the RE-MOBILIZE110 trial, however,failed to show noninferiority to enoxaparin based on the crite-ria used for noninferiority. In Europe and Canada dabigatranat a dose of 220 mg is recommended for a majority of patients

and the 150-mg dose is reserved for patients older than 75 years111 for VTE prevention following orthopedic surgery.For treatment of patients with DVT with or without PE,

dabigatran was compared with warfarin in the RE-COVERtrial.112 Over 2500 patients with acute symptomatic DVT withor without PE were enrolled, and all patients were initiallytreated with a standard 5- to 7-day course of unfractionatedheparin or LMWH. Patients were then randomly assigned toreceive either dabigatran (150 mg twice daily) or warfarin (to atarget INR of 2.5) and followed for the next 6 months. Resultsof the trial, summarized in Table 39-10, showed that dabigatranwas noninferior to warfarin in preventing recurrent symptom-atic VTE or fatal PE. Rates of major bleeding with dabigatranwere similar to those with warfarin; however, a significantly

lower rate of occurrence of any bleeding event was observed fordabigatran compared with warfarin. The use of dabigatran forextended secondary prevention in patients who had undergonea standard course of therapy for VTE was also studied. In theRESONATE trial113 dabigatran significantly reduced the recur-rence of VTE compared with placebo but was associated withan increase in major nonfatal bleeding. The results of this trialare summarized in Table 39-10. Target-specific oral anticoagu-lants have also been tested for the primary prevention of VTEand PE (Table 39-11).

Dabigatran was also compared with warfarin for stroke pre-vention in atrial fibrillation in the Randomized Evaluation of

Figure 39-2 Coagulation cascade and factors inhibitedor impaired by both standard anticoagulants and newtarget-specific oral anticoagulants.

VII

X

VIII

IX

XI

XII

V

II

I

Fibrin clot

Lowmolecular

weightheparin

Unfractionatedheparin

New oral IIa

inhibitors

Dabigatran etexilate

New oral Xa

inhibitors

RivaroxabanApixabanEdoxaban

Betrixaban

Warfarin


11/19


Parameter Dabigatran Rivaroxaban Apixaban

Target Factor IIa (thrombin) Factor Xa Factor XaTime of maximal

concentration2 hr 2.5-4 hr 3 hr

Half-life* 12-14 hr 9-13 hr 8-11 hr Metabolism/elimination 80% renal

20% biliary

No liver metabolism

33% renal (unchanged)33% renal (inactive)

33% liver-dependent metabolism

25% renal (mostly unchanged)55% fecal (metabolites)

15% liver metabolismDosing in renal

impairment† for AFCrCl ≥ 30 mL/min: 150 mg orally

twice dailyCrCl 15-29 mL/min: 75 mg orally

twice daily

CrCl ≥ 50 mL/min: 20 mg orallyonce daily

CrCl 30-49 mL/min: 15 mg orallyonce daily

5 mg orally twice daily2.5 mg orally twice daily if two or

more of following:Cr level ≥ 1.5 mg/dLAge ≥ 80 yr Weight ≤ 60 kg

Dose frequency for AF Twice daily Once daily Twice dailyMonitoring Not needed Not needed Not neededRecommended assay

to detect drugPTTThrombin time‡Dilute thrombin time‡Ecarin clotting time

PT (not INR)§Anti-Xa assay calibrated for

rivaroxaban

PTAnti-Xa assay calibrated for

apixaban

Drug interactions Potent P-gp inhibitors, protonpump inhibitors may decreaseabsorption.

Potent P-gp inhibitors maydecrease absorption.

Potent CYP 3A4 inhibitors mayalter levels.

Potent P-gp inhibitors maydecrease absorption.

Potent CYP 3A4 inhibitors mayalter levels.

Antidote/reversal No specific antidote.Suggested:

Graded response to degreeof bleeding; short half-lifefavors rapid drug elimination;supportive measures forall patients; for major orlife-threatening bleedinganimal studies are variablysupportive of use of activatedor nonactivated PCCs and/orrFVIIa.¶

Can be removed by hemodialysis.Activated charcoal for acute

ingestion.

No specific antidote.Suggested:


Cannot be removed byhemodialysis.

Activated charcoal for acuteingestion.

No specific antidote.Suggested:


Cannot be removed byhemodialysis.

Activated charcoal for acuteingestion.

*Half-life varies with renal function to a greater or lesser degree depending on agent.†Dosing in renal impairment taken either from package insert or clinical trials.‡PTT recommended in package insert; thrombin time or dilute thrombin time most linear, but thrombin time may be too sensitive.§Dose-dependent elevation of PT; sensitivity may vary with thromboplastin reagents.¶PCCs are factor concentrates of the vitamin K–dependent factors (II, VII, IX, X) with variable concentrations of factor VII. Some preparations

contain activated forms of these factors. rFVIIa is an activated factor VII concentrate. PCCs and rFVIIa carry a risk of inducing thrombosis (~1%and 7%-10%, respectively).

TABLE 39-8 Pharmacokinetic Properties and Other Attributes of New Target-Specific Oral Anticoagulants

AF, Atrial fibrillation; Cr, creatinine; CrCl, creatinine clearance; CYP, cytochrome oxidase hepatic enzymes; INR, international normalized ratio;PCC, prothrombin complex concentrates; P-gp, P-glycoprotein; PT, prothrombin time; PTT, partial thromboplastin time; rFVIIa, recombinantfactor VIIa.

Rivaroxaban was shown to be superior to enoxaparin withregard to the primary outcome of preventing VTE without

causing a significant increase in bleeding. These results wereobtained using both the European and North American regi-mens for administering enoxaparin.

The use of rivaroxaban to treat patients with acute DVT wasalso studied.119 Unlike in the dabigatran trial for this indication,rivaroxaban was given at the time of diagnosis and comparedwith standard LMWH therapy followed by warfarin for 3, 6, or12 months of follow-up. Rivaroxaban was dosed at 15 mg twicedaily for the first 3 weeks and then reduced to 20 mg daily forthe duration of treatment. Rivaroxaban was shown to be non-inferior to enoxaparin/warfarin for prevention of recurrentsymptomatic VTE or fatal PE with no increase in the risk of

major bleeding. A similar study was performed in patients whohad PE with or without DVT, and the results also showed non-

inferiority compared to standard therapy without an increasedrisk of bleeding.120 An extension of the initial DVT trial inpatients who had already undergone standard therapy for 6months compared rivaroxaban with placebo.119 The resultsshowed a significant reduction in recurrent symptomatic VTEin the rivaroxaban group, but with a small increase in nonfatalmajor bleeding. These studies are summarized in Table 39-10.Rivaroxaban has also been studied as an agent to prevent VTEin hospitalized patients with medical illnesses. In the MAGEL-LAN trial,121 rivaroxaban was just as effective as enoxaparinduring the inpatient phase of the study and significantly reducedsymptomatic DVT during the outpatient phase (compared with


12/19


13/19


S t u d y

D r u g

/ D o s a g e

N o .

o f

P a

t i e n

t s /

T r i a

l

D u r a

t i o n

I n d i c a

t i o n

C o m p a r i s o n

D r u g

P r i m a r y

O u

t c o m e

M e a s u r e

P r i m

a r y

S a

f e t y

M e a s u r e

P r i m a r y

O u

t c o m e

R e s u

l t s

P r i m a r y

S a

f e t y

R e s u

l t s

R E - C O V E R

( S c h u l m a n ,

e t a l ) 1 1 2

D a b i g a t r a n

1 5 0 m g t w i c e

d a i l y

2 5 6 4 ,

6 m o

T r e a t m e n t f o r

a c u t e V T E

U F H o r

L M W H t o

w a r f a r i n

( I N R 2 - 3 )

R e c u r r e n t

s y m p t o m a t i c

V T E a n d r e l a t e d

d e a t h s

M a j o r b l e e d i n g

D a b : 2 . 4 % ( 3 0 / 1 2 7 4 )

W a r f : 2 . 1 % ( 2 7 / 1 2 6 5 )

D a b i g a t r a n

n o n i n f e r i o r

D a b : 1 . 6 % ( 2 0 / 1 2 7 4 )

W a r f : 1 . 9 % ( 2 4 / 1 2 6 5 )

N o s i g n i fi c a n t

d i f f e r e n c e

E I N S T E I N - D V T

( E I N S T E I N

I n v e s t i g a t o r s ) 1 1 9

R i v a r o x a b a n

1 5 m g t w i c e

d a i l y

f o r 3 w k , t h e n

2 0 m g d a

i l y

3 4 4 9 ,

3 , 6 , o r

1 2 m o


a c u t e D V T

( w i t h o u t P E )

E n o x a p a r i n

t o W a r f a r i n

( I N R 2 - 3 )

R e c u r r e n t


V T E

M a j o r b l e e d i n g o r

c l i n i c a l l y r e l e v a n t

n o n m a j o r

b l e e d i n g

R i v : 2 . 1 % ( 3 6 / 1 7 3 1 )

W a r f : 3 % ( 5 1 / 1 7 1 8 )



R i v : 8 . 1 % ( 1 3 9 / 1 7 1 8 )

W a r f : 8 . 1 % ( 1 3 8 / 1 7 1 1 )


d i f f e r e n c e

E I N S T E I N - P E

( E I N S T E I N

I n v e s t i g a t o r s ) 1 2 0


1 5 m g t w i c e

d a i l y

f o r 3 w k , t h e n

2 0 m g d a

i l y


a c u t e P E ( w i t h

o r w i t h o u t

D V T )

E n o x a p a r i n

t o W a r f a r i n

( I N R 2 - 3 )

R e c u r r e n t


V T E

M a j o r b l e e d i n g o r

c l i n i c a l l y r e l e v a n t

n o n m a j o r

b l e e d i n g

R i v : 2 . 1 % ( 5 0 / 2 4 1 9 )

W a r f : 1 . 8 % ( 4 4 / 2 4 1 3 )



R i v : 1 0 . 3 % ( 2 4 9 / 2 4 1 2 )

W a r f : 1 1 . 4 %

( 2 7 4 / 2 4 0 5 )


d i f f e r e n c e

E I N S T E I N - E X T

( E I N S T E I N

I n v e s t i g a t o r s ) 1 1 9


2 0 m g d a i l y

1 1 9 6 ,

6 o r 1 2 m o

P r e v e n t i o n o f

r e c u r r e n t V T E

P l a c e b o

R e c u r r e n t


V T E


R i v : 1 . 3 % ( 8 / 6 0 2 )

P l a c e b o : 7 . 1 %

( 4 2 / 5 9 4 )

R i v a r o x a b a n s u p e r i o r

R i v : 0 . 7 % ( 4 / 6 0 2 )

P l a c e b o : 0 %


d i f f e r e n c e

R E S O N A T E

( S c h u l m a n ,

e t a l ) 1 1 3

D a b i g a t r a n

1 5 0 m g t w i c e

d a i l y

1 3 4 3 ,

6 m o



P l a c e b o

R e c u r r e n t


V T E


D a b : 0 . 4 % ( 3 / 6 8 1 )

P l a c e b o : 5 . 6 %

( 3 7 / 6 6 2 )

D a b i g a t r a n s u p e r i o r

D a b : 0 . 3 9 % ( 2 / 6 8 1 )

P l a c e b o : 0 %


d i f f e r e n c e

A M P L I F Y - E X T

( A g n e l l i ,

e t a l ) 1 2 5 a

A p i x a b a n 2 . 5 o r

5 m g t w i c

e

d a i l y

2 4 8 2 , 1 2

m o n t h s



P l a c e b o

R e c u r r e n t


V T E o r d e a t h

f r o m V T E


A p i x : 2 . 5 m g

1 . 7 % ( 1 4 / 8 4 0 ) ;

5 m g 1 . 7 % ( 1 4 / 8 1 3 )

P l a c e b o : 8 . 8 %

( 7 3 / 8 2 9 )

A p i x : 2 . 5 m g 0 . 2 %

( 2 / 8 4 0 )

5 m g 0 . 1 % ( 1 / 8 1 3 )

P l a c e b o : 2 . 3 % ( 4 / 8 2 9 )

D A B ,

D a

b i g a

t r a n ; D V T ,

d e e p v e

i n

t h r o m

b o s

i s ; I N R ,

i n t e r n a

t i o n a

l n o r m a

l i z e

d r a

t i o ; L M W H ,

l o w

m o

l e c u

l a r w e

i g h t h e p a r i n

; P E ,

p u

l m o n a r y e m

b o

l i s m ; R I V ,

r i v a r o x a

b a n ; U F H ,

u n

f r a c

t i o n a

t e d

h e p a r i n ; V K A ,

v i t a m

i n K a n

t a g o n

i s t ; V T E ,

v e n o u s

t h r o m

b o e m

b o

l i s m ; W A R F ,

w a r f a r i n .

T A B L E

3 9 - 1 0

R e s u l t s o f P h a s e 3 C

l i n i c a l T r i a l s o f N e w

T a r g e t - S p e c i fi c

O r a l A n t i c o a g u l a n t s f o r S e c o n d a r y

P r e v e n t i o n o f V e n o u s T h r o m b o e m b

o l i s m


14/19


StudyDrug/Dosage

No. ofPatients/TrialDuration Indication

ComparisonDrug

PrimaryOutcomeMeasure

PrimarySafetyMeasure

PrimaryOutcomeResults

Primary SafetyResults

ADOPT(Goldhaber,

et al)126

Apixaban2.5 mg

twicedaily

6528,30 days

VTEprophylaxis

in medicallyill patients

Enoxaparin40 mg daily

(6-14 days)

30-Daycomposite

of deathrelated to VTE, PE,DVT

Majorbleeding

Apix: 2.71%(60/2211)

Enox: 3.06%(70/2284)Apixaban not

superior toenoxaparin

Apix: 0.47%(15/3184)

Enox: 0.19%(6/3217)Apixaban

increasedmajor bleeding

MAGELLAN(Cohen,et al)121

Rivaroxaban10 mg daily

8100,35 days

VTEprophylaxisin medicallyill patients

Enoxaparin40 mg daily

(10 days)

Compositeof VTE-relateddeath, PE,DVT

Majorbleedingandclinicallyrelevantnonmajorbleeding

Day 10: Riv: 2.7%

(79/2939) Enox: 2.7%

(80/2993)Day 35: Riv: 4.4%

(130/2967) Enox: 5.7%

(174/3057)Rivaroxaban

noninferiorat day 10,

superior atday 35

Day 10: Riv: 2.8%

(111/3997) Enox: 1.2%

(48/4001)Day 35: Riv: 4.2%

(167/3997) Enox: 1.7%

(68/4001)Rivaroxaban

increasedclinically

significantbleeding

Apix, Apixaban; DVT, deep vein thrombosis; Enox, enoxaparin; PE, pulmonary embolism; Riv, ribaroxaban; VTE, venous thromboembolism.

TABLE 39-11

Results of Phase 3 Clinical Trials of New Target-Specific Oral Anticoagulants for Primary Prevention of VenousThromboembolism

StudyDrug/Dosage

No. ofPatients/TrialDuration/CHADS2 Score Indication

ComparisonDrug

PrimaryOutcomeMeasure

PrimarySafetyMeasure

PrimaryOutcomeResults

Primary SafetyResults

RE-LY

(Connolly,et al)114

Dabigatran

110 mg or150 mgtwicedaily

18,113,

2 yr,CHADS2

= 2

Prevention of

stroke innonvalvularatrialfibrillation

Warfarin

INR 2-3

Stroke and

systemicembolism

Major

bleeding

Dab 110 mg:

1.53%/yr Dab 150 mg:

1.11%/yr Warf: 1.69%/yr Dabigatran

110 mgsuperior towarfarin;dabigatran150 mgnoninferiorto warfarin

Dab 110 mg:

0.12%/yr Dab 150 mg:

0.1%/yr Warf: 0.38%/yr Dabigatran 110 mg

not significantlydifferent fromwarfarin;dabigatran150 mg causedsignificantly lessbleeding

ROCKET-AF(Patel,et al)122

Rivaroxaban20 mg daily

14,264,707 days,CHADS2

= 3.5

Prevention ofstroke innonvalvularatrialfibrillation

WarfarinINR 2-3

Stroke andsystemicembolism

Majorbleedingandclinicallyrelevantnonmajor

bleeding

Riv: 1.7%/yr Warf: 2.2%/yr Rivaroxaban

noninferiorto warfarin

Riv: 14.9%/yr Warf: 14.5%/yr Not significantly

different

ARISTOTLE(Granger,et al)127

Apixaban5 mg twice

daily

15,000,18 mo,CHADS2

= 2


WarfarinINR 2-3

Ischemic orhemorrhagicstroke andsystemicembolism

Majorbleeding

Apix: 1.27%/yr Warf: 1.6%/yr Apixaban

superior towarfarin

Apix: 2.13%/yr Warf: 3.09%/yr Significantly

reduced

AVERROES(Connolly,et al)128

Apixaban5 mg twice

daily

5600,18 moCHADS2

= 2


Aspirin81 to

324 mgdaily

Stroke andsystemicembolism

MajorBleeding

Apix: 1.6%/yr Aspirin: 3.7%/

yr Apixaban

reduced riskof stroke

Apix: 1.4%/yr Aspirin: 1.2%/yr Not significant

Apix, Apixaban; CHADS 2 , system for scoring thromboembolic risk that assigns points for congestive heart failure, hypertension, age ≥ 75,diabetes mellitus, and prior stroke or transient ischemic attack; Dab, dabigatran; INR, international normalized ratio; Riv, rivaroxaban;Warf, warfarin.

TABLE 39-12

Results of Phase 3 Clinical Trials of New Target-Specific Oral Anticoagulants for Stroke Prevention inNonvalvular Atrial Fibrillation


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placebo), but at a cost of significantly more major bleedingepisodes during both the inpatient and outpatient phases of thetrial (see Table 39-11).

In the ROCKET-AF trial,122 rivaroxaban was compared withwarfarin for stroke prevention in patients with nonvalvularatrial fibrillation (see Table 39-12). Over 14,000 patients receivedeither rivaroxaban 20 mg once daily (15 mg once daily forpatients with a creatinine clearance of 30 to 49 mL/min) orwarfarin (to a target INR of 2.5). Patients comprised a high-riskpopulation with a mean CHADS2 score of approximately 3.5.Rivaroxaban was found to be noninferior to warfarin for theprevention of stroke (ischemic and hemorrhagic) and systemicembolism without causing a significant increase in majorbleeding. The rate of intracranial hemorrhage was significantlydecreased with rivaroxaban, whereas the rate of GI bleeding wassignificantly increased. A significant increase in the rate of isch-emic stroke occurred in the rivaroxaban group at the end of thestudy when patients transitioned from rivaroxaban to warfarin.This increase might have been a result of the trial design, whichincluded a washout period after rivaroxaban was stopped andbefore warfarin was restarted. Many patients took weeks toachieve a therapeutic INR, and anticoagulation remained in the

subtherapeutic range. Nevertheless, this finding caused the U.S.Food and Drug Administration (FDA) to issue a black boxwarning against early discontinuation without direction from ahealth care provider.

Apixaban

Apixaban is a selective direct factor Xa inhibitor administeredtwice daily. It has a 3-hour onset and 8- to 15-hour half-life.106 Approximately 25% of apixaban is eliminated via the kidneywith the rest metabolized by CYP 3A4. Its elimination may beimpaired if it is given with strong CYP 3A4 inhibitors (e.g., keto-conazole, ritonavir). Table 39-8 reviews apixaban’s properties.

Apixaban’s efficacy in VTE prevention following orthopedicsurgery was compared with that of enoxaparin in three phase

3 trials in patients undergoing major orthopedic surgery (seeTable 39-9).123-125 When compared with enoxaparin dosed usingthe European regimen, apixaban proved to be superior in thereduction of VTE, but it failed noninferiority criteria whencompared with enoxaparin dosed according to the North Amer-ican regimen. The rate of major bleeding was either the sameor lower in all studies.

Apixaban is currently being tested in phase 3 clinical trials,which are not yet complete, for prevention of recurrent symp-tomatic VTE in patients with DVT and PE. However, investiga-tors recently completed a phase 3 trial of extended VTEprophylaxis in patients already treated for 6 to 12 months fortheir acute event.125a The AMPLIFY-EXT trial showed that in2,482 patients randomized to apixaban, either 2.5 mg or 5 mg

BID versus placebo, that both apixaban arms achieved a signifi-cant reduction in symptomatic VTE or death from VTE com-pared with palacebo (Table 39-10). There was no sinificantdifference in major bleeding in either of the apixaban armscompared with placebo. Apixaban has also been studied for theprimary prevention of VTE in patients hospitalized for medicalconditions. The ADOPT trial126 (see Table 39-11) showed thatapixaban was as effective in preventing VTE as enoxaparinduring the inpatient stay and reduced symptomatic DVT duringthe outpatient phase compared with placebo. However, apixa-ban was also associated with an increase in major bleedingduring the outpatient phase of treatment.

In the phase 3 ARISTOTLE trial,127 over 18,000 patients withatrial fibrillation and at least one additional risk factor for strokewere randomly allocated to receive either apixaban 5 mg twicedaily (2.5 mg twice daily in patients who met two or more ofthe following criteria: age ≥ 80 years, body weight ≤ 60 kg, orserum creatinine level ≥ 1.5 mg/dL) or dose-adjusted warfarin(target INR of 2.0 to 3.0). This double-blinded, double-dummytrial showed apixaban to be superior to warfarin for preventionof stroke or systemic embolism (see Table 39-12). Patients inthe ARISTOTLE trial had a mean CHADS2 score of 2.1, similarto that of patients in the RE-LY study, but a lower risk of strokeor systemic embolism than patients in the ROCKET-AF trial.The overall rate of stroke in the ARISTOTLE trial was signifi-cantly reduced with apixaban. However, as in ROCKET-AF,when individual components of the primary end point wereexamined, ischemic stroke was not significantly reduced withapixaban, and the reduction in the primary end point was drivenby a significant reduction in the rate of hemorrhagic stroke withapixaban compared with warfarin. The rate of all-cause deathwas also significantly lower with apixaban than with warfarin.These benefits occurred in the apixaban group without anincrease in major bleeding or intracranial hemorrhage.

The AVERROES trial

128

(see Table 39-12) compared apixa-ban with aspirin in patients with atrial fibrillation in whomwarfarin therapy had failed; for whom warfarin was expectedto be unsuitable due to concerns about adherence to the dosingregimen, monitoring schedule, or diet or alcohol restrictions;or for whom the risks outweighed the benefits. Investigatorsin the AVERROES trial studied 5599 patients who were ran-domly allocated to receive either apixaban 5 mg twice daily oraspirin 81 to 324 mg once daily. Apixaban led to a significantreduction in the risk of stroke or systemic embolic events anda reduction in cardiovascular hospitalizations, with no signifi-cant increase in rates of bleeding, including intracranial hemor-rhage. In addition, apixaban seemed to be better tolerated thanaspirin, with a 12% lower rate of permanent discontinuation

and a significantly lower incidence of serious adverse events.Although these efficacy results (compared with aspirin) are notunexpected, the AVERROES trial provides evidence that patientsdeemed to be at too great a risk to receive warfarin therapy canbe treated safely with apixaban.

LIMITATIONS OF THE NEW TARGET-SPECIFICORAL ANTICOAGULANTS

The potentially superior efficacy or safety profiles found inphase 3 studies may not be the only advantages that the neworal anticoagulants possess over warfarin. Their rapid onset ofaction compared with warfarin enables these agents to producean anticoagulant response in the same time frame as the

LMWHs or fondaparinux without the requirement for subcu-taneous administration, which eliminates the need for a two-anticoagulant regimen for the treatment of VTE or the need forbridging therapy before and after invasive procedures. Anotheradvantage is that they do not require routine coagulation moni-toring. The lack of a monitoring requirement can reduce healthcare practitioners’ workloads compared with the managementof warfarin, and because their therapeutic effect is predictableand more stable than that of warfarin, their use may lead tofewer adverse events (from both underanticoagulation andoveranticoagulation) requiring emergency department visitsand hospitalizations.


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desired. Dabigatran can be removed through dialysis, buthis is unlikely to be sufficient or timely in life-threateninbleeding. The other agents are not dialyzable. There are limitedata in animal studies showing that the anticoagulant effecof dabigatran and rivaroxaban can be reversed by infusionof rFVIIa or prothrombin concentrates, especially activateconcentrates, although these agents also have the potential tinduce thrombosis. The topic of reversibility and guidelines foreversal of these agents has recently been reviewed, but at thtime, there is no clear recommendation other than providinthe usual supportive interventions in the event of majohemorrhage.131,132

Finally, warfarin is relatively inexpensive, whereas neweagents will be significantly more expensive. Third-party payemay require prior approval ensuring that patients meet prespecified criteria to receive such new, expensive oral anticoagulants, and patients who are unable to afford their medicationmay sometimes not take them or skip days to extend thesupply.

IMPLICATIONS FOR CLINICAL PRACTICE

How will clinicians translate emerging data on the pros ancons of the target-specific oral anticoagulants into everydayreal-world use? At first, given their limited indications, thimpact of the new agents may be minimal and will depend oan orthopedic surgeon’s level of comfort in using such agentA patient screening process may be put into place involvincareful selection of candidates for treatment with these neagents. Enoxaparin or warfarin will likely continue to be thmainstay of treatment until the results of more phase 3 trials ithe atrial fibrillation and VTE populations are published anshow that the new agents are as safe and effective as warfarinWarfarin will also remain the mainstay of treatment for patienwith mechanical heart valves, since studies in this populatio

are just getting under way. Warfarin may also be favored fotreatment of patients who are considered noncompliant wittherapy and may be preferred as an option for patients whexperience treatment failure or experience an event while takinone of the new agents. Finally, patients taking warfarin who aclinically defined as “nonresponders” or who have difficultmaintaining a stable INR on warfarin may be ideal candidatefor treatment with a new oral anticoagulant, but only if the INinstability is not due to poor compliance. Certainly, convenience of therapy will be a major motivating factor in changinto a new, nonmonitored anticoagulant drug.

Despite their advantages, these agents also have potentialdisadvantages.129 The short half-lives of the new agents in com-bination with the fact that they do not require routine coagula-tion monitoring makes the issue of medication adherenceextremely important. Studies show that approximately 50% ofpatients fail to follow their prescribed medication regimens.130 Poor adherence to warfarin therapy is noted to be associatedwith poor anticoagulation control, but missing a dose or two ofwarfarin only lowers the INR given warfarin’s long half-life,whereas missing a dose or two of a new agent will bring theindividual back to a near-normal coagulation status.

INR monitoring for warfarin therapy may be bothersome,but frequent visits allow the provider to deliver patient educa-tion and also to detect problems at an earlier stage. Without asimple assay to measure the effects of the newer agents, onecannot tailor therapy in patients who have a higher or lowerbleeding risk as is often done with warfarin. The absence of agood monitoring assay prevents the clinician from assessingdrug effect in emergent situations such as in major bleeding,emergent surgery, or trauma. Similarly, failure of therapy cannotbe easily evaluated to determine whether it is due to poor com-pliance or drug failure. Dosing adjustments for renal or hepatic

failure (if needed) are difficult without a monitoring assay. Toassess drug effect, the thrombin time is a sensitive measure fordabigatran, and a normal thrombin time assures that very little,if any, drug is on board. A dilute thrombin time assay is beingdeveloped for clinical use. The dabigatran package insert rec-ommends the use of partial thromboplastin time; this test isreadily available at all hospitals and the result has some linearcorrelation with dabigatran levels, but it is generally imprecise.For rivaroxaban or apixaban, a specially calibrated anti–factorXa assay reflect drug effect, but such assays are not readily avail-able. There are no other recommended assays for these agents.Given the short half-lives of the thrombin and factor Xa inhibi-tors, determining the time of the last dose is important in esti-mating remaining drug effect, provided renal function is not

impaired.These drugs do not have readily available reversal agents,and the treatment of major bleeding remains a problem. Giventhat they have short half-lives compared with warfarin, drugconcentrations will decline rapidly when the drug is withheld,which may be all that is needed in cases of mild bleeding. Renalfunction is an important factor in determining drug half-lifefor dabigatran but is less so for rivaroxaban and apixaban. Thetime of the last dose is an important consideration in an emer-gent situation. In cases of serious or life-threatening bleedingor the need for emergent surgery rapid reversibility would be

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