INSIDE THIS ISSUE: ROFLUMILAST (DALIRESP®): A SELECTIVE

PHOSPHODIESTERASE-4 INHIBITOR FOR THE PREVENTION OF ACUTE EXACERBATIONS OF

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

APIXABAN (ELIQUIS®) FOR ORAL ANTICOAGULATION IN NONVALVULAR ATRIAL

FIBRILLATION

hronic obstructive pulmonary disease (COPD) is a progressive lung disease involving an exag-gerated inflammatory response to harmful par-

ticles and gases. The American Thoracic Society de-fines COPD as a preventable and treatable disease state characterized by airflow limitation that is not fully reversible.1 Patients with COPD generally present with characteristics of chronic bronchitis, characterized by inflammation and sputum production, and emphyse-ma, characterized by structural changes of the alveoli.2,3

Chronic obstructive pulmonary disease is associated with significant morbidity and mortality and was the 3rd leading cause of death in the United States and the 4th leading cause of death in the world.2,4 An estimated 15 million Americans have a diagnosis of COPD.5 How-ever, many adults with COPD are unaware that they have impaired lung function, thus the number of peo-ple affected may actually be much higher.6 The number of deaths attributable to COPD is expected to increase by up to 30% over the next decade owing to continued exposure to causative agents (e.g., tobacco smoke) and an aging population.2,7

According to the American Thoracic Society and

European Respiratory Society Task Force, COPD ac-counts for over 15 million physician office visits, 1.5 million emergency room visits, and 700,000 hospitali-zations annually.8 The direct and indirect costs of COPD in the United States are estimated at $29.5 bil-lion and $20.4 billion, respectively.9 Acute exacerba-tions of COPD (AECOPDs) account for a significant proportion of the disease burden, estimated at any-where from 35% to 84% of the total economic costs of COPD.10 Moreover, a direct relationship exists be-tween the severity of disease, characterized by acute exacerbations and hospitalizations, and the total cost of care.2 Aside from economic burden, AECOPDs are associated with hospitalizations, further decline in lung function, and reduced quality of life.11-13

Prevention of AECOPDs is a major focus of dis-ease management. Strategies for preventing exacerba-

MATERIA MEDICA Volume 2, Issue 5 www.ucdenver.edu/pharmacy/materiamedica Oct 2013 1

Roflumilast (Daliresp®): A Selective Phosphodiesterase-4 Inhibitor for the Prevention of Acute Exacerbations of

Chronic Obstructive Pulmonary Disease

Holly Smith, PharmD candidate

C

ATERIA EDICA Volume 2, Issue 5 October 2013

Editor’s Summary: Roflumilast (Daliresp®)

Description & Indication

Selective phosphodiesterase-4 inhibitor; not a bronchodi-lator and thus not useful for acute bronchospasms

Indicated for reducing COPD exacerbations in patients with severe COPD associated with bronchitis and a histo-ry of exacerbations

Dosing

Administered as a 500 mcg oral tablet once daily, with or without food

No renal adjustments needed; caution is recommended in mild hepatic impairment (Child-Pugh A), whereas use is not recommended in moderate-to-severe hepatic failure

Efficacy

Effective at improving FEV1 (by ~40-100 mL) and reduc-ing acute exacerbations in more advanced COPD dis-ease (GOLD III-IV) in placebo-controlled trials

Improves FEV1 when used in combination with long-acting β2-agonists and tiotropium

Safety

Generally well-tolerated; adverse events are primarily GI-related (diarrhea, nausea, decreased appetite and weight-loss); between 14% and 29% of roflumilast-treated pa-tients withdrew from phase 3 trials (vs. 11% to 22% of placebo-treated patients)

samples of the roflumilast-treated group.17 Moreover, the sputum samples collected from the roflumilast-treated group also had significantly fewer inflammatory markers.17 Another study confirmed that roflumilast inhibited endotoxin-induced migration of neutrophils and eosinophils into the airway as determined by bron-choalveolar lavage.18 Pharmacokinetics

Roflumilast is rapidly absorbed following oral ad-ministration, reaching peak plasma concentrations in approximately 1 hour. Roflumilast has relatively high bioavailability, a large volume of distribution, and is highly protein bound. Roflumilast is metabolized to its active metabolite via hepatic enzymes CYP 1A2 and 3A4. Further metabolism results in inactive metabo-lites, 70% of which are excreted in urine.14 The phar-macokinetic properties of roflumilast are summarized in Table 1. Drug Interactions

Roflumilast and roflumilast N-oxide are not known to induce or inhibit the P450 enzymes. Strong inducers of CYP 1A2 or 3A4 enzymes may decrease systemic exposure to roflumilast and concomitant use should be avoided. These drugs include, most notably, rifampicin, phenobarbital, carbamazepine, and phenytoin.14 Alter-natively, concomitant use of inhibitors of CYP 1A2 and 3A4 enzymes could increase systemic exposure to roflumilast. Cimetidine, fluvoxamine, erythromycin, and ketoconazole should be used with caution if con-comitant roflumilast therapy is planned, although phar-macokinetic studies indicate that significant interac-tions are unlikely between roflumilast and either eryth-romycin or ketoconazole.14,19,20

Importantly, roflumilast has no known drug inter-actions with other respiratory medications indicated for use in COPD, including inhaled budesonide, theo-phylline, formoterol, montelukast, or salbutamol.21-25 Additionally, no relevant drug interactions were ob-served with midazolam, magnesium or aluminum hy-

tions include smoking cessation, vaccinations (influenza and pneumococcal), proper inhaler tech-nique, and pharmacologic therapy.2 Pharmacologic op-tions for reducing AECOPDs have traditionally in-cluded inhaled corticosteroids, long-acting β2 agonists, and long-acting antimuscarinic agents.2,10 Roflumilast, manufactured by Forest Pharmaceuticals under the brand name Daliresp®, was granted a FDA-approved indication for the treatment of COPD in 2011, and represents a new treatment modality with a novel mechanism of action to be added in the arsenal of pharmacologic therapy aimed at preventing AECOPDs.14 The purpose of this article is to review the role of roflumilast as add-on therapy in preventing AECOPDs.

Mechanism of Action Roflumilast and its active metabolite (roflumilast N

-oxide) are selective phosphodiesterase inhibitors.14

Phosphodiesterases are a family of enzymes that inacti-vate cyclic AMP and cyclic GMP.15 Roflumilast, being selective for phosphodiesterase-4 (PDE4), specifically inhibits activation of cyclic AMP. The exact mecha-nism of action of roflumilast in COPD is not well de-fined, but it is thought to promote accumulation of cyclic AMP in lung cells.14 Accumulation of cyclic AMP activates protein kinase A which inhibits the in-flammatory process by inactivating transcription fac-tors that ultimately promote inflammation.15 Pharmacodynamics

By inhibiting PDE4, roflumilast increases cyclic AMP in immune cells, including neutrophils, eosino-phils, and monocytes. Increased cyclic AMP limits cel-lular infiltration of the lungs, thereby suppressing the immune response.16 A four week crossover study eval-uating sputum samples of subjects treated with roflumilast or placebo found a significant reduction in the number of neutrophils and eosinophils in sputum

CLINICAL PHARMACOLOGY

MATERIA MEDICA Volume 2, Issue 5 www.ucdenver.edu/pharmacy/materiamedica Oct 2013 2

Table 1 | Roflumilast and roflumilast N-oxide pharmacokinetic parameters.14 Parameter Roflumilast Roflumilast N-Oxide Bioavailability 80% n/a Time to Peak Concentration 0.5-2 hours 4-13 hours Time to Steady State 4 days 6 days Volume of Distribution 2.9 L/kg NR Protein Binding 97% 99% Elimination Half-Life 17 hours 30 hours Metabolism CYP 1A2, 3A4 Conjugation n/a = not applicable; NR = not reported.

MATERIA MEDICA Volume 2, Issue 5 www.ucdenver.edu/pharmacy/materiamedica Oct 2013 3

droxide, warfarin, digoxin, or sildenafil in premarketing studies.14

Roflumilast is administered as a 500 microgram oral tablet once daily. Roflumilast can be administered with or without food. Food does not affect the maxi-mum absorption of roflumilast but does impact time to maximal concentration and the maximum concen-tration achieved. Specifically, administration with food decreases the maximum concentration of roflumilast by 40% and the time required to reach this concentra-tion is delayed by 1 hour. The time to maximum con-centration and the maximum concentration achieved of the active metabolite roflumilast N-oxide are unaf-fected by food, thus allowing for administration of roflumilast irrespective of meals.14

Several phase III, multi-center, double-blind, ran-domized, placebo-controlled trials have evaluated the clinical efficacy of roflumilast. Roflumilast has been studied in more than 7500 patients with COPD rang-ing from moderate to very severe GOLD staging. All patients studied were ≥40 years of age and were cur-rent or ex-smokers with a history of ≥10 pack-years. Patients were generally excluded if they had long term oxygen use requirements, other lung diseases, or known alpha-1-antitrypsin deficiency. Concomitant respiratory treatments permitted, chronic bronchitis history, and exacerbation history requirements were variable among trials. A summary of trials can be found in Table 2.

Rabe, et al., evaluated roflumilast versus placebo in a 6-month study in patients who had stable disease and were GOLD stage II-III with a FEV1 of 30% to 80%.26 Patients were randomly assigned to roflumilast or placebo. The only concomitant respiratory treat-ment permitted was salbutamol, a short-acting β2 ago-nist similar to albuterol, or short-acting anticholinergic agents (e.g., ipratropium). Primary efficacy outcomes included post-bronchodilator FEV1 and health-related quality of life assessed with St. George’s respiratory questionnaire (SGRQ), a disease specific instrument to assess symptoms, activity, and impacts. At the end of 6 months, mean FEV1 had declined by 45 mL from baseline in the placebo group and improved by 51 mL in the roflumilast group. The mean difference in FEV1 between groups was 97 mL (p<0.0001), representing a clinically significant improvement in FEV1 of

roflumilast-treated patients. An improvement in SGRQ score was observed in both treatment and pla-cebo groups with no clinically significant difference between treatment groups. 26

In a subsequent longer-term (1-year) study in a sim-ilar patient population (i.e., GOLD Stage III-IV), Cal-verley, et al., randomly assigned patients to roflumilast or placebo.27 Patients included in this study had stable disease with a FEV1 ≤50% and were permitted to use concomitant salbutamol, short-acting anticholinergic agents, and inhaled corticosteroids. Primary efficacy outcomes again included post-bronchodilator FEV1, and also the number of moderate or severe exacerba-tions per patient per year. A moderate exacerbation was defined as symptomatic deterioration requiring treatment with systemic corticosteroids or antibiotics. A severe exacerbation was defined as requiring hospi-talization. This study found a mean decline from base-line FEV1 of 26 mL in the placebo group and an im-provement in FEV1 of 12 mL in the roflumilast group. The difference in FEV1 between groups was 39 mL (p=0.001) representing a clinically significant improve-ment in FEV1 of roflumilast-treated patients. The total number of exacerbations and the number of patients requiring hospitalization did not differ significantly be-tween groups; however, the number of patients requir-ing treatment with systemic corticosteroids as outpa-tients was significantly lower in those treated with roflumilast. Additionally, 36% fewer exacerbations oc-curred in GOLD stage IV patients treated with roflumilast compared to similarly staged patients treat-ed with placebo. These results were independent of concomitant inhaled corticosteroid use.27

Calverley, et al., went on to conduct two additional 1-year trials to determine if roflumilast would reduce the frequency of exacerbations requiring systemic cor-ticosteroids in patients with COPD.28 Patients were randomly assigned to roflumilast or placebo. Patients included in these trials again had a FEV1 ≤50%, but also had a history of chronic bronchitis and exacerba-tions, having had at least one exacerbation requiring systemic corticosteroids or hospitalization within the past year. Concomitant use of short-acting β2 agonists, short-acting anticholinergic agents, and continuation of long-acting β2 agonists was permitted. Concomitant use of inhaled corticosteroids and long-acting antimus-carinic agents was excluded. Primary efficacy outcomes included pre-bronchodilator FEV1 and rate of moder-ate or severe exacerbations. Pooled analyses of these studies revealed a 40 mL improvement in mean pre-bronchodilator FEV1 in roflumilast-treated patients, while a 9 mL decline in pre-bronchodilator FEV1 was

DOSING & ADMINISTRATION

CLINICAL EFFICACY

MATERIA MEDICA Volume 2, Issue 5 www.ucdenver.edu/pharmacy/materiamedica Oct 2013 4

Tab

le 2

| S

um

mar

y o

f tr

ials

ass

essi

ng

clin

ical

eff

icac

y o

f ro

flu

mila

st.

Tri

al

Des

ign

In

terv

enti

on

&

Du

rati

on

Co

nco

mit

ant

Th

erap

ies

P

erm

itte

d

Po

pu

lati

on

P

rim

ary

O

utc

om

es

Res

ult

s R

abe,

et

al.

(200

5)26

P

hase

III

M

ultic

ente

r

Dou

ble-

blin

d

Ran

dom

ized

Pla

cebo

-co

ntro

lled

R

oflu

mila

st

vers

us p

la-

cebo

6-m

onth

s

S

albu

tam

ol &

sh

ort-

actin

g an

ticho

liner

-gi

c ag

ents

14

11 p

atie

nts,

≥ 4

0 ye

ars

of a

ge

C

urre

nt o

r ex

-sm

oker

s ≥

10 p

ack

year

s

FE

V1

30%

to 8

0%

G

OLD

II-I

II

S

tabl

e di

seas

e

P

ost-

bron

chod

ilato

r F

EV

1

HR

QoL

as-

sess

ed w

ith

the

SG

RQ

S

igni

fican

t im

prov

emen

t in

FE

-V

1 in

rof

lum

ilast

-tre

ated

pat

ient

s

No

diffe

renc

e be

twee

n gr

oups

in

SG

RQ

sco

re

Cal

verl

ey,

et

al.

(200

7)27

P

hase

III

M

ultic

ente

r

Dou

ble-

blin

d

Ran

dom

ized

Pla

cebo

-co

ntro

lled

R

oflu

mila

st

vers

us p

la-

cebo

1-ye

ar

S

albu

tam

ol,

inha

led

cort

i-co

ster

oids

, &

shor

t-ac

ting

antic

holin

er-

gic

agen

ts

15

13 p

atie

nts,

≥ 4

0 ye

ars

of a

ge

C

urre

nt o

r ex

-sm

oker

s ≥

10 p

ack

year

s

FE

V1 ≤

50%

GO

LD II

I-IV

Sta

ble

dise

ase

P

ost-

bron

chod

ilato

r F

EV

1

No.

of m

oder

-at

e or

sev

ere

exac

erba

tions

/ pa

tient

/yea

r

S

igni

fican

t im

prov

emen

t in

FE

-V

1 in

rof

lum

ilast

-tre

ated

pat

ient

s

No

diffe

renc

e be

twee

n gr

oups

in

num

ber

of m

oder

ate

or s

e-ve

re e

xace

rbat

ions

Cal

verl

ey,

et

al.

M2-

124

(200

9)28

P

hase

III

M

ultic

ente

r

Dou

ble-

blin

d

Ran

dom

ized

Pla

cebo

-co

ntro

lled

R

oflu

mila

st

vers

us p

la-

cebo

1-ye

ar

S

hort

-act

ing

β2 ag

onis

ts,

long

-act

ing β

2 ag

onis

ts, &

sh

ort-

actin

g an

timus

ca-

rinic

age

nts

15

25 p

atie

nts,

≥ 4

0 ye

ars

of a

ge

C

urre

nt o

r ex

-sm

oker

s ≥

20 p

ack

year

s

FE

V1 ≤

50%

GO

LD II

I-IV

Chr

onic

bro

nchi

tis &

his

tory

of f

re-

quen

t exa

cerb

atio

ns

P

re-

bron

chod

ilato

r F

EV

1

Rat

e of

mod

er-

ate

or s

ever

e ex

acer

batio

ns

S

igni

fican

t im

prov

emen

t in

pre-

bron

chod

ilato

r F

EV

1 in

ro

flum

ilast

-tre

ated

pat

ient

s

Sig

nific

ant r

educ

tion

in th

e ra

te

of m

oder

ate

or s

ever

e ex

acer

-ba

tions

in r

oflu

mila

st-t

reat

ed

patie

nts

Cal

verl

ey,

et

al.

M2-

125

(200

9)28

P

hase

III

M

ultic

ente

r

Dou

ble-

blin

d

Ran

dom

ized

Pla

cebo

-co

ntro

lled

R

oflu

mila

st

vers

us p

la-

cebo

1-ye

ar

S

hort

-act

ing

β2 ag

onis

ts,

long

-act

ing β

2 ag

onis

ts, &

sh

ort-

actin

g an

timus

ca-

rinic

age

nts

15

71 p

atie

nts,

≥40

yea

rs o

f age

Cur

rent

or

ex-s

mok

ers ≥

20 p

ack

year

s

FE

V1 ≤

50%

GO

LD II

I-IV

Chr

onic

bro

nchi

tis &

his

tory

of f

re-

quen

t exa

cerb

atio

ns

P

re-

bron

chod

ilato

r F

EV

1

Rat

e of

mod

er-

ate

or s

ever

e ex

acer

batio

ns

S

igni

fican

t im

prov

emen

t in

pre-

bron

chod

ilato

r F

EV

1 in

ro

flum

ilast

-tre

ated

pat

ient

s

Sig

nific

ant r

educ

tion

in th

e ra

te

of m

oder

ate

or s

ever

e ex

acer

-ba

tions

in r

oflu

mila

st-t

reat

ed

patie

nts

Fab

bri

, et

al.

M2-

127

(200

9)29

P

hase

III

M

ultic

ente

r

Dou

ble-

blin

d

Ran

dom

ized

Pla

cebo

-co

ntro

lled

R

oflu

mila

st

& s

alm

eter

-ol

ver

sus

salm

eter

ol

alon

e

6-m

onth

s

S

hort

-act

ing

β2

agon

ists

935

patie

nts,

≥ 4

0 ye

ars

of a

ge

C

urre

nt o

r ex

-sm

oker

s ≥

10 p

ack

year

s

FE

V1

40%

to 7

0%

G

OLD

II-I

II

S

tabl

e di

seas

e

P

re-

bron

chod

ilato

r F

EV

1

S

igni

fican

t im

prov

emen

t in

pre-

bron

chod

ilato

r F

EV

1 in

ro

flum

ilast

-tre

ated

pat

ient

s

Fab

bri

, et

al.

M2-

128

(200

9)29

P

hase

III

M

ultic

ente

r

Dou

ble-

blin

d

Ran

dom

ized

Pla

cebo

-co

ntro

lled

R

oflu

mila

st

& ti

otro

pi-

um v

ersu

s tio

trop

ium

al

one

6-

mon

ths

S

hort

-act

ing

β2 ag

onis

ts

74

4 pa

tient

s, ≥

40

year

s of

age

Cur

rent

or

ex-s

mok

ers ≥1

0 pa

ck

year

s

FE

V1

40%

to 7

0%

G

OLD

II-I

II

C

hron

ic c

ough

& s

putu

m p

rodu

c-tio

n &

freq

uent

use

of s

hort

-act

ing

β2

agon

ist d

urin

g ru

n in

per

iod

P

re-

bron

chod

ilato

r F

EV

1

S

igni

fican

t im

prov

emen

t in

pre-

bron

chod

ilato

r F

EV

1 in

ro

flum

ilast

-tre

ated

pat

ient

s

GO

LD

= G

loba

l Ini

tiativ

e fo

r C

hro

nic

Obs

truc

tive

Lung

Dis

ease

; F

EV

1 =

forc

ed e

xpir

ator

y vo

lum

e in

one

sec

ond;

HR

Qo

L =

hea

lth-r

elat

ed q

ualit

y of

life

; S

GR

Q =

St.

Ge

orge

’s r

espi

rato

ry q

uest

ion-

naire

.

observed in placebo-treated patients. The between group difference in mean pre-bronchodilator FEV1 was 48 mL (p<0.0001), representing a clinically signifi-cant improvement in FEV1 for roflumilast-treated pa-tients compared to placebo. A significant reduction in exacerbations was also observed among those treated with roflumilast (relative risk [RR] 0.83; p=0.0003). The reduced number of exacerbations was driven by a reduction of moderate exacerbations requiring system-ic corticosteroids. No difference in the number of se-vere exacerbations (those requiring hospitalization) was observed. These results were independent of long-acting β2 agonist use.28

Finally, two 6-month studies were conducted by Fabbri, et al., to determine the effects of roflumilast in patients already being treated with long-acting bron-chodilators. The first study randomly assigned patients to salmeterol plus roflumilast or salmeterol alone.29 Pa-tients included in this trial had stable, GOLD stage II-III disease. The second study randomly assigned pa-tients to tiotropium plus roflumilast or tiotropium alone.29 Patients included in this trial had GOLD stage II-III disease, but also had a history of bronchitis and frequent use of short-acting β2 agonists during the run-in period. The primary efficacy outcome of both stud-ies was pre-bronchodilator FEV1. Roflumilast-treated patients in each of the two trials had significant im-provement in pre-bronchodilator FEV1 indicating ad-ditive effects with long-acting β2 agonists and tiotropi-um.29

Roflumilast is generally well-tolerated. Serious ad-verse effects occurred in a similar proportion of pa-tients in clinical trials in both roflumilast and placebo groups; however, a higher rate of discontinuation at-tributable to adverse effects was observed in patients

MATERIA MEDICA Volume 2, Issue 5 www.ucdenver.edu/pharmacy/materiamedica Oct 2013 5

treated with roflumilast. Study withdrawal due to ad-verse events was observed in 14% to 29% of roflumilast-treated patients and in 11% to 22% of pa-tients receiving placebo.26-28 The most common ad-verse effects associated with roflumilast were gastroin-testinal adverse effects, weight loss, headache, and in-somnia. The majority of gastrointestinal adverse effects such as nausea and diarrhea occurred within the first several weeks of treatment and resolved during the study periods. Weight loss was more common in pa-tients also experiencing other gastrointestinal adverse effects. Roflumilast was associated with higher inci-dence of both headache and insomnia compared to placebo. No increase in respiratory infections was ob-served in roflumilast-treated patients.26-29 Common ad-verse effects occurring in ≥2% of patients treated with roflumilast are summarized in Table 3.

Roflumilast is contraindicated in patients with moderate-to-severe liver impairment including Child-Pugh B or C. The AUC of roflumilast is increased sig-nificantly in patients with decreased hepatic function.14

Roflumilast has not been observed to have bronchodi-latory effects in humans and should not be thought of as a bronchodilator nor considered for rescue therapy during acute bronchospasm.14 In addition, clinical trials and post-marketing observations have demonstrated an association between roflumilast and increased psy-chiatric adverse events including insomnia, anxiety, and depression. Three cases of suicidal adverse events were reported in roflumilast-treated patients, including two attempted suicides and one completed suicide. These psychiatric adverse events were not associated with pre-existing depressive disorders.14,28,29

Roflumilast was associated with weight loss in clini-cal trials. On average 7.5% of patients treated with roflumilast lost weight (mean, 2 kg), and this weight loss was independent of baseline body mass in-dex.14,28,29 Both moderate (5% to 10% of body weight), and severe (>10% of body weight) losses have been reported.14

The cost associated with treating COPD is signifi-cant. Preferred treatment options generally cost well over two hundred dollars per month, with the excep-tion of some inhaled corticosteroids with generic avail-ability. Retail prices of roflumilast and alternative treat-ments for COPD are detailed in Table 4.

WARNINGS & PRECAUTIONS

SAFETY & TOLERABILITY

ECONOMIC CONSIDERATIONS

Table 3 | Average incidence of adverse effects in phase III clinical trials of roflumilast.14

Adverse Effect Roflumilast Placebo

Diarrhea 9.5% 2.7%

Nausea 4.7% 1.4%

Decreased Appetite 2.1% 0.4%

Weight Loss 7.5% 2.1%

Headache 4.4% 2.1%

Insomnia 2.4% 1.0%

Influenza 2.8% 2.7%

Back Pain 3.2% 2.2%

Dizziness 2.1% 1.1%

MATERIA MEDICA Volume 2, Issue 5 www.ucdenver.edu/pharmacy/materiamedica Oct 2013 6

Roflumilast, a selective PDE4 inhibitor targeting the underlying inflammatory process mediating COPD, has demonstrated efficacy in multiple clinical trials. Roflumilast has been shown to significantly im-prove pre-bronchodilator FEV1 as well as post-bronchodilator FEV1. Improvements in lung function are sustained over at least 1-year and appear to be addi-tive to effects of long-acting β2 agonists and long-acting antimuscarinic agents. Roflumilast decreases acute exacerbations of COPD, particularly moderate exacerbations requiring systemic corticosteroids in pa-tients with GOLD stage III and IV disease who have chronic bronchitis or a history of exacerbations at baseline. However, comparative data against other commonly-used COPD medications are lacking. Nev-ertheless, roflumilast has been incorporated into the 2013 GOLD guidelines as a treatment option in com-bination with at least one long-acting bronchodilator for patients with chronic bronchitis who are classified as GOLD group C or D.2 A study is currently under-way to determine the effects of roflumilast in patients with COPD who are already managed with combina-tion therapy including a long-acting β2 agonist and in-haled corticosteroid yet still having frequent exacerba-tions.30

REFERENCES

1. Akinbami LJ, Liu X. Chronic obstructive pulmonary disease

among adults aged 18 and over in the United States, 1998-2009. National Center for Health Statistics Data Brief 2011 Jun;(63):1-8.

2. Global Initiative for Chronic Obstructive Lung Disease. Global Stragety for the Diagnosis, Management, and Preven-tion of Chronic Obstructive Pulmonary Disease; 2013. h t tp ://www.go ldcopd .org/up loads/use r s/ f i l e s/GOLD_Report_Feb20.pdf. Accessed September 2013.

3. Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysio-

logic Approach. 8th ed. New York: McGraw-Hill; 2011. h t tp ://www.acce s spha rmacy . com/con ten t . a spx?aID=7975888. Accessed September 2013.

4. Hoyert DL, Xu JQ. Deaths: preliminary data for 2011. Natl Vital Stat Rep. 2012;61(6):1-65.

5. Centers for Disease Control and Prevention. Chronic ob-structive pulmonary disease among adults—United States, 2011. MMWR. 2012;61(46):938-943.

6. Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Exami-nation Survey 1988-1994. Arch Intern Med. 2000;160:1683-1689.

7. World Health Organization. Chronic respiratory diseases: Burden of COPD. Available at: http://www.who.int/respiratory/copd/burden/en/index.html. Accessed Septem-ber 2013.

8. Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A sum-mary of the ATS/ERS position paper. Eur Respir J 2004;23:932-946.

9. National Heart, Lung, and Blood Institute. Morbidity and mortality chartbook on cardiovascular, lung and blood diseas-es. Bethesda, Maryland: US Department of Health and Hu-man Services, Public Health Service, National Institutes of Health; 2012. Available at: http://www.nhlbi.nih.gov/resources/docs/2012_ChartBook_508.pdf. Accessed Sep-tember 2013.

10. Marchetti N, Criner GJ, Albert RK. Preventing acute exacer-bations and hospital admissions in COPD. Chest 2013 May;143(5):1444-54.

11. Donaldson GC , Seemungal TA , Bhowmik A , Wedzicha JA . Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847–852.

12. Seemungal TA , Donaldson GC , Paul EA , Bestall JC , Jef-fries DJ , Wedzicha JA . Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157(5.1):1418–1422.

13. Conners AF, Dawson NV, Thomas C, Harrell FE, Desbriens N, Fulkerson WJ, et al. Outcomes Following Acute Exacer-bation of Severe Chronic Obstructive Lung Disease. Am J Respir Crit Care Med 1997;155(1):386.

14. Dalirespâ [package insert]. St. Louis, MO: Forrest Pharma-ceuticals, Inc.;2013.

15. Barnette MS. Phosphodiesterase 4 (PDE4) inhibitors in asth-ma and chronic obstructive pulmonary disease (COPD). Prog Drug Res. 1999;53:193-229.

16. Taegtmeyer AB, Leuppi JD, Kullak-Ublick GA. Roflumilast-a phosphodiesterase-4 inhibitor licensed for add-on therapy in severe COPD. Swiss Med Wkly. 2012;142:w13628.

17. Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62:1081-1087.

18. Hohlfeld JM, Schoenfeld K, Lavae-Mokhtari M, et al. Roflumilast attenuates pulmonary inflammation upon seg-mental endotoxin challenge in healthy subjects: A random-ized placebo-controlled trial. Pulmonary Pharmacology & Therapeutics 2008;21:616-623.

19. Lahu G, Huennemeyer A, Herzog R, McCracken N, Her-mann R, Elmlinger M, Zech K. Effect of repeated dose of

CONCLUSIONS

Table 4 | Retail cost of roflumilast and alternative COPD medications.

Medication Rite Aid Walgreens IM Lowry

Roflumilast $234.59 $239.20 $220.28 Salmeterol $226.94 $269.99 $210.37

Advair $246.49 $286.99 $237.69

Tiotropium $316.19 $349.99 $285.97 Fluticasone $282.19 $345.99 $276.55

MATERIA MEDICA Volume 2, Issue 5 www.ucdenver.edu/pharmacy/materiamedica Oct 2013 7

erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. Int J Clin Pharmacol Ther 2009;47(4):236-45.

20. Lahu G, Huennemeyer A, von Richter O, Hermann R, Her-zog R, McCracken N, Zech K. Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide. J Clin Pharmacol 2008;48(11):1339-49.

21. Hermann R, Siegmund W, Giessmann T, Westphal K, Weinbrenner A, Hauns B, Reutter F, Lahu G, Zech K, Bethke TD. The oral, once-daily phosphodiesterase 4 inhibi-tor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide. J Clin Pharmacol 2007;47(8):1005-13.

22. Bohmer G, Gleiter CH, Hunnemeyer A, Lahu G, Bethke TD. Study investigating pharmacokinetic interaction between theophylline and roflumilast in healthy adults. Int J Clin Phar-macol Ther 2011;49(7):451-60.

23. De Mey C, Nassr N, Lahu G. No relevant cardiac, pharmaco-kinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study. BMC Clin Pharmacol 2011;11:7.

24. Bohmer GM, Nassr N, Wenger M, et al. The targeted oral, once-daily phosphodiesterase inhibitor roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions. J Clin Pharmacol 2009;49(4):389-97.

25. Bethke TD, Giessmann T, Wstphal K, et al. Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects. Int J Clin Pharmacol Ther 2006;44(11):572-9.

26. Rabe KF, Bateman ED, O’Donnell D, et al. Roflumilast-an oral anti-inflammatory treatment for chronic obstructive pul-monary disease: a randomised controlled trial. Lancet 2005;366:563-71.

27. Calverley PM, Sanchez-Toll F, McIvor A, et al. Effect of 1-Year Treatment with Roflumilast in Severe Chronic Obstruc-tive Pulmonary Disease. Am J Respir Crt Care Med 2007;176:154-161.

28. Calverley PM, Rabe, KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685-94.

29. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pul-monary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009: 374:695-703.

30. Calverley PM, Martinez FJ, Fabbri LM, et al. Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol. Int J Chron Obstructive Pulmon Dis 2012;7:375-82.

trial fibrillation (AFib) is the most common cardiac arrhythmia, affecting over 2.2 million individuals in the US.1 As a result of an aging

population, this figure is expected to double by 2050, given the higher prevalence of AFib in the elderly.2 The greatest concern with AFib is the increased risk of stroke. In comparison to the general population, per-sons with nonvalvular AFib are at a 5-fold increased risk of stroke, and stroke remains the third leading cause of death and the principal cause of serious long-term disability in the US.3

Pharmacologic antithrombotic strategies have be-come the first line therapy to prevent cardioembolic stroke.3 Historically, vitamin K antagonist (VKA) ther-apies (e.g., warfarin) have been the antithrombotic of choice for patients with AFib, and these agents reduce the risk of stroke by approximately 65%.4 However, VKA therapy is associated with several limitations, in-cluding a narrow therapeutic range, the need for life-

Apixaban (Eliquis®) for Oral Anticoagulation in Nonvalvular

Atrial Fibrillation

Alex Giannakopoulos, PharmD candidate

A

Editor’s Summary: Apixaban (Eliquis®)

Description & Indication

Reversible and selective Factor Xa inhibitor (both free and clot-bound) that ultimately inhibits thrombin formation

Indicated for the prevention of stroke and systemic embo-lism in patients with nonvalvular atrial fibrillation in the U.S. (additional indications outside of the U.S.)

Dosing

Administered as a 5 mg oral tablet twice daily, with or without food; lower dose (2.5 mg twice daily) indicated for patients with ≥2 of the following: age ≥80 years, weight ≤60 kg, SCr ≥1.5 mg/dL

See Dosing section for hepatic and renal impairment dose adjustments

Efficacy

More effective at reducing risk of cardioembolic stroke due to nonvalvular atrial fibrillation compared with dose-adjusted warfarin and aspirin (in patients for whom warfa-rin was unsuitable)

Safety

Generally well-tolerated; lower risk of bleeding relative to warfarin and similar risk relative to aspirin in phase 3 tri-als; approximately 2% of patients/year had major bleed-ing while using apixaban

No antidote available for reversal of anticoagulant effect

long monitoring, increased risk of bleeding, and the potential for drug, lifestyle and food interactions. The complexity of VKAs has led to the development and approval of new anticoagulants to decrease the cardio-embolic complications associated with AFib.3

To determine which persons with AFib are candi-dates for oral anticoagulation, patients with AFib are stratified according to stroke risk stratification tools, most commonly CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack).5 Current guidelines recommend that anticoagulation be initiated in those with a CHADS2 score of 1 or greater.5 At the time of the most recent release of the AFib management guidelines, the only anticoagulants with FDA-approved indications for cardioembolic stroke prevention in pa-tients with AFib were the VKAs and dabigatran etexi-late (thrombin inhibitor); therefore, rivaroxaban and apixaban, both factor Xa inhibitors, were not included in the recommendations.5 However, rivaroxaban and apixaban are now FDA-approved for the prevention of stroke and systemic embolism in persons with non-valvular AFib.

The development of apixaban, an oral agent that directly inhibits factor Xa represents an important ad-vance in the prevention of stroke and systemic embo-lism in patients with AFib, due to its ease of use, effi-cacy and safety established in clinical trials. In addition to apixaban's FDA-approved indication for stroke pre-vention in persons with AFib, apixaban is used in oth-er countries for postoperative venous thromboprophy-laxis and venous thromboemoblism (DVT or PE) treatment. The purpose of this article is to review the pharmacology, efficacy, safety, dosing, and cost-effectiveness of apixaban for the indication of throm-boprophylaxis in patients with nonvalvular AFib.

Administered orally, apixaban is a direct, highly se-lective, reversible inhibitor of factor Xa.6 Factor Xa converts prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation.7 Apixaban inhibits factor Xa activity by binding to the active site on factor Xa, thereby decreas-ing thrombin generation and thrombus formation.8

In patients with DVT and acute coronary syn-dromes, apixaban has demonstrated significantly re-duced markers of thrombin generation and fibrin for-mation.9 In vitro studies, apixaban has demonstrated no direct effect on platelet aggregation, but has demonstrated the ability to indirectly inhibit thrombin-induced platelet aggregation.10 The combination of apixaban's indirect antiplatelet effect and direct an-tithrombotic and anticoagulant activity suggests that apixaban may prove beneficial in the prevention and treatment of both venous and arterial thrombosis, however further clinical trials are needed to determine this.10

Apixaban does not require routine anticoagulation monitoring, however, an assay (Rotachrom® anti-FXa assay) is available if necessary, but it is not used rou-tinely in clinical practice. Although apixaban doses of 2.5 mg or 5 mg twice daily have resulted in modest prolongation of the INR, prothrombin time (PT) and activated partial thromboplastin time (aPTT) changes in these tests were not clinically useful for measuring the anticoagulant activity of apixaban. Unfortunately, the degrees of change in the INR, PT and aPTT were not reported.11

Currently, no antidote is available to reverse the anticoagulant effect of apixaban which can be expected to persist for approximately 24 hours following the last

PHARMACOLOGY

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Table 1 | Pharmacokinetics of apixaban.12

Absorption GI tract; 55% occurring in distal small bowel and ascending colon Absolute bioavailabilitya 50% Pharmacokinetic dose-to-response dose-related linear pharmacokinetic exposure Effect of food No change in bioavailability of apixaban Plasma protein binding 87% Volume of distribution 21 L Metabolism Cytochrome P450 3A4 (CYP3A4) Main component in human plasma Parent Drug Recovery in feces and urine 25% as metabolites Renal excretion 27% of total apixaban clearance Renal excretion clearance rate 3.3 L/hour Elimination of apixaban into feces Through biliary and direct intestinal excretion Half-life 12 hours with repeat dosing aDoses up to 10 mg.

dose.12 However a potential antidote is currently under investigation (PRT064445).14 See Table 1 for the phar-macokinetic profile of apixaban.13

The safety and efficacy of apixaban for prevention of stroke in persons with nonvalvular AFib was as-sessed in two phase III randomized controlled trials.

ARISTOTLE

The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events) trial com-pared oral apixaban versus warfarin on the risk of stroke or systemic embolism in patients with AFib.16 All patients enrolled in the ARISTOTLE trial met CHADS2 criteria indicating anticoagulation; however, the inclusion criteria (age ≥75 years; previous stroke, TIA or systemic embolism; symptomatic heart failure within the previous 3 months or LVEF of ≤40%, dia-betes or hypertension requiring pharmacological treat-ment) did exclude some persons that met CHADS2 criteria indicating anticoagulation, such as those with asymptomatic heart failure. The ARISTOTLE trial was a randomized, double-blind, multinational, phase III trial that assigned 18,201 patients to treatment. See Ta-ble 2 for a description of study design. Efficacy was

assessed utilizing an intention-to-treat analysis. The median age of participants enrolled in the trial was 70 years. Median duration of follow-up was 1.8 years.16

At doses of 2.5 mg twice daily and 5 mg twice daily, apixaban was shown to be superior to warfarin for the prevention of stroke or systemic embolism in patients with AFib who had at least one additional risk factor for stroke (hazard ratio [HR] 0.79; 95% CI 0.66–0.95; p=0.01). In those patients taking apixaban, compared to warfarin, the rate of all-cause stroke (1.19% vs. 1.51% per year, respectively; HR 0.79; 95% CI 0.65–0.95; p=0.01) and hemorrhagic stroke (0.24% vs. 0.47% per year, respectively; HR 0.51; 95% CI 0.35–0.75; p <0.001). No significant between-group differ-ences were seen for rates of ischemic or uncertain types of strokes. All-cause death was significantly re-duced by 11% in patients receiving apixaban compared to those receiving warfarin (HR 0.89; 95% CI 0.80–0.99; p=0.047). The rate of myocardial infarction (MI) did not significantly differ between the apixaban and warfarin treatment groups.16

Adverse events occurred in almost equal propor-tions of patients, 81.5% of apixaban recipients and in 83.1% of warfarin recipients.16 The most common rea-son for treatment discontinuation in the ARISTOTLE trial was for bleeding-related adverse events. Discon-tinuation due to bleeding related events occurred in

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Table 2 | ARISTOTLE study design.16 Active treatment groups:  Apixaban 5 mg twice daily or apixaban 2.5 mg twice daily if any two or more of the following: age ≥80 years, body-

weight ≤60 kg, serum creatinine ≥1.5 mg/dL  Warfarin dose-adjusted target INR 2.0–3.0 (median time spent in INR therapeutic range = 66% across study duration) Inclusion criteria  AFib or atrial flutter at time of enrollment or at least two episodes of AFib or atrial flutter documented on ECG ≥2

weeks apart in the prior 12 months;  ≥1 risk factor for stroke (age ≥75 years; previous stroke, TIA or systemic embolism; symptomatic heart failure within

the previous 3 months or LVEF ≤40%; diabetes; hypertension requiring pharmacological treatment). Exclusion criteria:  AFib with a reversible cause  Moderate or severe mitral stenosis  Conditions other than AFib requiring anticoagulation (e.g. a prosthetic heart valve)  Stroke in the prior 7 days  Need for aspirin dosage of >165 mg/day or for both aspirin and clopidogrel  Severe renal insufficiency Primary efficacy endpointa:  Stroke or systemic embolism Primary safety outcome:  Major bleeding Secondary efficacy endpoints:  Death from any cause  Rate of myocardial infarction Secondary safety endpoints:  Composite of major bleeding and clinically relevant, nonmajor bleeding aTested beginning with noninferiority and then superiority.

CLINICAL TRIALS

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1.7% and 2.5% of patients treated with apixaban and warfarin, respectively.12

The risk of major bleeding was significantly re-duced by 31% in patients receiving apixaban compared with those receiving warfarin (HR 0.69; 95% CI 0.60–0.80, p<0.001). There were also significantly fewer in-tracranial bleeding and major bleeding events in the apixaban group. The rate for the composite of major bleeding and clinically relevant, non-major bleeding was significantly lower in the apixaban group than in the warfarin treatment arm (4.07% vs. 6.01% per year, respectively; HR 0.68; 95% CI 0.61–0.75; p<0.001).16

AVERROES

The efficacy of oral apixaban to reduce the risk of stroke or systemic embolism in patients with AFib was also compared to aspirin in the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients who have Failed or are Unsuitable for Vitamin K Antagonist Therapy) trial.17 The AVERROES study was a randomized, dou-ble-blind, multinational, phase III trial that assigned 5,599 patients to active treatment. All patients enrolled in the AVERROES trial were 50 years of age or older, had AFib and were unsuitable for VKA therapy. Pa-tients also had to have, at minimum, one of the follow-ing risk factors for stroke: age ≥75 years; prior stroke or TIA, heart failure (NYHA class ≥2), LVEF of ≤35%, diabetes, treated arterial hypertension, or docu-mented peripheral-artery disease. See Table 3 for a

description of study design. All primary efficacy and safety analyses were performed using intention-to-treat.17

At baseline, the median age of subjects was 70 years and the mean duration of study follow-up was 1.1 years. The AVERROES trial was stopped early by the data and safety monitoring committee based on predefined stopping rules for superiority compared to aspirin.17

Patients assigned to apixaban were significantly less likely than aspirin recipients to experience stroke or systemic embolism (HR 0.45; 95% CI 0.32–0.62; p<0.001). The rates of ischemic stroke were 1.1% vs. 3.0% per year (HR 0.37; 95% CI 0.25–0.55; p<0.001) when apixaban was compared to aspirin, respectively. Six cases of hemorrhagic stroke occurred among pa-tients receiving apixaban and nine among patients re-ceiving aspirin (p=0.45). The rate of death was 3.5% per year in the apixaban treatment group and 4.4% per year in the aspirin group (HR 0.79; 95% CI 0.62–1.02; p=0.07).17

Apixaban was also favored over aspirin for the composite endpoints of stroke, systemic embolism or death (4.6% per year vs. 7.2% per year; HR 0.64; 95% CI 0.51–0.78; p<0.001). No significant differences were observed in rates of MI, death from any cause, or death from a vascular cause between apixaban and as-pirin recipients. Apixaban recipients were significantly less likely than aspirin recipients to experience hospi-talization for a cardiovascular cause (12.6 vs. 15.9% per

Table 3 | AVERROES study design.17 Active treatment groups:  Apixaban 5 mg twice daily or apixaban 2.5 mg twice daily if any two or more of the following: age ≥80 years, body-

weight ≤60 kg, serum creatinine ≥1.5 mg/dL.  Aspirin 81 - 324 mg per day (dose selected at discretion of investigator) Inclusion criteria:  Age ≥50 years, AFib documented in the 6 months prior to enrolment or by ECG on the day of screening;  ≥1 risk factor for stroke (aged ≥75 years, previous stroke or TIA, heart failure [NYHA class ≥2], LVEF of ≤35%, diabe-

tes [receiving treatment], arterial hypertension [receiving treatment], documented peripheral arterial disease); not re-ceiving VKA therapy.

Exclusion criteria:  Conditions other than AFib requiring long-term anticoagulation;  Valvular disease requiring surgery;  Serious bleeding event in the prior 6 months or a high risk of bleeding,  Current alcohol/drug abuse or psychosocial issue;  Life expectancy of <1 year;  Severe renal insufficiency;  ALT or AST level >2 times the upper limit of normal;  Allergy to aspirin Primary efficacy endpoint:  Ischemic or hemorrhagic stroke or systemic embolism Primary safety outcome:  Major bleeding

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year; HR 0.79; 95% CI 0.69–0.91; p<0.001).17 In the AVERROES trial, significantly fewer pa-

tients in the apixaban group than in the aspirin group had a serious adverse event (22% vs. 27%, p<0.001). Also, no significant difference in the risk of major bleeding events was observed between apixaban recipi-ents and aspirin recipients.17 Treatment discontinua-tion due to bleeding-related adverse events occurred in 1.5% and 1.3% of patients treated with apixaban and aspirin, respectively.12 There were 44 reported cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (HR 1.13; 95% CI 0.74–1.75; p=0.57): 11 cases of intracranial bleeding occurred in the apixaban group and 13 oc-curred in the aspirin group. Rates of intracranial bleed-ing, major gastrointestinal bleeding, fatal bleeding and clinically relevant, non-major bleeding did not signifi-cantly differ between participants receiving apixaban and those receiving aspirin.17 There were also no sig-nificant differences in minor bleeding when comparing apixaban to aspirin, (6.3% per year with apixaban vs. 5.0% with aspirin). The rate of combined major or clinically relevant, non-major bleeding also did not sig-nificantly differ between apixaban and aspirin recipi-ents.18

Apixaban is supplied as 2.5 mg and 5 mg oral tab-lets. The recommended dosage of apixaban is 5 mg taken orally twice daily for most patients. The recom-mended dose is 2.5 mg twice daily for patients with any two of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.12 If administered with drugs that are strong dual inhibitors of CYP3A4 and P-glycoprotein (e.g., keto-conazole, itraconazole, ritonavir, clarithromycin), the recommended dose is 2.5 mg twice daily. For patients for whom the 2.5 mg dosage is indicated irrespective of drug interactions, coadministration with strong dual inhibitors of CYP3A4 and P-gp should be avoided. No dose adjustments are required in patients with mild hepatic impairment; however, apixaban is not recom-mended in patients with severe hepatic impairment. Apixaban has not been studied in patients with creati-nine clearance <15 mL/min or on dialysis, and it is therefore not recommended in these patient popula-tions.12

Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures that pose a moderate or high risk of clinically significant bleeding, and at least 24 hours prior to elective surgery

or invasive procedures with a low risk of bleeding. When switching from warfarin to apixaban, warfarin should be discontinued and apixaban started when the INR is below 2.0. When switching from apixaban to warfarin, apixaban should be discontinued and both a parenteral anticoagulant and warfarin should be admin-istered at the time the next dose of apixaban would have been taken; the parenteral anticoagulant should then be discontinued when INR reaches the target range.12 Concomitant use of NSAIDS, including aspi-rin should be avoided if possible.14

Decision analytic modeling has been applied to estimate the costs, quality-adjusted life years (QALYs) and cost-effectiveness of apixaban compared to adjust-ed-dose warfarin for the prevention of stroke in pa-tients with AFib and at least one additional risk factor for stroke.19 The two treatment strategies analyzed were apixaban 5 mg twice daily and adjusted-dose war-farin with a target INR of 2.0–3.0. The base-case co-hort was of 65-year-old patients with AFib who had a CHADS2 score of 2. Outcomes and drug-specific probabilities were derived predominately from the AR-ISTOTLE trial.16 Epidemiological risks of stroke, mor-bidity and mortality were incorporated from published studies of anticoagulation. The analysis utilized a life-time time horizon and was conducted from the healthcare payer perspective. The cost-effectiveness analysis examined direct costs only (healthcare expend-itures and drug costs). The cost of warfarin included the cost of drug plus 14 INR tests annually (i.e., ap-proximately one test every three to four weeks). The study was published prior to apixaban reaching the US market and the cost of apixaban was assumed to be the same as the wholesale acquisition cost of rivaroxaban or dabigatran. Costs were expressed in 2012 US dol-lars. Under base-case assumptions, the quality-adjusted life expectancy of 65-year-old AFib patients with a CHADS2 score of 2.1 was 10.89 and 11.23 years for warfarin and apixaban, respectively. Corresponding total costs for warfarin and apixaban were $90,225 and $87,592. Apixaban was shown to be a dominant (less costly, more effective) economic strategy compared with warfarin. The results of Monte Carlo simulation showed apixaban was a dominant strategy in 57% of the simulations and cost-effective in 98% of simula-tions at a willingness-to-pay threshold of $50,000 per QALY gained.19

Decision analytic modeling was also used to com-pare the cost-effectiveness of apixaban and warfarin

COST-EFFECTIVENESS

DOSING

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for stroke prevention in patients with AFib and prior stroke or transient ischemic attack (TIA).20 Using a Markov model adjusted-dose warfarin with a goal INR of 2.0–3.0 was compared to apixaban 5 mg twice daily. The base case population was a hypothetical cohort of 70-year-old patients with no contraindication to antico-agulation. The model adopted costs from a societal perspective. Quality-adjusted life expectancy and net costs (in 2010 U.S. dollars) were quantified over 20 years or until death, whichever occurred first. Rates of outcomes in the model were primarily based on a sub-group of subjects from the ARISTOTLE trial who had a history of prior stroke or TIA. In the base case, the time in therapeutic INR range (TTR) for patients re-ceiving warfarin therapy was 66%, the average TTR from the ARISTOTLE trial. Because apixaban was not yet approved for use in the US, the cost of apixaban was estimated based upon the European price and the cost of office visits for routine clinical monitoring were added. The cost of warfarin therapy was its wholesale cost, plus Medicare reimbursement and 14 laboratory tests to check the INR for each 90-day period of anti-coagulation management. It should be noted that, in sensitivity analyses, results were not shown to be sensi-tive to the number of annual INRs required.20

The results of the base case can be seen in Table 4. In Monte Carlo analyses, apixaban was found to be cost-effective in 62% of simulations using a threshold of $50,000 per QALY gained and 81% of simulations using a threshold of $100,000 per QALY gained. Therefore, apixaban appears to be cost-effective rela-tive to warfarin for secondary stroke prevention in pa-tients with AFib.20

Apixaban is an oral direct factor Xa inhibitor indi-cated to reduce the risk of stroke and systemic embo-lism in patients with nonvalvular AFib. Most patients with AFib should be treated with 5 mg taken orally twice daily. In patients with any two or more of the following: age ≥80 years, body weight ≤60 kg, or a se-rum creatinine ≥1.5 mg/dL, the recommended dose of

Table 4 | Results and total costs, secondary pre-vention analysis.20

Drug QALY Total Costs ICERa

Warfarin 3.91 years $378,500 — Apixaban 4.19 years $381,700 $11,429 ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year. aICER represents incremental change in cost per QALY gained for apixaban relative to warfarin, (i.e., [$381700-$378500]-[4.19-3.91]).

CONCLUSIONS

apixaban is 2.5 mg twice daily. Apixaban has demon-strated superiority to warfarin in preventing stroke and systemic embolism in patients with AFib and also re-duced the rate of major bleeding and death from any cause. In patients for whom VKA therapy was consid-ered unsuitable, apixaban, when compared with aspi-rin, reduced the risk of stroke or systemic embolism by more than 50%, without a significant increase in the risk of major bleeding or intracranial hemorrhage. Overall bleeding risk with apixaban is lower when compared to warfarin and similar to that of aspirin.

REFERENCES

1. Feinberg WM, Blackshear JL, Laupacis A, et al. Prevalence,

age distribution, and gender of patients with atrial fibrillation: analysis and implications. Arch Intern Med 1995;155(5):469-73.

2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diag-nosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagu-lation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA. 2001;285(18):2370-5.

3. Deedwania P, Huang GW. Role of emerging antithrombotic therapy in prevention of cardioembolic complications in pa-tients with atrial fibrillation. Am J Cardiovasc Drugs 2011;11(4):265-75.

4. Hart RG, Pearce LA, Aguilar ML. Meta-analysis: antithrom-botic therapy to prevent stroke in patients who have nonval-vular atrial fibrillation. Ann Intern Med 2007;146(12):857-67.

5. You JJ, Singer DE, Howard PA, et al. Antithrombotic Thera-py for Atrial Fibrillation: Antithrombotic Therapy and Pre-vention of Thrombosis, 9th ed. CHEST 2012;141(2)(Suppl):e531S-e575S.

6. Wong PC, Pinto DJP, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis 2011;31(4):478-92.

7. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmaco-dynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009;28(1):1-22.

8. Luettgen JM, Knabb RM, He K, et al. Apixaban inhibition of factor Xa: microscopic rate constants and inhibition mecha-nism in purified protein systems and in human plasma. J En-zyme Inhib Med Chem 2011;26(4):514-26.

9. Becker RC, Alexander JH, Newby LK, et al. Effect of apixa-ban an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome. Thromb Haemost 2010;104(5):976-83.

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MATERIA MEDICA Volume 2, Issue 5 www.ucdenver.edu/pharmacy/materiamedica Oct 2013 13

MATERIA MEDICA

A publication of the Department of Clinical Pharmacy, Skaggs School of Pharmacy and

Pharmaceutical Sciences

University of Colorado

Editor Steven M. Smith, PharmD, MPH, BCPS

The material contained in this newsletter has been prepared by the Skaggs School of Pharmacy for informational purposes only. The articles are the work product of the individual authors to whom each article is attributed. The articles contained herein should not be used without proper permission or citation. Should you have questions about any of the content in this newsletter please contact the Editor.

Associate Editor Katy E. Trinkley, PharmD, BCACP

12. Eliquis® [package insert]. Princeton, NJ: Bristol Myers Squibb Company; 2012.

13. Dolgin E. Antidoes edge closer to reversing effects of new blood thinners. Nat Med 2013;(19):251.

14. Alexander JH, Lopes RD, James S, et al. Apixaban with an-tiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365(8):699-708.

15. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009;37(1):74-81.

16. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981-92.

17. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in pa-tients with atrial fibrillation. N Engl J Med 2011;364(9):806-17.

18. Flaker GC, Eikelboom JW, Shestakovska O, et al. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial. Stroke 2012;43(12):3291-7.

19. Lee S, Mullin R, Blazawski J, et al. Cost-effectiveness of apix-aban compared with warfarin for stroke prevention in atrial fibrillation. PLoS ONE 2012;7(10):e47473.

20. Kamel H, Easton JD, Johnston SC, et al. Cost-effectiveness of apixaban vs warfarin for secondary stroke prevention in atrial fibrillation. Neurology 2012;79(14):1428-34.