PL Detail-Document #290407

This PL Detail-Document gives subscribers

additional insight related to the Recommendations published in

PHARMACISTS LETTER / PRESCRIBERS LETTER

April 2013

Off-Label Use of the Newer Anticoagulants

The recent proliferation of oral anticoagulants means that for the first time, there are effective oral alternatives to warfarin. These newer
anticoagulants are all approved for stroke prevention in patients with nonvalvular atrial fibrillation. In addition, rivaroxaban (Xarelto) is approved to
prevent VTE after hip or knee replacement, and for VTE treatment/prevention of recurrence. In Canada, dabigatran (Pradaxa) and apixaban (Eliquis)
are also approved for VTE prevention after hip or knee replacement. However, it may be tempting to use them for other indications. In many cases
this isnt appropriate. The chart below provides information on the off-label uses of most interest. If a newer anticoagulant is used for an off-label
indication, it would be prudent to heed the same contraindications and precautions as for labeled indications. See our PL Chart, Comparison of Oral
Antithrombotics, for additional information on these agents.
Abbreviations: INR = international normalized ratio; N/A = not applicable; PE = pulmonary embolism; VTE = venous thromboembolism
Drug
Use
Dose
Comments
Apixaban
VTE prevention post-hip or knee 2.5 mg twice daily for 32 to 38 days
Health Canada approved indication.
(Eliquis)
replacement (off-label, U.S.)
(hip) or 10 to 14 days (knee), starting
At least as effective as enoxaparin for preventing
12 to 24 hrs post-op1
VTE, with comparable bleeding [Evidence level
A; high-quality RCT].2,3

Continued

VTE prevention after initial

treatmentb

2.5 mg twice daily16

Reduces risk of symptomatic recurrent VTE or

death (combined endpoint) vs placebo [Evidence
level A; high-quality RCT].16

Prosthetic heart valve requiring

anticoagulation

N/A

May not provide adequate anticoagulation for this

use.1 Not recommended.1,11

Bridging (i.e., when warfarin

started/restarted or held pre-op)

N/A

Efficacy and safety evidence lacking for this use.

Dose unknown.
Can increase INR, making it hard to tell when
warfarin is therapeutic.1,11
Must discontinue at least 24 hours pre-op.14
More. . .

Copyright 2013 by Therapeutic Research Center

3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com

(PL Detail-Document #290407: Page 2 of 4)

Drug
Apixaban,
continued

Use
Acute coronary syndrome (with
antiplatelet therapy)

Dose
N/A

Comments
Increases bleeding without improving outcomes.8

Dabigatran
(Pradaxa)

VTE prevention post-hip or knee

replacement (off-label, U.S.)

220 mg once daily x 10 days (knee) or

28 to 35 days (hip).a If started 1 to 4 hrs
post-op, initial dose is 110 mg. Consider
150 mg once daily for patients over 75
years, with initial dose of 75 mg if
started 1 to 4 hrs post-op.4
150 mg twice daily for six months17

Health Canada approved indication.

Comparable to enoxaparin for prevention of VTE
& mortality (combined endpoint). Comparable
major bleeding [Evidence level A; high-quality
RCT].5-7

VTE prevention after initial

treatmentb

150 mg twice daily

Prosthetic heart valve requiring

anticoagulation

N/A

Comparable to warfarin for prevention of

recurrent symptomatic VTE or VTE death
(combined endpoint). Comparable major
bleeding [Evidence level A; high-quality RCT].18
Less effective than warfarin, with increased
bleeding risk.4,12 Contraindicated.4,12

Bridging (i.e., when warfarin

started/restarted or held pre-op)

N/A

Efficacy and safety evidence lacking for this

indication.
Dose unknown.
Can increase INR, making it hard to tell when
warfarin is therapeutic.4,12
Must discontinue at least 24 hours pre-op.14

VTE prevention in medical

patientsb

10 mg once daily for 35 days13

A little more effective than enoxaparin 40 mg

once daily for 10 days, but with higher bleeding
risk, so no overall benefit compared to enoxaparin
[Evidence level A; high-quality RCT].13

VTE initial treatmentb

Rivaroxaban
(Xarelto)

Comparable to warfarin for prevention of

recurrent symptomatic VTE or VTE death
(combined endpoint). Comparable major
bleeding [Evidence level A; high-quality RCT].17

Continued
More. . .
Copyright 2013 by Therapeutic Research Center
3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com

(PL Detail-Document #290407: Page 3 of 4)

Drug
Rivaroxaban,
continued

Use
PE treatment/prevention of
recurrence (off-label, Canada)

Dose
15 mg twice daily x 3 weeks, then 20 mg
once daily, with food to improve
absorption15

Prosthetic heart valve requiring

anticoagulation
Bridging (i.e., when warfarin
started/restarted or held pre-op)

N/A

Acute coronary syndrome (with

antiplatelet therapy)

2.5 mg twice daily plus low-dose aspirin

and clopidogrel

N/A

Comments
Comparable to enoxaparin/warfarin for
prevention of recurrent VTE, with lower rate of
major bleeding [Evidence level A; high-quality
RCT].21
May not provide adequate anticoagulation for this
indication.9 Not recommended.9
Efficacy and safety evidence lacking for this
indication.
Dose unknown.
Can increase INR, making it hard to tell when
warfarin is therapeutic.9,15
Must discontinue at least 24 hours pre-op.14
Might improve survival, but risk of major
bleeding is increased [Evidence level A; highquality RCT].10
Avoid, pending additional information.

a. 110 mg capsule not available in U.S.

b. Studies of these agents for VTE management specifically in patients with cancer or hypercoagulable disorders are lacking, although small
numbers of such patients were included in the clinical trials.13,16-21

Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making
clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national
organizations. Information and internet links in this article were current as of the date of publication.

More. . .
Copyright 2013 by Therapeutic Research Center
3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com

(PL Detail-Document #290407: Page 4 of 4)

7.

Levels of Evidence
In accordance with the trend towards Evidence-Based
Medicine, we are citing the LEVEL OF EVIDENCE
for the statements we publish.
Level
A

C
D

Definition
High-quality randomized controlled trial (RCT)
High-quality meta-analysis (quantitative
systematic review)
Nonrandomized clinical trial
Nonquantitative systematic review
Lower quality RCT
Clinical cohort study
Case-control study
Historical control
Epidemiologic study
Consensus
Expert opinion
Anecdotal evidence
In vitro or animal study

8.

9.
10.

11.
12.

13.

Adapted from Siwek J, et al. How to write an evidence-based clinical

review article. Am Fam Physician 2002;65:251-8.

14.

Project Leader in preparation of this PL DetailDocument: Melanie Cupp, Pharm.D., BCPS

15.

References

16.

1.
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3.

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Cite this document as follows: PL Detail-Document, Off-Label Use of the Newer Anticoagulants. Pharmacists
Letter/Prescribers Letter. April 2013.

Evidence and Recommendations You Can Trust

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Copyright 2013 by Therapeutic Research Center

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