New Oral Anticoagulants for Stroke Prevention in …...The new oral anticoagulants function by inhibiting the coagulation pathway via direct inhibition of thrombin (dabigatran) or

Review

Article

www.ajpblive.com Vol. 4, No. 6 • The American Journal of Pharmacy Benefi ts 269

ABSTRACTObjectives: To assess the pharmacologic and clinical benefi ts of 3 new oral anticoagulants—the direct thrombin inhibitor dabigatran and 2 Factor Xa inhibitors, rivaroxaban and apixaban—in patients with atrial fi brillation (AF).

Study Design: A PubMed literature search was performed using the criteria “atrial fi brillation” and “stroke” with each of the follow-ing: “dabigatran,” “apixaban,” and “rivaroxaban.”

Methods: Articles published from January 2009 to October 2011 were analyzed for randomized clinical studies suffi ciently powered to identify rates of stroke and non–central nervous system sys-temic embolism. Subgroup analyses were excluded. Articles were analyzed for randomized, controlled studies enrolling more than 500 patients. A search on www.clinicaltrials.gov was performed to identify additional studies. All searches were performed in January 2011 and updated in October 2011.

Results: All 3 new oral anticoagulants are at least as effective and safe as warfarin for the prevention of stroke and systemic embolism in patients with AF. Given the differences in the patient populations studied, conclusions about the relative effi cacy and safety of these agents cannot be made.

Conclusions: The new oral anticoagulants offer potential advan-tages over warfarin, particularly in terms of key safety end points and ease of use, while achieving a comparable level of protection against stroke in patients with AF. These advantages may increase adherence to therapy, improve clinical outcomes, and decrease overall healthcare costs, providing an increased benefi t for indi-viduals at greatest risk for AF-induced stroke.

(Am J Pharm Benefi ts. 2012;4(6):269-283)

A trial fi brillation (AF) is the most common sustained

cardiac arrhythmia, and its prevalence is expected

to increase signifi cantly over the next few decades.1

Currently, it is estimated that between 2.1 and 5.1 million

people are affected by AF in the United States.2,3 As the

population ages, this number is expected to increase to ap-

proximately 16 million people by 2050.3

Thromboembolic stroke is the most serious potential con-

sequence of AF, and patients with AF face 5-fold higher risk

of stroke than those without AF.3 Identifi cation of discrete

risk factors for stroke has enabled the development of risk

stratifi cation scoring systems to estimate the composite risk

of stroke in patients with AF. The most widely used risk strat-

ifi cation system is the CHADS2 score. This systems assigns

points based on various risk factors (ie, Congestive heart

failure, Hypertension, Age >75 years, Diabetes mellitus, and

prior history of Stroke or transient ischemic attack [TIA]),

and uses the composite score to stratify patients into groups

at low, moderate, or high risk of stroke.4 The most recent

evidence-based guidelines established by the American Col-

lege of Cardiology Foundation/American Heart Association/

European Society of Cardiology (ACCF/AHA/ESC) as well as

the guidelines of the American College of Chest Physicians

(ACCP) suggest oral anticoagulation therapy rather than no

therapy (level of evidence: grade 1B) for patients with AF at

moderate risk of stroke (CHADS2 = 1).5,6

Because stroke is the leading cause of serious long-term

disability and the third-leading cause of death in the United

States, effective strategies for stroke prophylaxis in patients

with AF have a signifi cant clinical and economic impact.7

BENEFITS AND LIMITATIONS OF TRADITIONAL ANTICOAGULANTS

The current standard of care recommended by ACCF/

AHA/ESC is anticoagulant therapy with warfarin, a vitamin

K antagonist (VKA), or antiplatelet therapy when anticoagu-

lation is contraindicated or inappropriate.5 However, many

At a Glance

Practical Implications p 270

Author Information p 281

Full text and PDF www.ajpblive.com

New Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation

Daniel E. Hilleman, PharmD

Vol. 4, No. 6 • The American Journal of Pharmacy Benefi ts

270 The American Journal of Pharmacy Benefi ts • November/December 2012 www.ajpblive.com

� Hilleman

P R A C T I C A L I M P L I C A T I O N S

Dabigatran, rivaroxaban, and apixaban are 3 new oral anticoagulants that can be used as alternatives to warfarin in patients with atrial fi brillation.

� The new oral anticoagulants have several clinical advantages over warfarin including lack of necessity for coagulation assay testing and fewer drug and food interactions.

� If the new oral anticoagulants are not used following FDA guidance, they could produce signifi cant adverse clinical outcomes.

� A longer duration of clinical experience with these new oral anticoagu-lants will be required to further defi ne their role in the prevention of stroke in patients with atrial fi brillation.

patients with AF are never prescribed warfarin, and those

who are may use it suboptimally, placing them at high

risk of thromboembolic stroke.8 In addition, warfarin has

several limitations, which makes its use diffi cult outside

the clinical trial setting.9,10

The pharmacodynamic effects of warfarin are infl u-

enced by diet, concomitant medications, comorbid con-

ditions, and genetics, making treatment individualization

and long-term monitoring mandatory. Dosing to maintain

a therapeutic range is adjusted according to a patient’s

international normalized ratio (INR), which is measured

at regular intervals. The potential consequences of exces-

sive anticoagulation (bleeding) or insuffi cient anticoagula-

tion (stroke) can be catastrophic, so frequent monitoring

is recommended during lifelong warfarin treatment.8 The

recently revised ACCP guidelines recommend quarterly

visitations for those with very stable INRs.6

The percentage of time within a therapeutic INR range

(TTR) is directly related to the risk of mortality in patients

with AF, with the lowest risk seen in patients who have

more than 70% of their INR levels within the therapeutic

range.11 Unfortunately, the real-world INR levels seen in

typical outpatient and community care settings are gener-

ally lower than those in patients enrolled in specialized

anticoagulation clinics.12,13 However, results of numerous

studies comparing patient TTRs before and after switch-

ing from a usual care setting to specialized anticoagula-

tion clinics have reported nominal improvements in TTR

levels.14-17 Moreover, the improved TTR levels observed

after switching to an anticoagulation clinic were all be-

low 70% and were associated with improved patient out-

comes, suggesting that the benefi ts associated with a TTR

of more than 70% might be more apparent than real.

Even in an ideal anticoagulation setting, factors such as

patient compliance, patient knowledge of and familiar-

ity with correct warfarin use, and drug discontinuation

inevitably play a role in variable and suboptimal INR

control.12,18,19

The limitations of warfarin have prompted exten-

sive research to develop alternative anticoagulants

that are at least as effective, but are safer and easier

to use. Recently approved oral anticoagulants may

provide simpler, more effective, and safer stroke pre-

vention compared with VKAs in patients with AF. Con-

sequently, the use of these agents as an alternative to

VKAs may improve patient adherence, improve out-

comes, and decrease overall healthcare costs. In 2010

and 2011, 2 new oral anticoagulants were approved

by the US Food and Drug Administration (FDA) for

prevention of stroke and systemic embolism in patients

with nonvalvular AF. These new drugs include the direct

thrombin inhibitor (DTI) dabigatran etexilate (approved

October 2010) and the Factor Xa (FXa) inhibitor rivaroxa-

ban (approved October 2011).20,21 In addition, the FXa

inhibitor apixaban is currently being considered for an

AF-indication approval and has already been approved

in the European Union for prophylaxis of deep vein

thrombosis in patients undergoing knee or hip replace-

ment surgery.22 Although dabigatran is currently recom-

mended as an alternative, the majority of patients with

AF continue to be treated with warfarin.23 This review

examines the pharmacologic and clinical benefi ts of the

new anticoagulants in the prevention of stroke and sys-

temic embolism in patients with AF, focusing on major

phase III study results.

STUDY IDENTIFICATIONA literature search was conducted of all PubMed in-

dexed articles from January 2009 to October 2011 to iden-

tify randomized clinical studies suffi ciently powered to

identify rates of stroke and non–central nervous system

systemic embolism. Subgroup analyses were excluded. A

total of 12 publications were identifi ed using the afore-

mentioned search terms and limitations. All studies were

screened for inclusion. Of these, 4 large randomized

studies were identifi ed. A search on www.clinicaltrials

.gov was performed to identify additional studies. Data

inclusion was based on study quality, not publication

date. All searches were performed in January 2011 and

updated in October 2011.

NOVEL ANTICOAGULANTS: COMPARATIVE PHARMACOLOGY

The new oral anticoagulants function by inhibiting the

coagulation pathway via direct inhibition of thrombin

(dabigatran) or selective site-specifi c inhibition of Factor


Stroke Prevention in Atrial Fibrillation

Xa (rivaroxaban and apixaban).10 In contrast, warfarin

modulates the formation of thrombin at multiple points

in the coagulation cascade by inhibiting the recycling of

vitamin K from its oxidized, inactive state to its reduced,

active form. This process is necessary for the biologic

activity of Factors II (prothrombin), VII, IX, and X, as

well as proteins C and S.24 Unlike warfarin, by specifi -

cally targeting a single coagulation factor, DTIs and FXa

inhibitors do not have broad effects on multiple coagu-

lation factors that may predispose to adverse events.25

Table 1 summarizes the pharmacologic profi les of these

agents.26-28

Dabigatran Dabigatran etexilate was the fi rst oral anticoagulant

to be approved in the United States for stroke preven-

tion in AF.21 Dabigatran has an oral bioavailability of

approximately 3% to 7%. It is administered as a prodrug,

dabigatran etexilate, which does not exhibit any phar-

macologic activity. Dabigatran etexilate is a substrate of

the effl ux transporter P-glycoprotein (P-gp). After oral

administration, dabigatran etexilate is rapidly absorbed

and converted to dabigatran by esterase-catalyzed hy-

drolysis in plasma and in the liver. This process occurs

independently of cytochrome P (CYP) 450 isozymes, but

concomitant use of potent P-gp inducers (eg, rifampin)

should be avoided.21 Originally, dose adjustments were

not required when dabigatran was combined with P-gp

inhibitors; however, because of postmarketing experi-

ence reports, dose adjustments (75 mg twice daily)

are recommended when dabigatran is combined with

potent P-gp inhibitors (ketoconazole, dronedarone) in

patients with reduced renal function (creatinine clear-

ance [CrCl] 15-30 mL/min). Dabigatran is also subject

to conjugation, forming pharmacologically active acyl

glucuronides. Four isomers of dabigatran glucuronide

exist, each accounting for less than 10% of total plasma

dabigatran. Dabigatran is not a substrate, inhibitor, or

inducer of CYP450 enzymes. In its active form, dabi-

gatran has a half-life of approximately 12 to 17 hours.

Approximately 80% of dabigatran is excreted via the

kidneys as unchanged drug. The safety of dabigatran in

patients with severe hepatic impairment has not been

established, but after administration to patients with a

Child-Pugh score of B, no consistent changes in expo-

sure or pharmacodynamic were observed.21

Approval of dabigatran in the United States was based

on the results of the phase III RE-LY (Randomized Evalu-

ation of Long-Term Anticoagulation Therapy) study.29 The

ACCP guidelines recommend 150 mg twice daily of dabi-

gatran rather than dose-adjusted VKA therapy for patients

with AF and paroxysmal AF when anticoagulation therapy

is advised (grade 2B).6 The ACCF/AHA Task Force update

on practice guidelines also recommends dabigatran as an

alternative to warfarin in patients with AF (class I, level B),

but indicates that switching patients already on warfarin

with excellent INR control is of little value.23

In the RE-LY study, 2 dosages of dabigatran—110 mg

twice daily and 150 mg twice daily—were compared with

dose-adjusted warfarin (INR 2.0-3.0) in more than 18,000

patients with AF over a median of 2 years.29 The compari-

son between dabigatran doses was double blind, whereas

warfarin was administered in an open-label fashion. The

primary end point was stroke or systemic embolism. The

primary safety outcome was major bleeding events. The

primary analysis was designed to test whether either dose

of dabigatran was noninferior to warfarin in reducing the

primary end point of stroke or systemic embolism. If non-

inferiority was established, the agents were compared for

statistical superiority.29

Table 1. Pharmacologic Profi les of Dabigatran, Rivaroxaban, and Apixaban Characteristic Dabigatran21,26-28 Rivaroxaban20,26 Apixaban22,26

Mechanism of action Direct thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor

Prodrug Yes (dabigatran etexilate) No No

Frequency of administration Twice daily Once daily Twice daily

Oral bioavailability 6.5% (absolute) 80% to 100% 66% (absolute)

Cmax in volunteers 1.5-3 h 2-4 h 1-3 h

t½ in volunteers 12-14 h 5-9 h 8-15 h

t½ in elderly patients 12-14 h 11-13 h ~12 h

Renal clearance of unchanged drug 80% 36% 25%

Plasma protein binding 35% >90% 87%

CYP450 metabolism No Yes (3A4, 2J2) Yes (3A4)

CYP450 indicates cytochrome P450; Cmax, time to achieve maximal serum concentration; t1/2, half-life.


� Hilleman

Patient eligibility for RE-LY included electrocardio-

graphically documented AF with at least 1 additional risk

factor for stroke (eg, previous stroke, TIA, left ventricular

ejection fraction less than 40%, heart failure symptoms of

New York Heart Association class II or higher in the pre-

ceding 6 months, and age >75 years or age 65 to 74 years

with diabetes, hypertension, or coronary artery disease).29

The mean age of all patients was 71 years; 63.6% were

male, and 20% had experienced a previous stroke or TIA.

When stroke risk was stratifi ed by CHADS2 score, 32% of

patients had a score of 0 to 1 (low risk), 36% had a score

of 2 (moderate risk), and 32% had a score of 3 to 6 (high

risk). Half of enrolled patients (50%) had not previously

been treated with warfarin.29

Compared with warfarin, both dabigatran doses were

noninferior (P <.001 for noninferiority) for the primary

end point of stroke or systemic embolism, and dabiga-

tran 150 mg was superior (P <.001) (Figure 1).29 These

fi ndings represented a 35% reduction in risk of stroke or

systemic embolism with dabigatran 150 mg twice daily

versus warfarin (relative risk [RR] 0.65; 95% confi dence

interval [CI] 0.52-0.81). In addition, both doses of dabiga-

tran signifi cantly reduced the risk of hemorrhagic stroke

compared with warfarin (P <.001), and dabigatran 150

mg twice daily reduced the risk of any stroke (P <.001),

ischemic or unspecifi ed stroke (P = .03), nondisabling

stroke (P = .01), and disabling or fatal stroke (P = .005).

The higher dose was also associated with a 15% reduc-

tion in the risk of vascular death compared with warfarin

(RR 0.85, 95% CI 0.72-0.99; P = .04), although a 12% re-

duction in risk of all-cause mortality did not reach statisti-

cal signifi cance (RR 0.88, 95% CI 0.77-1.00; P = .51). Both

doses of dabigatran were associated with a numerically

higher risk of myocardial infarction (MI). This risk was

originally reported as signifi cantly greater with the 150-

mg dose compared with warfarin (RR 1.38; 95% CI 1.00-

1.91; P = 0.048). After publication of the original study,

additional clinical events were discovered by the princi-

pal investigators.30 Among these events were 28 instances

of silent MI that were not reported by investigators during

the course of the study. This fi nding altered the RR value

in the dabigatran 150-mg dose compared with warfarin,

making the RR of MI in the dabigatran 150-mg arm no

longer statistically signifi cant (RR 1.27, 95% CI 0.94-1.71;

P = .12) and rendering the results somewhat less reliable.

Although the authors concluded that the primary effi cacy

and safety conclusions of the RE-LY trial were not altered

by the inclusion of these newly discovered events, these

fi ndings nonetheless reduce confi dence in the reliability

of the study’s fi ndings.30

The risk of major bleeding (primary safety end point),

which was defi ned according to the International Society

on Thrombosis and Hemostasis criteria,31 was reduced

in the dabigatran 110-mg twice-daily group versus the

Figure 1. Annual Rates of the Primary Effi cacy and Safety End Points in the RE-LY Studya

1.54

1.11

Stroke or Systemic Embolism

Rat

es, %

1.71

2.87

3.32

Major Bleeding

3.57

RR 0.65 (95% Cl 0.52-0.81)P = .001

RR 0.080 (95% Cl 0.70-0.93)P = .003

Dabigatran 110 mg twice daily Dabigatran 150 mg twice daily Warfarin

4.0

3.5

2.5

2.0

1.5

1.0

0.5

0

3.0

CI indicates confi dence interval; RR, relative risk.aThis fi gure was reproduced from Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fi brillation. N Engl J Med. 2009;361:1139-115129 by express permission of the owner of the copyright, the Massachusetts Medical Society.



warfarin group (RR 0.80; 95% CI 0.70-0.93), but was simi-

lar in frequency when the higher dabigatran dose was

compared with warfarin (RR 0.93; 95% CI 0.81-1.07). Ma-

jor bleeding rates per year are shown in Figure 1.29 Dys-

pepsia was the only adverse effect that was signifi cantly

more common in the dabigatran arm, occurring in 348

patients (5.8%) in the warfarin group and in 707 patients

(11.8%) and 688 patients (11.3%) in the dabigatran 110-

mg and 150-mg groups, respectively (P <.001 for both

comparisons). The rate of drug discontinuation for gas-

trointestinal (GI) symptoms was slightly higher than 2%

with either dose of dabigatran and 0.6% with warfarin.29

In a subsequent analysis, the rate of the primary end

point was higher in a subgroup of patients who had

experienced a previous stroke or TIA than in patients

without prior stroke/TIA (2.4% per year vs 1.2% per year;

P <.0001).32 In the subgroup with a prior stroke or TIA,

the reduction in the risk of stroke with dabigatran was

mainly due to a reduction in hemorrhagic stroke, because

both doses of dabigatran were associated with a signifi -

cantly lower rate of intracranial bleeding versus warfarin

in this subgroup. However, there was no signifi cant in-

teraction between previous stroke or TIA and the effects

on the primary outcome with either 110-mg (P = .62) or

150-mg (P = .34) dabigatran. In patients with previous

stroke/TIA, major bleeding occurred in fewer patients on

110-mg twice-daily dabigatran versus warfarin (2.7% vs

4.2% per year) and GI bleeding was more common with

150-mg twice-daily dabigatran versus warfarin (2.3% vs

1.4% per year). Because of the relatively small propor-

tion of patients with prior stroke/TIA (20% of the total

study population), the observed differences in outcomes

between dabigatran and warfarin did not reach statistical

signifi cance, but the direction of effects was consistent

with those seen in the overall study population.32

There was a wide variation in INR values among par-

ticipating centers in the RE-LY trial.33 This variation may

have infl uenced differences observed between warfarin

and dabigatran. The mean warfarin recipient TTR in the

RE-LY study was 64% overall, but ranged from 44% in

Taiwan to 77% in Sweden.29,33 Among warfarin recipients,

there was a signifi cant association between TTR and the

primary end point of stroke or pulmonary embolism (P

= .001), major bleeding (P <.0001), total mortality (P

<.0001), and net clinical benefi t (a composite of stroke,

systemic embolism, pulmonary embolism, death, and

major bleeding; P <.0001).33 Moreover, the difference be-

tween dabigatran 150 mg and warfarin for the second-

ary end points of nonhemorrhagic stroke and mortality

was attenuated at higher quartiles of TTR (ie, better INR

control), such that dabigatran 150 mg twice daily was

not superior to warfarin. Dabigatran was associated with

a lower rate of major bleeding versus warfarin at lower

quartiles of TTR, but with a similar rate of major bleeding

and a higher rate of GI bleeding at higher TTR.33

Patients in the dabigatran arms of RE-LY were given

the option to continue in an ongoing long-term extension

study called RELY-ABLE. The primary end point is ma-

jor bleeding, with secondary end points of stroke, non–

central nervous system systemic embolism, pulmonary

embolism, MI, deep vein thrombosis, all-cause mortality,

and a composite of all of these. This study also includes a

cluster-randomized trial of a knowledge translation inter-

vention, which will assess its impact on patient outcomes.

Caution should be used in administration of dabigatran to

the elderly because conditions such as renal impairment,

reduced body weight, and drug interactions may result in

increased risk of major bleeding and fatality.34,35

In most countries outside of the United States, both

doses of dabigatran used in the RE-LY trial were ap-

proved by the countries’ regulatory agencies. In the Uni-

ted States, the FDA approved the 150-mg twice-daily dose

for patients with a CrCl greater than 30 mL/min. For pa-

tients with a CrCl of 15 to 30 mL/min, the FDA approved

the 75-mg twice-daily dose based on pharmacokinetic

and pharmacodynamic modeling. The FDA published its

rationale for its decision to approve the 150-mg twice-

daily dose and not the 110-mg twice-daily dose.36 A basic

assumption in the FDA’s rationale was that stroke was

a considerably more clinically important outcome than

nonfatal and extracranial bleeding episodes. The FDA

looked at 3 subgroups of patients in whom the benefi ts of

a lower risk of bleeding might be expected to outweigh

the higher risk of stroke associated with the 110-mg dose.

These included patients older than age 75 years, patients

with renal dysfunction, and patients with a higher risk of

bleeding. In the 7238 patients in RE-LY 75 years or older,

the rate of stroke and systemic embolism was 1.4 per 100

patient-years for the 150-mg dose and 1.9 per 100 patient-

years for the 110-mg dose. The rate of major bleeding

was higher with the 150-mg dose compared with the 110-

mg dose (5.1 vs 4.4 per 100 patient-years). These rates

indicate similar risk-benefi t assessments of the 2 doses.

In the 3343 patients in RE-LY with a CrCl of 30 to 50

mL/min, the rate of the primary composite effi cacy out-

come was 1.3 per 100 patient-years for the 150-mg dose

compared with 2.4 per 100 patient-years for the 110-mg

dose. The rate of major bleeding for the 150-mg dose

was no different from the rate for the 110-mg dose (5.3

vs 5.7 per 100 patient-years). Hence, the 150-mg dose


� Hilleman

had a superior benefi t-risk profi le

in patients with renal dysfunc-

tion. In RE-LY, 57% of patients

who suffered a major bleeding

event either resumed taking their

study medication or had no inter-

ruption in therapy, continuing to

take the same dose. The percent-

ages of these patients who had

an additional major hemorrhage

were similar: 16%, 14%, and

12% in the 110-mg dabigatran,

150-mg dabigatran, and warfarin

groups, respectively. These data

do not support the strategy of

dose reduction if patients have

a bleeding event while taking a

higher dose. Hence, the FDA’s

decision to approve only the 150-

mg strength was based on its in-

ability to identify any subgroup

in which use of the lower dose

would not represent a substantial

disadvantage.

Dabigatran has also been as-

sessed for effi cacy and safety

in patients with acute coronary

syndrome in the phase II dose-

fi nding study Randomised Dabi-

gatran Etexilate Dose Finding

Study In Patients With Acute

Coronary Syndromes Post Index

Event With Additional Risk Fac-

tors For Cardiovascular Complica-

tions Also Receiving Aspirin And

Clopidogrel (RE-DEEM). A total

of 1861 patients presenting with

ST-segment elevation MI (STEMI)

or non-ST-segment elevation MI

(NSTEMI) and at least 1 cardio-

vascular risk factor were random-

ized to receive dabigatran (50, 75,

110, or 150 mg twice daily) or pla-

cebo in addition to standard dual

antiplatelet therapy.37 Following

6 months of treatment, adjuvant

dabigatran treatment increased

the incidence of the primary end

point (composite of major or

clinically relevant minor bleeding

Figure 2. Cumulative Rates of the Primary End Point (Stroke or Systemic Embolism) in the Per Protocol Population (Panel A) and Intention-to-Treat Population (Panel B) in the ROCKET AF Studya

B. Events in Intention-to-Treat Population

A. Events in Per Protocol Population

Days Since Randomization

Days Since Randomization

Cu

mu

lati

ve E

ven

t R

ate,

%C

um

ula

tive

Eve

nt

Rat

e, %

aThis fi gure was reproduced from Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fi brillation. N Engl J Med. 2011;365(10):883-89139 by express permission of the owner of the copyright, the Massachusetts Medical Society.



events) in a dose-dependent manner (3.5%, 4.3%, 7.9%,

and 7.8% for increasing dabigatran doses and 2.2% for

placebo; P <.001). There was no clear difference between

the placebo and dabigatran groups for the composite of

cardiovascular death, nonfatal MI, or stroke. It is currently

unknown whether a phase III trial of dabigatran in acute

coronary syndrome will be conducted.37

RivaroxabanRivaroxaban is approved for once-daily administra-

tion in patients with AF.20 The effi cacy of rivaroxaban for

stroke prevention in patients with AF was investigated in

the phase III trial ROCKET AF (Rivaroxaban Once Daily,

Oral, Direct Factor Xa Inhibition Compared with Vitamin

K Antagonism for Prevention of Stroke and Embolism

Trial in Atrial Fibrillation) (Figure 2).38,39 Unlike RE-LY,

ROCKET AF was conducted in a double-blind fashion

through use of a double-dummy double-blind technique

as described by the ROCKET AF Study Investigators.38 In

addition, ROCKET AF enrolled a much higher risk patient

population.38,39 Qualifying criteria included prior stroke,

TIA, or systemic embolism or >2 of the following risk

factors: clinical heart failure or left ventricular ejection

fraction <35%, hypertension, age >75 years, or diabetes

mellitus (ie, a CHADS2 score of >2). The proportion of

patients who had not had a previous ischemic stroke,

TIA, or systemic embolism who had <2 risk factors was

capped at 10% of the cohort for each region; the remain-

der were required to have had either previous throm-

boembolism or >3 risk factors (CHADS2 >3). As a result,

90% of patients in ROCKET-AF had a CHADS2 score of >3

versus ~30% of patients who met the same criteria in RE-

LY.36,39 The primary effi cacy end point was the composite

of stroke (ischemic or hemorrhagic) and systemic embo-

lism. The principal safety end point was a composite of

major and nonmajor clinically relevant bleeding events.31

Briefl y, 14,264 patients with nonvalvular AF and in-

creased risk for stroke were randomly assigned rivaroxa-

ban 20 mg once daily or dose-adjusted warfarin.39 The

results of ROCKET AF demonstrated that in the intention-

to-treat analysis, rivaroxaban was noninferior to warfarin

for the prevention of subsequent stroke or systemic em-

bolism (2.1% vs 2.4% per 100 patient-years; hazard ratio

[HR] 0.88, 95% CI 0.75-1.03; P <.001 for noninferiority;

P = .12 for superiority). In the per protocol population

the primary end point occurred in 188 patients in the

rivaroxaban group (1.7% per 100 patient-years) and 241

in the warfarin group (2.2% per 100 patient-years; HR

0.79, 95% CI 0.66-0.96; P <.001 for noninferiority). Princi-

pal safety end point rates (major and nonmajor clinically

relevant bleeding) were similar between the rivaroxaban

and warfarin treatment arms (14.9% vs 14.5% per 100

patient-years; HR 1.03, 95% CI 0.96-1.11; P = .44) with

signifi cantly reduced incidents of intracranial and fatal

bleeding rates (0.5% vs 0.7% and 0.2% vs 0.5%, respec-

tively, per 100 patient-years) in the rivaroxaban group.

Major bleeding was defi ned according to the Internation-

al Society on Thrombosis and Hemostasis criteria.31 There

was a signifi cant increase in the number of rivaroxaban

patients with a >2 g/dL reduction in hemoglobin and

transfusions, which was predominantly due to a higher

risk of GI bleeding (3.2% vs 2.2%, P <.001).39

One notable caveat was the lower TTR with warfa-

rin (55%) in the ROCKET AF study compared with that

observed with warfarin in the other studies of the new

anticoagulants in AF patients (range 64%-68%).27,38-40

However, the TTR in ROCKET AF was closer to the rates

observed outside of clinical trials or specialty clinics.13

This may have been a primary reason that the differences

observed between warfarin and rivaroxaban were not

statistically signifi cant in the ROCKET AF study. The trials

with higher warfarin TTR rates included fewer higher-risk

patients than the ROCKET AF study. Patients with higher

CHADS2 scores receiving warfarin are typically more dif-

fi cult to maintain in the TTR than patients with lower

CHADS2 scores.

Adverse events that occurred more frequently in pa-

tients receiving rivaroxaban during the ROCKET AF study

included epistaxis and hematuria. Rivaroxaban is a sub-

strate for both the P-gp transport protein and the CYP iso-

zymes 3A4, 3A5, and 2J2; concomitant administration of

rivaroxaban with combined P-gp and strong CYP3A4 in-

hibitors may cause a signifi cant increase in drug exposure

and bleeding risk.20 In addition, pharmacokinetic studies

have demonstrated that patients with renal impairment

may have a heightened drug response, and caution is ad-

vised when coadministering combined P-gp and weak or

moderate CYP3A4 inhibitors such as diltiazem and amio-

darone.20,41,42 Patients in ROCKET AF were allowed use of

combined P-gp and weak or moderate CYP3A4 inhibitors;

however, no increase in bleeding was observed in patients

who had a CrCl of 30 to 50 mL/min.

A similar large, randomized, phase III trial evaluating

the safety of rivaroxaban for prevention of stroke and

systemic embolism was conducted in 1280 Japanese pa-

tients with AF and either prior stroke, TIA, or non–central

nervous system systemic embolism, or >2 risk factors for

stroke (J-ROCKET AF).43 Patients were randomized to ri-

varoxaban 15 mg once daily (10 mg once daily in patients

with CrCl of 30-50 mL/min) or dose-adjusted warfarin. The


� Hilleman

15-mg once-daily dose was chosen to address character-

istics of Japanese patients and the lower anticoagulation

targets of Japanese clinical practice. The primary analysis

tested for noninferiority of the principal safety outcome of

adjudicated major and nonmajor clinically relevant bleed-

ing events. Although the study was powered only for the

primary safety outcome, the primary effi cacy end point

was the composite of adjudicated stroke (ischemic and

hemorrhagic) and non–central nervous system systemic

embolism.43

Consistent with the results of ROCKET AF, rivaroxa-

ban was noninferior to warfarin for the primary safety

outcome (18.0 vs 16.4 per 100 patient-years; HR 1.11; P

<.001 for noninferiority) with fewer fatal bleeding events

and intracranial hemorrhages. For the primary effi cacy

end point, there was a strong trend toward a reduction in

stroke/systemic embolism with rivaroxaban (1.3 vs 2.6 per

100 patient-years; HR 0.49, P = .050).43

Rivaroxaban has also been evaluated for safety and ef-

fi cacy in patients with acute coronary syndrome in the re-

cently completed randomized, placebo-controlled, phase

III trial ATLAS ACS2-Thrombolysis in Myocardial Infarc-

tion 51 (Anti-Xa Therapy to Lower Cardiovascular Events

in Addition to Standard in Subjects with Acute Coronary

Syndrome-Thrombolysis in Myocardial Infarction 51).44 The

trial enrolled 15,570 patients who had presented with symp-

toms suggestive of acute coronary syndrome and in whom

STEMI, NSTEMI, or unstable angina had been diagnosed.

In addition to standard medical therapy (low-dose aspirin

and a thienopyridine), patients were randomly assigned to

twice-daily administration of either 2.5 mg or 5.0 mg of riva-

roxaban or placebo. The primary effi cacy end point was the

composite of cardiovascular death, MI, or stroke.44

Results of the study showed that both doses of riva-

roxaban signifi cantly reduced the primary effi cacy end

point compared with placebo (8.9% vs 10.7%; HR 0.84,

P = .008 [combined effi cacy for 2.5- and 5-mg doses]).

However, compared with placebo, rivaroxab an increased

the risk of major bleeding and intracranial hemorrhage,

but not the risk of fatal bleeding.44

Rivaroxaban is a potent and selective Factor Xa inhibi-

tor with a relatively high bioavailability (~80%) and pre-

dictable pharmacokinetic/pharmacodynamic profi le.20 The

mean half-life of rivaroxaban is 5 to 9 hours in healthy

individuals, and 11 to 13 hours in the elderly. Rivaroxaban

is metabolized primarily in the liver via CYP450 and CY-

P3A4 enzymes, and more than 30% of the drug is excreted

in the feces unchanged—a process mediated, at least in

part, by P-gp. Concomitant administration of rivaroxaban

with strong CYP3A4 or P-gp inhibitors (eg, ritonavir, ke-

toconazole) signifi cantly interferes with the metabolism of

rivaroxaban and should be avoided to prevent increased

drug exposure and risk of bleeding events.20,45 Because

rivaroxaban is cleared primarily by the liver and kidneys,

caution should be exercised when prescribing rivaroxa-

ban to patients with moderate to severe renal impairment

(CrCl 15-30 mL/min) or hepatic impairment (Child-Pugh

Class B and C).

Rivaroxaban is currently approved for stroke preven-

tion in AF at a dose of 20 mg once daily with the evening

meal, and in patients with CrCl of 15 to 50 mL/min at a

dose of 15 mg once daily with the evening meal; rivar-

oxaban is not recommended for use in patients with a

CrCl of <15 mL/min or severe hepatic impairment (Child-

Pugh C) (Table 2).20 Results of clinical studies have shown

that discontinuation of rivaroxaban places patients with

AF at increased risk for thrombotic events. If anticoagula-

tion with rivaroxaban must be discontinued for a reason

other than pathologic bleeding, alternative anticoagula-

tion measures should be considered.20

ApixabanAlthough apixaban is not yet approved in the United

States, its use for stroke prevention in patients with AF

Table 2. Dose Adjustment Requirements of Oral Anticoagulants According to Degree of Renal Impairmenta

Degree of Renal Impairment (GFR CrCl)b Warfarin Dabigatran Rivaroxaban Apixabanc

Mild (50-89 mL/min/1.73 m2) Not required Not required Not required Not required

Moderate (30-49 mL/min/1.73 m2) Not required Not required Dose reduction to15 mg/d

2.5 mg twice dailyd if 2 or more of the following:

• Age >80 y

• Weight <60 kg

• SCr >1.5 mg/dL

Severe (15-29 mL/min/1.73 m2) Not required Dose reduction to 75 mg/d

Dose reduction to15 mg/d

Renal failure (<15 mL/min/1.73 m2) Not required Contraindicated Contraindicated

CrCl indicates creatinine clearance; GFR, glomerular fi ltration rate; SCr, serum creatinine.aAdapted from Harder S. Renal profi les of anticoagulants. J Clin Pharmacol. 2012;52(7):964-975.46 Copyright © 2012 SAGE Publications. Reprinted by permission of SAGE Publications.bCrCl based on Cockroft-Gault equation. cApixaban is not approved, so labeled dose recommendations are not available. dBased on dosing used in the ARISTOTLE trial.



has been evaluated in 2 large-scale phase III clinical tri-

als: ARISTOTLE (Apixaban for Reduction In Stroke and

Other Thromboembolic Events) and AVERROES (Apixa-

ban Versus Acetylsalicylic Acid to Reduce the Risk Of

Stroke) (Table 3). Apixaban is currently approved in the

European Union for thromboprophylaxis following total

hip and knee replacement surgeries in adults.21

In the ARISTOTLE study, 18,201 patients with AF and >1 additional risk factor for stroke were randomized to

receive either apixaban 5 mg twice daily or dose-adjusted

warfarin (Figure 3).40,48 Patient inclusion criteria were simi-

lar to those in RE-LY; eligible stroke risk factors in ARIS-

TOTLE included age >75 years, prior stroke/TIA/systemic

embolism, symptomatic congestive heart failure or left

ventricular ejection fraction <40%, diabetes, and hyper-

tension requiring treatment.40,48 The key objective of ARIS-

TOTLE was to demonstrate noninferiority to warfarin for

the primary outcome of ischemic or hemorrhagic stroke or

systemic embolism. Secondary objectives included testing

for superiority with respect to the primary outcome, rates

of major bleeding events, and death from any cause.

Apixaban met the primary effi cacy objective of non-

inferiority to warfarin in the ARISTOTLE trial on the

combined outcome of stroke (ischemic, hemorrhagic, or

unspecifi ed type) and systemic embolism. The rate of the

primary outcome was 1.27% per year in the apixaban

group versus 1.60% per year in the warfarin group (HR

with apixaban of 0.79; 95% CI 0.66-0.95; P <.001 for non-

inferiority, P = .01 for superiority).40 In addition, apixaban

met the key secondary end points of superiority to warfa-

rin with respect to the primary outcome and to the rates

of major bleeding (defi ned according to the International

Society on Thrombosis and Hemostasis criteria31) and

death from any cause (2.13% per year in the apixaban

group vs 3.09% per year in the warfarin group; HR 0.69,

95% CI 0.60-0.80; P <.001).40

In the apixaban group, the rate of hemorrhagic stroke

was 0.24% per year versus 0.47% per year in the warfarin

group (HR 0.51, 95% CI 0.35-0.75; P <.001). Moreover, the

rate of ischemic or uncertain-type stroke was 0.97% per

year in the apixaban group versus 1.05% per year in the

warfarin group (HR 0.92, 95% CI 0.74-1.13; P = .42).40 Pa-

tients in the warfarin group were within the therapeutic

range for a mean of 62.2% of the time after the exclusion

of INR values during the fi rst 7 days after randomization.

The investigators concluded that apixaban was superior

to warfarin in patients with AF for prevention of stroke or

systemic embolism, decreased bleeding risk, and reduced

mortality.40

In the AVERROES trial, 5599 patients with AF (mean

age 70 years) who were deemed clinically unsuitable for

VKA treatment were randomized to receive apixaban (5

Table 3. Comparison of the Phase III Studies With Dabigatran, Rivaroxaban, and Apixaban in Patients With Atrial Fibrillation

Study Design Drug/Dose Comparator No.AF Patient

CharacteristicsPrimary

End PointSecondary End Points Follow-up

RE-LY29 Randomized, double blind (dabi-gatran) and open label (warfarin)

Dabigatran etexilate 110 mg or 150 mg twice daily

Warfarin adjusted to INR 2.0-3.0

18,113 >1 stroke risk fac-tor; mean age 71 y; 50% VKA-naïve; 20% previous stroke/TIA

Composite of stroke and systemic embolism

Stroke; systemic embolism; total mortality;MI; PE; TIA; hospitalization

Event driven (median follow-up 2 y)

ARISTOTLE40 Randomized, double blind (sham INR)

Apixaban 5 mg twice daily

Warfarin adjusted to INR 2.0-3.0

18,206 >1 stroke risk factor; 40% VKA- naïve


Primary effi cacy outcomes plus all-cause death; major bleeding

Event driven (448 events)

AVERROES47 Randomized, double blind

Apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients)

Aspirin 81-324 mg once daily

5559 >1 stroke risk factor; mean age 70 y; failed (40%) or are unsuitable for VKA


MI; vascular mortality; total mortality; com-posite of major vascular events; net clinical benefi t

Event driven (mean follow-up 1.1 y)

ROCKET AF39 Randomized, double blind (sham INR)

Rivaroxaban 20 mg once daily

Warfarin adjusted to INR 2.5 (2.0-3.0)

14,246 Prior stroke, TIA, or systemic embolism OR >2 stroke risk factors; mean age 73 y; VKA-naïve/experienced


Composite of TIA, total mortal-ity, vascular mortality, and MI

Event driven (405 events)

INR indicates international normalized ratio; MI, myocardial infarction; PE, pulmonary embolism; TIA, transient ischemic attack; VKA, vitamin K antagonist.


� Hilleman

mg twice daily) or aspirin (81-324 mg/day) to determine

whether apixaban was superior to aspirin (Figure 4).47,49

The primary outcome was the occurrence of stroke or

systemic embolism. The primary safety outcome was

the occurrence of major bleed-

ing. AVERROES was terminated

early after an interim analysis

showed a clear effi cacy advantage

of apixaban over the comparator

(aspirin).47,50 Briefl y, a total of 51

primary outcome events (1.6% per

year) were recorded in the apixa-

ban group and 113 (3.7% per year)

in the aspirin cohort (apixaban HR

0.45, 95% CI 0.32-0.62; P <.001).

Death rates were 3.5% per year in

the apixaban group and 4.4% per

year in the aspirin group (HR 0.79,

95% CI 0.62-1.02; P = .07). Major

bleeding was seen in 44 patients

in the apixaban group (1.4% per

year) and 39 (1.2% per year) in the

aspirin group (apixaban HR 1.13,

95% CI 0.74-1.75; not signifi cant);

intracranial bleeding was seen in

11 patients in the apixaban group

and 13 taking aspirin. Finally,

hospitalization for cardiovascular

causes was signifi cantly reduced

in the apixaban group (12.6% per

year vs 15.9% per year; P <.001). It

was concluded that apixaban re-

duced the risk of stroke or system-

ic embolism without signifi cantly

increasing the risk of major bleed-

ing or intracranial hemorrhage.47

In both AVERROES and ARISTO-

TLE, there were no distinct side

effects associated with apixaban,

and patients receiving apixaban

had lower rates of discontinuation

than those assigned to aspirin or

warfarin.40,47

The randomized, multicenter,

phase III APPRAISE-2 (Apixaban

for Prevention of Acute Ischemic

and Safety Events) trial evaluated

apixaban for safety and effi cacy

in patients with acute coronary

syndrome (STEMI, NSTEMI, or

unstable angina). Patients were randomly assigned in a

1:1 ratio to apixaban 5 mg twice daily or placebo in ad-

dition to treatment with aspirin (acetylsalicylic acid) and

clopidogrel.51 The primary end point was the composite

Figure 3. Kaplan-Meier Curves for the Per Protocol (Panel A) and Intention-to-Treat (Panel B) Outcomes in the ARISTOTLE Studya,b

Hazard ratio 0.69 (95% Cl 0.60-0.80) P <.001

Hazard ratio 0.79 (95% Cl 0.66-0.95) P = .01

A. Events in Per Protocol Population

Months

Months

Pati

ents

Wit

h E

ven

t, %

Pa

tien

ts W

ith

Eve

nt,

%

B. Events in Intention-to-Treat Population

aThe primary effi cacy outcome was stroke or systemic embolism. The primary safety outcome was major bleeding, as defi ned according to the criteria of the International Society on Thrombosis and Haemostasis.31 The inset in each panel shows the same data on an enlarged segment of the y axis.bThis fi gure was reproduced from Granger CB, Alexander JH, McMurray JV, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial. N Engl J Med. 2011;365(11):981-99240 by express permission of the owner of the copyright, the Massachusetts Medical Society.



of cardiovascular death, MI, or

ischemic stroke, and the primary

safety end point was major bleed-

ing according to the Thrombolysis

in Myocardial Infarction defi ni-

tion.52 However, in November

2010, the trial was discontinued

prematurely by the Data and Safe-

ty Monitoring Board because of an

increase in major bleeding events

with apixaban in the absence of a

signifi cant reduction in recurrent

ischemic events.51,53

Apixaban is a small-molecule

inhibitor that selectively and re-

versibly targets Factor Xa in both

its free and bound states.22 The bio-

availability of apixaban is approxi-

mately 50%, with peak plasma

levels reached in approximately

3 hours, resulting in a half-life of

12 hours. Similar to the other new

anticoagulants, apixaban has mini-

mal drug interactions. Concomi-

tant use of CYP3A4 inhibitors and

P-gp should be avoided because

they increase the risk of bleeding

events signifi cantly. In addition,

combined inducers of CYP3A4 and

P-gp (eg, rifampin, phenytoin, St.

John’s wort) can signifi cantly re-

duce antithrombotic effi cacy.22

EXPERT OPINIONThe new generation of oral an-

ticoagulants for stroke prophylaxis

in AF includes a DTI (dabigatran)

and 2 FXa inhibitors (rivaroxaban

and apixaban). The pharmaco-

logic profi les of these agents—in-

cluding their specifi c targeting of

single coagulation factors, a wider

therapeutic window, once-daily or

twice-daily fi xed dosing, obviation

of the need for therapeutic drug

monitoring, and lower propensity

for harmful drug or dietary interactions—are likely to re-

sult in signifi cant clinical advantages over warfarin. Based

on the data available from the published trials comparing

the new anticoagulants with warfarin, it is not possible to

reach conclusions about the relative effi cacy of one agent

against another. Differences in the characteristics of the

study populations, the study designs of the trials, and def-

initions of some key study end points make cross-study

Figure 4. Cumulative Hazard Rates for the Primary Effi cacy (Panel A) and Safety (Panel B) Outcomes According to Treatment Group in the AVERROES Studya,b

Months

Months

Cu

mu

lati

ve H

azar

dC

um

ula

tive

Haz

ard

Hazard ratio with apixaban, 0.45(95% Cl 0.32-0.62)

Hazard ratio with apixaban, 1.13(95% Cl 0.74-1.75)

A. Stroke or Systemic Embolism

B. Major Bleeding

P <.001

P = .57

aThe primary effi cacy outcome was stroke or systemic embolism. The primary safety outcome was major bleeding. Patients received either apixaban or aspirin.bThis fi gure was reproduced from Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fi brillation. N Engl J Med. 2011;364:806-81747 by express permission of the owner of the copyright, the Massachusetts Medical Society.


� Hilleman

comparisons impossible. In addition to different mecha-

nisms of action, the new oral anticoagulants have dif-

ferent pharmacokinetic properties (Table 1), potential

drug interactions, and dose-adjustment requirements in

patients with renal impairment (Table 2),20-22,42,46,54 further

hampering the possibility of any meaningful comparative

analyses. Ultimately, the drug product selection and deci-

sion process will be dictated by the level of postmarket-

ing experience, as well as the number and various types

of FDA-approved indications.

Data from phase III studies and recent FDA approvals

indicate that these drugs may provide promising alterna-

tives to warfarin in the prevention of stroke in patients

with AF. Dabigatran and apixaban demonstrated superior

effi cacy compared with warfarin in reducing stroke and

systemic embolism29,40; rivaroxaban demonstrated nonin-

feriority to warfarin with regard to this end point.39 Dabi-

gatran 150 mg twice daily and rivaroxaban had similar

rates of major hemorrhage, while dabigatran 110 mg and

apixaban were shown to have lower rates of major bleed-

ing events compared with warfarin. All of the new agents

were associated with signifi cantly lower rates of critical/

fatal and intracranial bleeding compared with warfa-

rin.29,39,40,47 However, dabigatran and rivaroxaban increased

the risk of GI bleeding compared with warfarin, whereas

apixaban did not.29,39 Furthermore, in January 2012, the

Institute for Safe Medication Practices reported FDA data

from the fi rst quarter of 2011 indicating a 19.5% increase

in reports of serious, disabling, or fatal injuries associated

with dabigatran therapy compared with reports from the

fi rst quarter of 2010.55 These fi ndings were corroborated

in a multicenter observational study of periprocedural

dabigatran compared with warfarin treatment in patients

undergoing AF ablation.56 Results of the study showed that

periprocedural dabigatran (150 mg twice daily) use for AF

ablation was associated with an increased risk of bleeding

and thromboembolic complications compared with war-

farin (6% vs 1%; P = .019).56

Findings from reports and studies such as the afore-

mentioned have increased physician concerns regarding

the potential risks associated with dabigatran and empha-

size the need for ongoing postmarketing surveillance and

adverse-event reporting to detect specifi c risk factors in

patients that may not be apparent in a clinical trial setting.

In addition, because bleeding is potentially compounded

by poor renal function and low body weight, careful

evaluation of the risks and benefi ts of dabigatran must be

exercised in all patients prior to treatment.

As demonstrated in the AVERROES trial, apixaban of-

fers clear benefi ts over aspirin in warfarin-intolerant or

warfarin-unsuitable patients.47 In terms of study design,

ARISTOTLE and ROCKET-AF used a more rigorous ap-

proach to minimizing bias through the double-dummy

and sham INR methodology.40,48 However, many ques-

tions remain unanswered with regard to these agents.

First, the reduced 75-mg dose of dabigatran approved

by the FDA was never tested in RE-LY and was based

solely on pharmacokinetic data modeling.54 In addition,

according to the recently updated ACCP guidelines, this

dose is contraindicated in patients with severe renal

impairment6; thus, it remains unclear whether this dose

will be as effi cacious as warfarin in stroke prevention.

Second, the variable INR control of patients in the RE-

LY and ROCKET AF study had an important impact on

the difference between dabigatran 150 mg twice daily

and rivaroxaban and warfarin.30 This type of subanalysis

based on the results of the ARISTOTLE trial has not been

published to date. Finally, the true comparative effi cacy

of dabigatran, apixaban, and rivaroxaban can only be

determined in head-to-head clinical trials, and it is highly

unlikely that such trials will be conducted.

From a formulary perspective, the cost-effectiveness

of these agents is also unclear. Warfarin is inexpensive,

and its cost-effectiveness has been proved in a number

of clinical trials, with substantial savings arising from pre-

vention of strokes.7,57,58 However, the cost-effectiveness

of warfarin is highly dependent on INR control, and the

need for frequent monitoring is a substantial economic

burden.7,57 Indirect costs associated with transportation

to anticoagulation clinics, lost time from work, appoint-

ments, and blood tests are seldom considered in cost-ef-

fectiveness studies, which tend to focus on direct medical

costs, but these may be important factors to patients.59

Unlike warfarin, none of the new anticoagulants require

monitoring—an important advantage in terms of both

convenience and cost. However, the absence of neces-

sary monitoring may not be suffi cient to designate the

novel agents more cost-effective than warfarin.

Recent cost-comparison analyses have indicated that

dabigatran 150 mg twice daily is cost-effective compared

with warfarin in AF patient populations at high risk of

hemorrhage or high risk of stroke. Using a decision anal-

ysis model, Shah and Gage demonstrated that dabigatran

was cost-effective versus warfarin in a hypothetical co-

hort of 70-year-old AF patients, based on patient crite-

ria derived from the RE-LY study.60 Their model showed

that dabigatran was cost-effective in patients with a

high stroke risk (CHADS2 >3) and in lower-risk patients

(CHADS2 of 2) with high risk of major hemorrhage. Ka-

mel and colleagues used a similar model to show the



cost-effectiveness of dabigatran 150 mg twice daily in AF

patients with prior stroke or TIA.61 However, in both stud-

ies, the cost-effectiveness of dabigatran was associated

with the adequacy of warfarin INR management.

Another potential economic advantage of the new an-

ticoagulants is improved patient compliance. Data indi-

cate that discontinuation of warfarin is common among

patients, particularly after a bleeding event and as a result

of safety concerns and the economic burden of INR test-

ing and dose adjustments. Discontinuation of treatment

has been demonstrated to signifi cantly increase healthcare

costs by placing patients at high risk for stroke.57

Despite the clinical and potential economic advan-

tages of the new anticoagulants, complications such as

bleeding remain at the forefront of physician and patient

concerns due to the limited strategies available for re-

versal of their anticoagulant effects. Regardless of the

relatively short half-lives of these agents, immediate an-

ticoagulation reversal may be required in cases of major

bleeding or emergency surgery. Prothrombin complex

concentrate has been considered for use as a potential

antidote due to its high concentration of clotting fac-

tors and ability to enhance thrombin generation. Eeren-

berg and colleagues were the fi rst to evaluate the use

of prothrombin complex concentrate for anticoagulation

reversal of dabigatran and rivaroxaban in humans.62 The

results of the clinical trial showed that the anticoagulant

effect of rivaroxaban was completely reversed immedi-

ately after infusion of prothrombin complex concentrate

in all subjects, whereas the anticoagulant effect of dabi-

gatran remained unaffected. While this study may have

important clinical implications, it is important to note

that all tests were performed in healthy volunteers; the

effect of prothrombin complex concentrate has yet to

be confi rmed in patients with bleeding events who are

treated with these anticoagulants.62

Unlike traditional anticoagulants, a defi ning disadvan-

tage of the new agents is the absence of an antidote.

Furthermore, because there are currently no defi nitive

methods by which to monitor the anticoagulant activ-

ity and intensity of the these agents, it is important that

physicians take into consideration various patient charac-

teristics (eg, age, weight, CrCl, CHADS2 score) and align

therapy choice with clinical outcomes seen in similar pa-

tient populations.

SUMMARYPharmacists have an important role to play in the

pharmacologic management of patients on warfarin. The

identifi cation of potential food and drug interactions,

patient counseling and guidance, and frequent INR test-

ing are all factors that must be carefully monitored during

anticoagulation therapy. The new oral anticoagulants of-

fer potential advantages over warfarin, particularly related

to major hemorrhage, ease of use, and ability to maintain

similar levels of protection against stroke in AF patients.

However, a number of questions remain unanswered, such

as the comparative effi cacy and safety of these agents rela-

tive to one another, the impact of administration sched-

ules on compliance, and the cost-effectiveness of these

agents relative to warfarin. Additional research is needed

to answer these questions, and future head-to-head stud-

ies examining the effi cacy of these new anticoagulants

are unlikely. Ultimately, the drug product selection and

decision process, as well as the number and various types

of FDA-approved indications, will be important in further

defi ning the relative effi cacy and safety of these agents

when used in real-world settings.

Acknowledgment

The author would like to acknowledge Lisa Grauer, MSc, who pro-vided editorial support with funding from Janssen Scientifi c Affairs, LLC.

Author Affi liation: From Department of Pharmacy Practice, Creigh-ton University School of Pharmacy and Health Professions, Omaha, NE.

Funding Source: None.

Author Disclosures: Dr Hilleman reports that he has received grants from Baxter, sanofi -aventis, and Gilead, as well as lecture fees from Janssen, Abbot, sanofi -aventis, Baxter, and AstraZenca.

Authorship Information: Concept and design; acquisition of data; drafting of the manuscript; critical revision of the manuscript for impor-tant intellectual content; and supervision.

Address correspondence to: Daniel E. Hilleman, PharmD, Depart-ment of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, 2500 California Plaza, Omaha, NE 68178. E-mail: [email protected].

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