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Table 11-5

Approved Dosing of the DOACs for AF and VTE

Atrial Fibrillation

a VTE Treatment

Dabigatran CrCl > 30 mL/minute: 150 mg

BID

CrCl 30–50 mL/minute on

dronedarone or ketoconazole:

decrease to 75 mg BID

CrCl 15–30 mL/minute: 75 mg

BID or avoid if on P-gp inhibitor

CrCl < 15 mL/minute or on

dialysis: dosing

recommendations cannot be

provided

CrCl > 30 mL/minute: LMWH or UFH × 5–10 days

then dabigatran 150 mg BID

CrCl < 50 mL/minute and on P-gp inhibitor: avoid

coadministration

CrCl ≤ 30 mL/minute or on dialysis: dosing

recommendations cannot be provided

Extended treatment to prevent VTE recurrence (CrCl

> 30 mL/minute): 150 mg BID

Rivaroxaban Dosed with evening meal:

CrCl > 50 mL/minute: 20 mg

daily

CrCl 15–50 mL/minute: 15 mg

CrCl ≥ 30 mL/minute: 15 mg BID × 21 days then 20

mg daily

CrCl < 30 mL/minute: avoid

Extended treatment to prevent VTE recurrence: 20 mg

daily

CrCl < 15 mL/minute: avoid

daily

Apixaban Most patients: 5 mg BID

Any two of the following: 2.5mg

BID:

SCr ≥ 1.5mg/dL

Age ≥ 80 years

Weight ≤ 60 kg

10 mg BID × 7 days then 5 mg BID

No dose adjustment recommended for renal function

b

Extended treatment to prevent VTE recurrence: 2.5

mg BID

Strong dual inhibitors of CYP3A4 and p-glycoprotein

(P-gp): reduce dose by 50% if taking 5 mg or 10 mg

If already taking 2.5 mg BID: avoid use

Dual P-gp inducers and strong CYP3A4 inducers:

avoid concomitant use

Edoxaban CrCl > 95 mL/minute: do not

use

CrCl > 50–95 mL/minute: 60 mg

daily

CrCl 15–50 mL/minute: 30 mg

daily

CrCl < 15 mL/minute: use is not

recommended

CrCl > 50 mL/minute: LMWH or UFH × 5–10 days

then edoxaban 60 mg daily

CrCl 15–50 mL/minute: 30 mg daily

CrCl < 15 mL/minute: use is not recommended

Pts ≤ 60 kg or on P-gp inhibitors: 30 mg daily

aDOACs are only indicated for nonvalvular AF.

bPatients with CrCl < 25 mL/minute excluded from clinical trials for apixaban.

BID, twice daily.

Source: Pradaxa (dabigatran) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2017;

Xarelto (rivaroxaban) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2017; Eliquis (apixaban)

[package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2017; Savaysa (edoxaban) [package insert].

Parsippany, NJ: Daiichi Sankyo; 2017.

Table 11-6

Drug Interactions with the DOACs

Drug Recommendation

Dabigatran P-gp inhibitors: Reduced dose recommended with CrCl 30–50 mL/min and

ketoconazole or dronedarone CrCl 15–30 mL/minute: AVOID concomitant

use

P-gp inducers: AVOID concomitant use with rifampin

Rivaroxaban P-gp inhibitors and strong CYP3A4 inhibitors: Avoid concomitant use (e.g.,

ketoconazole, itraconazole, ritonavir, indinivir, conivaptan)

P-gp inducers and strong CYP3A4 inducers: Avoid concomitant use (e.g.,

carbamazepine, phenytoin, rifampin, St. John’s wort)

Apixaban P-gp inhibitors and strong CYP3A4 inhibitors: Reduced dose recommended, or

avoid concomitant use if currently on lowest dose (2.5mg)

P-gp inducers and strong CYP3A4 inducers: Avoid concomitant use (e.g.,

carbamazepine, phenytoin, rifampin, St. John’s wort)

Edoxaban P-gp inhibitors (e.g., verapamil, quinidine, azithromycin, clarithromycin,

erythromycin, itraconazole, or ketoconazole)

AF: No dose reduction is recommended

VTE: Reduced dose recommended

P-gp inducers: AVOID concomitant use with rifampin

Betrixaban P-gp inhibitors (e.g., amiodarone, azithromycin, verapamil, ketoconazole,

clarithromycin)

Medical prophylaxis: Reduced dose recommended

P-gp inducers: no warnings at this time

Source: Pradaxa (dabigatran) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc., 2017;

Xarelto (rivaroxaban) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc., 2017; Eliquis (apixaban)

[package insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2017; Savaysa (edoxaban) [package insert].

Parsippany, NJ: Daiichi Sankyo, 2017; BEVYXXA (betrixaban) [package insert]. South San Francisco, California:

Portola Pharmaceuticals, Inc., 2017.

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Table 11-7

Pharmacologic and Clinical Properties of Injectable Direct Thrombin Inhibitors

Bivalirudin Argatroban

Route of administration IV IV

FDA-approved indication Patients with UA undergoing PTCA;

PCI with provisional use of GPI;

patients with or at risk of HIT/HITTS

undergoing PCI

Treatment of thrombosis in patients

with HIT; patients at risk for HIT

undergoing PCI

Binding to thrombin Partially reversible at catalytic site

and exosite-1

Reversible at catalytic site

Half-life in healthy subjects 25 minutes 40–50 minutes

Monitoring aPTT/ACT

SCr/CrCl

aPTT/ACT

Liver function

Clearance Enzymatic (80%)

Renal (20%)

Hepatic

Antibody development May cross-react with antihirudin

antibodies

No

Effect on INR Slight increase Increase

Initial dose for HIT No bolus

Infusion: 0.15 mg/kg/hour

No bolus

Infusion: 2 mcg/kg/minute

a

In critically ill patients: consider lower

infusion rate of 0.2–1 mcg/kg/minute

Initial dose for PCI Bolus: 0.75 mg/kg

Infusion: 1.75 mg/kg/hour

Bolus: 350 mcg/kg

Infusion: 25 mcg/kg/minute

a

In some cases, an initial infusion rates of < 1.5 mcg/kg/minute may be more appropriate.

ACT, activated clotting time; aPTT, activated partial thromboplastin time; BID, twice daily; CrCl, creatinine

clearance; GPI, glycoprotein IIb-IIIa inhibitor; HD, hemodialysis; HIT, heparin-induced thrombocytopenia; HITTS,

heparin-induced thrombocytopenia and thrombosis syndrome; IV, intravenous; PCI, percutaneous coronary

intervention; PTCA, percutaneous transluminal coronary angioplasty; SC, subcutaneous; SCr, serum creatinine;

UA, unstable ang

ngina.

Figure 11-3 Mechanism of action of warfarin.

Table 11-8

Elimination Half-lives of Vitamin K-Dependent Clotting Factors

Clotting Factor Half-Life (hours)

II 42–72

VII 4–6

IX 21–30

X 27–48

Protein C 9

Protein S 60

Warfarin is rapidly and completely absorbed in the upper gastrointestinal (GI)

tract by passive diffusion, with nearly 100% bioavailability. Peak absorption of

warfarin occurs in 60 to 120 minutes. It is approximately 99% bound to serum

albumin. The volume of distribution for warfarin is 12.5% of body weight. This

small volume of distribution is consistent with the extensive binding of warfarin to

albumin. The primary laboratory test for monitoring warfarin therapy is the

prothrombin time (PT). No correlation appears to exist between PT and the dose of

warfarin, the total warfarin concentration, or the free warfarin concentration for any

population of treated patients, although in individual patients an increasing dose of

warfarin will increase the serum concentration (free and total) and the PT.

Warfarin is administered orally as a racemic mixture containing equal parts of the

enantiomers R(+)-warfarin and S(−)- warfarin. The S(−)-isomer is 2.7 to 3.8 times

more potent as an anticoagulant than the R(+)-isomer, has a longer elimination halflife, and is primarily metabolized by CYP2C9. Comparatively, R(+)-warfarin is

metabolized primarily by CYP1A2 and CYP3A4. Many drugs interact with warfarin

by stereoselectively inhibiting the metabolism of either the R(+)-isomer or the S(−)-

isomer (see Drug Interactions section).

Genetic expression of CYP2C9 influences the rate of metabolism of warfarin and

thus impacts dosing requirements to meet a particular therapeutic end point.

7

Variability in genetic expression of VKORC1 (the C1 subunit on the gene that codes

for VKOR) also influences dosing requirements in patients taking warfarin. Genetic

testing for CYP2C9 genotype and VKORC1 haplotype can be incorporated with

clinical and demographic information to predict warfarin dose requirements in

individual patients, using dosing algorithms that have

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been developed and investigated. A practical example is available online at

www.warfarindosing.org. Routine pharmacogenomic testing of warfarin is not

currently endorsed at this time.

Tests Used to Monitor Antithrombotic Therapy

Before the initiation of any antithrombotic therapy, an assessment of baseline

hemostatic status is necessary. The clinician should obtain a baseline platelet count

and hemoglobin (Hgb) and/or hematocrit (Hct), as well as evaluate the baseline

integrity of the extrinsic and intrinsic coagulation pathways with PT and aPTT, the

tests used to monitor warfarin and heparin, respectively. The DOACs do not require

routine monitoring of laboratory tests to monitor their efficacy; however, because

they have different doses based on renal function, baseline CrCl is needed with these

agents.

PROTHROMBIN TIME/INTERNATIONAL NORMALIZED RATIO

The PT is prolonged by deficiencies of clotting factors II, V, VII, and X, as well as

by low levels of fibrinogen and very high levels of heparin. It reflects alterations in

the extrinsic and common pathways of the clotting cascade, but not in the intrinsic

system.

8 The PT is measured by adding calcium and tissue thromboplastin to a

sample of plasma from which platelets have been removed by centrifugation. The

time to clot formation is detected by automated instruments using light scattering

techniques that measure optical density. The mean normal PT, obtained by averaging

a number of PT results from nonanticoagulated subjects, is approximately 12 seconds

for most reagents.

The thromboplastins used in PT monitoring are extracted from various tissue

sources by a number of techniques and prepared for commercial use as reagents.

Unfortunately, thromboplastins are not standardized among manufacturers or among

batches of reagent produced by the same manufacturer, leading to significant

variability in PT results for anticoagulated patients. To standardize PT results, the

World Health Organization developed a system by which all commercially available

thromboplastins are compared with an international reference thromboplastin and

then assigned an international sensitivity index (ISI). This value is used to

mathematically convert PT to the international normalized ratio (INR) by

exponentially multiplying the PT ratio to the power of the ISI of the thromboplastin

being used in the laboratory to measure the test:

The ISI of the international reference thromboplastin is 1.0.

The INR is the internationally recognized standard for monitoring warfarin

therapy.

9 Current recommendations for intensity of oral anticoagulation therapy for

accepted clinical indications are summarized in Table 11-9. Regular intensity

therapy is defined as dosing warfarin to reach a goal INR of 2.5 (range, 2.0–3.0) and

is appropriate for most settings that require the prevention and/or treatment of

thromboembolic disease. High-intensity therapy is used in mechanical valve

replacement and certain situations of thromboembolic recurrence, despite adequate

anticoagulation, and is defined as dosing warfarin to reach a goal INR of 3.0 (range,

2.5–3.5).

ACTIVATED PARTIAL THROMBOPLASTIN TIME

The aPTT reflects alterations in the intrinsic pathway of the clotting cascade and is

used to monitor heparin and injectable direct thrombin inhibitors.

8,9 The test is

performed by adding a surface-activating agent (kaolin or micronized silica), a

partial thromboplastin reagent (phospholipid; platelet substitute), and calcium to the

plasma sample. Mean normal values vary among reagents, but typically fall between

24 and 36 seconds.

Like PT, the aPTT is a highly variable test based on differences among

commercially available partial thromboplastin reagents. However, a system

equivalent to the INR has not been developed for standardization of aPTT results.

Heparinization to prolong the aPTT to 1.5 to 2.5 times the mean normal value

historically was considered adequate to prevent propagation or extension of

thrombus, but is no longer recommended because it is not appropriate for all reagents

and testing systems. Instead, the aPTT should be calibrated for each reagent lot and

coagulometer, and a reagent-specific therapeutic range in seconds should be

determined that corresponds to therapeutic heparin levels of 0.3 to 0.7 international

units/mL by factor Xa inhibition (anti-Xa activity).

3,9 For direct thrombin inhibitors,

the same aPTT goal range is used.

Hospital-based and independent clinical laboratories that offer aPTT monitoring

will report the reagent-specific therapeutic range in seconds and adjust it as new

reagents are purchased and used clinically.

ANTI-FACTOR Xa ACTIVITY

Although LMWHs do not require coagulation monitoring to ensure an appropriate

antithrombotic effect or to adjust dosing, certain clinical situations may require

assessment of the anti-factor Xa activity of LMWHs.

3 Because these agents are

eliminated renally, patients with renal failure may accumulate LMWHs, leading to an

increased risk of hemorrhagic complications. Evaluation of trough anti-factor Xa

activity at the end of the dosing interval can assess this accumulation of effect.

LMWHs are dosed according to total body weight, but clinical trials have included

only limited numbers of obese patients. Therefore, it may be appropriate to monitor

anti-factor Xa activity in patients who weigh more than 150 kg. Anti-factor Xa

activity may also be evaluated in patients who experience unexpected bleeding

complications secondary to anticoagulation with LMWHs, and in pregnant patients in

whom LMWHs are used for treatment or prevention of thrombosis.

Anti-factor Xa activity is measured using a chromogenic assay. If peak activity

levels are used to assess dosing in obese and pregnant patients, they should be

obtained once the patient has reached steady state, typically after three or four doses

of LMWH. The anti-factor Xa level should be drawn approximately 4 hours after a

SC dose of LMWH, with empiric dosing adjustments to maintain a level of roughly

0.5 to 1.0 international units/mLfor therapeutic anticoagulation given every 12 hours,

and slightly higher peaks up to 1.5 for therapeutic doses given every 24 hours.