Approved Dosing of the DOACs for AF and VTE
Dabigatran CrCl > 30 mL/minute: 150 mg
BID or avoid if on P-gp inhibitor
CrCl > 30 mL/minute: LMWH or UFH × 5–10 days
CrCl < 50 mL/minute and on P-gp inhibitor: avoid
CrCl ≤ 30 mL/minute or on dialysis: dosing
recommendations cannot be provided
Extended treatment to prevent VTE recurrence (CrCl
Rivaroxaban Dosed with evening meal:
CrCl ≥ 30 mL/minute: 15 mg BID × 21 days then 20
Extended treatment to prevent VTE recurrence: 20 mg
Apixaban Most patients: 5 mg BID
Any two of the following: 2.5mg
10 mg BID × 7 days then 5 mg BID
No dose adjustment recommended for renal function
Extended treatment to prevent VTE recurrence: 2.5
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:
Edoxaban CrCl > 95 mL/minute: do not
CrCl < 15 mL/minute: use is not
CrCl > 50 mL/minute: LMWH or UFH × 5–10 days
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.
Parsippany, NJ: Daiichi Sankyo; 2017.
Drug Interactions with the DOACs
Dabigatran P-gp inhibitors: Reduced dose recommended with CrCl 30–50 mL/min and
ketoconazole or dronedarone CrCl 15–30 mL/minute: AVOID concomitant
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
P-gp inducers: AVOID concomitant use with rifampin
Betrixaban P-gp inhibitors (e.g., amiodarone, azithromycin, verapamil, ketoconazole,
Medical prophylaxis: Reduced dose recommended
P-gp inducers: no warnings at this time
Portola Pharmaceuticals, Inc., 2017.
Pharmacologic and Clinical Properties of Injectable Direct Thrombin Inhibitors
FDA-approved indication Patients with UA undergoing PTCA;
PCI with provisional use of GPI;
patients with or at risk of HIT/HITTS
Treatment of thrombosis in patients
with HIT; patients at risk for HIT
Binding to thrombin Partially reversible at catalytic site
Half-life in healthy subjects 25 minutes 40–50 minutes
Antibody development May cross-react with antihirudin
Effect on INR Slight increase Increase
In critically ill patients: consider lower
infusion rate of 0.2–1 mcg/kg/minute
Initial dose for PCI Bolus: 0.75 mg/kg
In some cases, an initial infusion rates of < 1.5 mcg/kg/minute may be more appropriate.
Figure 11-3 Mechanism of action of warfarin.
Elimination Half-lives of Vitamin K-Dependent Clotting Factors
Clotting Factor Half-Life (hours)
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
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.
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
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
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
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
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
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,
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.
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
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.
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.
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.
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