PHARMACOLOGY FACTS

Rivaroxaban: A New Oral AnticoagulantJulie Golembiewski, PharmD

UNTIL RECENTLY, WARFARIN was the only oral

anticoagulant available in the United States. Indica-

tions for warfarin therapy include reducing the

risk of systemic embolism (deep vein thrombosisand pulmonary embolism) in patients with a bio-

prosthetic or mechanical heart valve or atrial fibril-

lation. Warfarin exerts its anticoagulant effect by

inhibiting the production of vitamin K-dependent

coagulation factors. Warfarin has a highly variable

dose response and a narrow therapeutic index,

necessitating frequent monitoring of the interna-

tional normalized ratio (INR).

In October 2010, dabigatran (Pradaxa; Boehringer

Ingelheim Pharmaceuticals Inc., Ridgefield, CT)

was approved by the US Food and Drug Adminis-

tration (FDA) for the prevention of stroke and

systemic thromboembolism in patients with non-

valvular atrial fibrillation. In 2011, rivaroxaban

(Xarelto; Janssen Pharmaceuticals, Inc., Titusville,NJ) received FDA approval for the prophylaxis of

deep vein thrombosis in patients undergoing

knee or hip replacement surgery (July 2011) and

to reduce the risk of stroke and systemic embolism

in patients with nonvalvular atrial fibrillation

(November 2011). These new oral anticoagulants

differ from warfarin (and from each other) in their

mechanism of action and clinical pharmacology.

Blood coagulation and thrombus formation occur

when soluble fibrinogen is converted into insoluble

fibrin. The coagulation process begins when injury

to the smooth muscle of the vessel exposes tissue

factor (TF), which then binds to the circulating fac-

Julie Golembiewski, PharmD, Clinical Associate Professor,

Department of Anesthesiology, University of Illinois Hospi-

tal & Health Sciences System, Chicago, IL.

Conflict of interest: None to report.

Address correspondence to JulieGolembiewski, Department

of Anesthesiology, University of Illinois Hospital & Health Sci-

ences System, 1740West Taylor Street, Suite 3200,MC515, Chi-

cago, IL 60612-7239; e-mail address: jgolemb@uic.edu.

� 2012 by American Society of PeriAnesthesia Nurses

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doi:10.1016/j.jopan.2012.01.007

Journal of PeriAnesthesia Nursing, Vol 27, No 2 (April), 2012: pp 123-126

tor VII. The activated TF VII complex catalyzes the

activation of factor IX and factor X. Activated factor

Xcleavesprothrombin (factor II) to generate throm-

bin (factor IIa). These first traces of thrombin acti-vate factor V and factor VIII (on the surface of

circulating platelets) and the formation of a pro-

thrombinase complex. This prothrombinase com-

plex amplifies the conversion of prothrombin to

thrombin. Thrombin converts fibrinogen to fibrin,

which is cross-linked into fibrin strands that (with

platelets) form a blood clot.1-4 Warfarin exerts its

anticoagulant effect by inhibiting all of the vitaminK-dependent clotting factors (factors II, VII, IX,

and X). However, the new oral anticoagulants in-

hibit only one coagulation factor in the common

coagulation pathway. Rivaroxaban is a direct fac-

tor Xa inhibitor, whereas dabigatran is a direct

thrombin inhibitor (Figure 1). Drugs that affect

these specific targets (inhibition of factor Xa or

thrombin formation) in the coagulation processcan provide safe and effective anticoagulation.3,4

Rivaroxaban has good oral bioavailability, with its

peak effect occurring 2 to 4 hours after ingestion.

Its elimination half-life is long enough to provide

a pharmacologic effect for 24 hours (eg, once daily

dosing) for its current FDA-approved indications.

Rivaroxaban is hepatically metabolized (to inactivemetabolites) and approximately one-third is re-

nally excreted unchanged. Patients receiving rivar-

oxaban for nonvalvular atrial fibrillation who have

renal impairment (creatinine clearance [CrCl]: 15

to 50 mL/minute) should receive a lower dose. Ri-

varoxaban should be avoided in patients with CrCl

less than 15 or 30 mL/minute (depending on the

indication) and in patients with moderate or se-vere hepatic impairment or hepatic disease associ-

ated with coagulopathy. Drug interactions with

rivaroxaban are few and generally not significant,

with the exception of drugs that are potent cyto-

chrome (CYP) 3A4 inducers or inhibitors. Coad-

ministration of potent CYP3A4 inhibitors, such

as azole antifungals (eg, itraconazole) or antiretro-

viral protease inhibitors (eg, ritonavir), can in-crease the plasma levels of rivaroxaban (owing to

123

Vessel Injury

Tissue Factor / Factor VIIa

Factor X Factor IX

Factor Xa

Factor IXa

Factor II (prothrombin)

First traces of thrombin activation of platelets, factor V, factor VIII, and prothrombinase formation amplification of thrombin formation

Factor IIa (thrombin)

Fibrinogen Fibrin

Factor Va DABIGATRAN

(direct inhibition of thrombin)

RIVAROXABAN

(direct inhibition of Factor Xa)

Figure 1. The coagulation cascade and sites of action of the new oral anticoagulants. This figure is available in

color online at www.jopan.org.

124 JULIE GOLEMBIEWSKI

inhibition of its hepatic metabolism). However, co-

administration of potent CYP3A4 inducers, such as

phenytoin or carbamazepine can lower the plasma

concentration (and effectiveness) of rivaroxaban(Table 1).4-8

The most common adverse effects of rivaroxaban

are bleeding complications. In the trial that com-

pared rivaroxaban with warfarin to reduce the

risk of stroke and systemic embolism in nonvalvu-

lar atrial fibrillation (ROCKET AF trial), the

incidence of bleeding complications from rivarox-aban was approximately 4%.5 In the trials that

compared rivaroxaban with enoxaparin for pro-

phylaxis of deep vein thrombosis following hip or

knee replacement surgery (RECORD 1-4 trials),

the incidence of any bleeding complication from

rivaroxaban was approximately 5%. The incidence

of major bleeding complications was 0.1% to 0.7%,

with most occurring during the first week aftersurgery.5,8

Routine laboratory monitoring while receiving ri-

varoxaban is not necessary. Routine coagulation

tests, such as the prothrombin time (PT), acti-

vated partial thrombin time (PTT), and INR are

not appropriate for measurement of rivaroxaban

activity. Rivaroxaban may prolong the PT and

PTT, but that effect is short-lived and occurs

only if measured at the peak effect of rivaroxaban.The best method for determining plasma rivarox-

aban concentrations appears to be an antifactor

Xa assay.10,11

Rivaroxaban should be stopped at least 24 hours be-

fore an invasive procedure as the risk of bleeding

from the procedure warrants discontinuation of an-

ticoagulation.5,12 Performing an epidural or spinalpuncture in a patient receiving rivaroxaban places

the patient at risk for developing an epidural or

spinal hematoma. If an epidural catheter is placed,

removal of the catheter and administration of the

next dose of rivaroxaban must be appropriately

timed. Removal of the catheter should occur when

only 25% of circulating rivaroxaban remains (eg, at

least 18 hours after the last dose) and the nextdose of rivaroxaban administered at an interval

long enough for adequate hemostasis to occur (eg,

at least 6 hours after catheter removal) (Table 2).13

Like dabigatran, rivaroxaban may be an alternative

to warfarin in select patients. Advantages of

Table 1. Properties of Rivaroxaban and Dabigatran*

Property Rivaroxaban Dabigatran

Mechanism of action Direct factor Xa inhibitor Direct thrombin inhibitor

Route of administration Oral Oral

Peak effect 2 to 4 h 2 h

Half-life 5 to 9 h (9 to 13 h in elderly patients) 12 to 17 h

Route of elimination 60% Hepatic 80% Renal

36% Renal (unchanged) 20% Fecal/biliary

Dosing Once daily Twice daily

Dosing adjustments For nonvalvular atrial fibrillation:

Reduce dose if CrCl is 15 to 50 mL/

min; not recommended if CrCl is

less than 15 mL/min or for patients

with moderate-to-severe hepatic

impairment or hepatic disease

associated with coagulopathy

Reduce dose if CrCl is 15 to 30 mL/

min; not recommended if CrCl is

less than 15 mL/min

For postoperative

thromboprophylaxis: use with

caution if CrCl is 30 to 50 mL/min;

avoid if CrCl is less than 30 mL/min

Drug interactions Strong CYP3A4 inducers or inhibitors

may lower or raise (respectively)

the plasma concentration of

rivaroxaban

Drugs that induce or inhibit

P-glycoprotein

Risk of bleeding Yes Yes

Routine coagulation monitoring None needed None needed

Specific antidote for bleeding None None

CrCl, creatinine clearance; CYP, cytochrome.

*Based on data from references 3-9.

PHARMACOLOGY FACTS 125

rivaroxaban over warfarin include the lack of rou-

tine coagulation monitoring, as well as minimal

drug-drug interactions and drug-food interactions.

Disadvantages of rivaroxaban include its shorter

Table 2. Perioperative Consid

Discontinuation of rivaroxaban before an invasive pro

Stop rivaroxaban for at least 24 h before the procedure if disc

Rivaroxaban and regional anesthesia/analgesia5,13

Spinal anesthesia

� Not indicated in patients in whom rivaroxaban was not app

� Atraumatic spinal: may administer first dose of rivaroxaban

� Traumatic puncture: wait 24 h to administer first dose of ri

Epidural anesthesia/analgesia

� Not indicated in patients in whom rivaroxaban was not app

� Remove epidural catheter or deep nerve block catheter at le

of rivaroxaban should be given at least 6 h after removal of

� If a traumatic puncture occurs, wait at least 24 h to admini

symptoms

half-life and lack of a standardized method of coag-

ulation monitoring. Missing one dose of rivaroxa-

ban may result in insufficient anticoagulation and

when dose adjustments are made, the effect of

erations for Rivaroxaban

cedure5,12

ontinuation of anticoagulation is indicated

ropriately discontinued before spinal puncture

6 to 8 h after wound closure

varoxaban

ropriately discontinued before epidural placement

ast 18 h after the last dose of rivaroxaban. The next dose

the epidural catheter

ster rivaroxaban; monitor for neurological signs and

126 JULIE GOLEMBIEWSKI

the adjustment cannot be easily measured. In sum-

mary, rivaroxaban is a new oral anticoagulant that

may be a more predictable, reliable, and safer alter-

native to warfarin in select patients.

References

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and antiplatelet drugs. In: Bruton BA, Knollman BC, eds. Good-

man & Gilman’s The Pharmacological Basis of Therapeutics,

12e. Chapter 30. China: The McGraw-Hill Companies, Inc;

2011. Available at: http://www.accesspharmacy.com/content

.aspx?aID516668944.

2. Poon BP, Widmer C, Prvemer J. Coagulation disorders. In:

DiPiro J, Talbert RL, YeeGC, et al, eds. Pharmacotherapy: A Path-

ophysiologic Approach, 8e. Chapter 110. China: The McGraw-

Hill Companies, Inc; 2011. Available at: http://www.accessphar

macy.com/content.aspx?aID58000061.

3. Hankey GJ, Eikelboom JW. Dabigatranetexilate: A new oral

thrombin inhibitor. Circulation. 2011;123:1436-1450.

4. Samama MM. The mechanism of action of rivaroxaban—

an oral, direct factor Xa inhibitor—compared with other antico-

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5. Xarelto. Product Information. Titusville, NJ: Janssen

Pharmaceuticals, Inc; 2011.

6. Perzborn E, Roehrig S, Straub A, et al. Rivaroxaban: A new

oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol. 2010;

30:376-381.

7. Potpara TS, Lip GYH. New anticoagulation drugs

for atrial fibrillation. Clin Pharmacol Ther. 2011;90:

502-506.

8. Chen T, Lam S. Rivaroxaban. An oral direct factor Xa inhib-

itor for the prevention of thromboembolism.Cardiol Rev. 2009;

17:192-197.

9. Pradaxa. Product Information. Ridgefield, CT: Boeh-

ringer Ingelheim Pharmaceuticals, Inc; 2010.

10. Gross PL, Weitz JI. New anticoagulants for treatment

of venous thromboembolis. Arterioscler Thromb Vasc Biol.

2008;28:380-386.

11. Lindhoff-Last E, Samama MM, Ortel TL, et al. Assays for

measuring rivaroxaban: Their suitability and limitations. Ther

Drug Monit. 2010;32:673-679.

12. Eikelboom JW, Weitz JI. New oral anticoagulants for

thromboprophylaxis in patients having hip or knee arthros-

copy. BMJ. 2011;342:c7270.

13. Liau JV, Ferrandis R. New anticoagulants and

regional anesthesia. Curr Opin Anaesthesiol. 2009;22:

661-666.