The medical letter on drugs and therapeutics october 27 2014

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 56

ISSUE
ISSUE
No.

1433
1454

October 27, 2014

IN THIS ISSUE

Antithrombotic Drugs ................................................................................................ p 103

Volume 56

Important Copyright Message
FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS

The Medical Letter, Inc. publications are protected by U.S. and international copyright laws.
Forwarding, copying or any distribution of this material is prohibited.
Sharing a password with a non-subscriber or otherwise making the contents of this site
available to third parties is strictly prohibited.

By accessing and reading the attached content I agree to comply with U.S. and international
copyright laws and these terms and conditions of The Medical Letter, Inc.

For further information click: Subscriptions, Site Licenses, Reprints
or call customer service at: 800-211-2769

Published by The Medical Letter, Inc. • A Nonprofit Organization


Revised 11/12/14: A paragraph on dipyridamole has been added to the first page (after aspirin).

The Medical Letter publications are protected by US and international copyright laws.
Forwarding, copying or any other distribution of this material is strictly prohibited.
For further information call: 800-211-2769

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 56

ISSUE

ISSUE No.

October 27, 2014
Take CME exams

IN THIS ISSUE

1433
1454 Antithrombotic Drugs
Volume 56
Related article(s) since publication

Antiplatelet drugs are the drugs of choice for
prevention and treatment of arterial thrombosis.
Anticoagulants are the drugs of choice for prevention
and treatment of venous thromboembolism and for
prevention of cardioembolic events in patients with
atrial fibrillation.
ANTIPLATELET DRUGS
Antiplatelet drugs are used mainly for acute coronary
syndrome (ACS), which includes unstable angina/
non-ST-elevation myocardial infarction (UA/NSTEMI),
ST-elevation myocardial infarction (STEMI), and percutaneous coronary intervention (PCI).
ASPIRIN — Aspirin acetylates cyclooxygenase-1,
blocking thromboxane synthesis and inhibiting platelet
activation and aggregation for the life of the platelet (up
to 10 days). Aspirin prophylaxis reduces the incidence
of myocardial infarction (MI) and/or death by 1525% in patients with UA/NSTEMI, STEMI, or ischemic
stroke, and in those undergoing PCI or a coronary
artery bypass graft (CABG).1,2 In one randomized trial in
patients undergoing noncardiac surgery, use of aspirin
did not reduce the rate of cardiovascular events, and it
increased the incidence of major bleeding.3
Aspirin can cause asthma and other hypersensitivity
reactions in aspirin-intolerant patients.

DIPYRIDAMOLE — A pyrimidopyrimidine derivative, dipyridamole (Persantine, and generics) inhibits platelet
uptake of adenosine and blocks adenosine diphosphate (ADP)-induced platelet aggregation. It is also
available in combination with aspirin (Aggrenox, and
generics). Dipyridamole can cause severe headache
and diarrhea, which tend to resolve with continued
use. A randomized, controlled trial (ESPRIT) in 2739
patients who had experienced a transient ischemic

attack (TIA) or minor stroke in the previous 6 months
found that a combination of extended-release dipyridamole (200 mg bid) and low-dose aspirin (30-325
mg per day) was more effective than aspirin alone in
preventing a composite of vascular death, stroke, MI,
or major bleeding (173 vs. 216 events). However, more
patients discontinued the combination (470 vs. 184),
mainly because of headache.3a The combination was
not more effective than clopidogrel alone in preventing recurrent stroke.3b Recent guidelines recommend
a combination of extended-release dipyridamole 200
mg and aspirin 25 mg twice daily after a TIA or stroke
for prevention of future stroke.3c
THIENOPYRIDINES — The thienopyridines ticlopidine
(seldom used now because of its toxicity), clopidogrel
(Plavix, and generics), and prasugrel (Effient) bind
to P2Y12 ADP receptors on the platelet surface,
inhibiting platelet aggregation for the life of the
platelet (up to 10 days).
Ticlopidine can cause skin reactions, cytopenias, and
thrombotic thrombocytopenic purpura; it has largely
been replaced by clopidogrel.
Clopidogrel is converted to its active form by CYP2C19.
The delayed onset of action can be problematic in

patients who require a rapid antithrombotic effect.
Whether patients who are poor metabolizers of clopidogrel have a higher incidence of cardiovascular events
is controversial.4 Proton pump inhibitors, particularly
omeprazole (Prilosec, and others) and esomeprazole
(Nexium, and others), inhibit CYP2C19 and can interfere
with activation of clopidogrel. Patients taking clopidogrel who have a clinical indication for a proton pump
inhibitor should probably take pantoprazole (Protonix,
and generics), lansoprazole (Prevacid, and others), or
dexlansoprazole (Dexilant) instead.5
103

Published by The Medical Letter, Inc. • A Nonprofit Organization


The Medical Letter

®

October 27, 2014

Vol. 56 (1454)

Table 1. Some Antiplatelet Drugs for Acute Coronary Syndrome
Dosage Adjustment
for Renal Impairment

Antiplatelet Effect1

Cost2

75-81 mg PO once/d

CrCl <10 mL/min:
do not use

Irreversible, 50-100%
dialyzable

$0.80

Clopidogrel – generic
Plavix (BMS)

300-600 mg PO loading dose,3
then 75 mg once/d

None

Irreversible

10.20
193.30

Prasugrel4 – Effient (Lilly)

60 mg PO loading dose,
then 10 mg once/d5

None

Irreversible,
not dialyzable

270.00

Ticagrelor6 – Brilinta
(AstraZeneca)

180 mg PO loading dose,
then 90 mg bid

None

Reversible,7
not dialyzable

251.70

Vorapaxar8,9 – Zontivity
(Merck)

2.08 mg PO once/d

None

Reversible,10
not dialyzable

267.30

Abciximab – ReoPro
(Janssen Biologics/Lilly)

PCI: 0.25 mg/kg IV bolus,
then 0.125 mcg/kg/min
(max 10 mcg/min) for 12 hrs

None

Reversible,
not dialyzable

956.00

Eptifibatide – Integrilin
(Merck)

UA/NSTEMI or PCI: 180 mcg/kg
IV bolus 1-2x11 (10 min apart),
then 2 mcg/kg/min

CrCl <50 mL/min:
reduce maintenance
dose to 1 mcg/kg/min

Reversible,
dialyzable

863.60

Tirofiban – Aggrastat
(Medicure)

UA/NSTEMI: 25 mcg/kg IV over
3 min, then 0.15 mcg/kg/min
PCI: 25 mcg/kg IV bolus over
3 min, then 0.15 mcg/kg/min12,13

CrCl ≤60 mL/min:
reduce maintenance
dose by 50%

Reversible,
dialyzable

517.80

Drug

Usual Dosage

Aspirin – generic

1. Irreversibility of antiplatelet drugs means that the effect persists for the life of the platelet (up to 10 days). Reversibility means that the antiplatelet effect
persists only until the drug is cleared.
2. Approximate wholesale acquisition cost (WAC) for 30 days’ treatment with oral formulations or 12 hours’ treatment for a 70-kg patient with parenteral
formulations at the lowest usual maintenance dosage. Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) October 5, 2014. Reprinted with
permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.
3. Loading dose is optional for STEMI.
4. Not recommended for patients ≥75 years old, unless high risk (diabetes or prior MI), or in those with a history of stroke or TIA.

5. Reduce dose to 5 mg for patients <60 kg.
6. Label warns that use of aspirin maintenance doses >100 mg per day reduces its effectiveness and should be avoided.
7. Recovery of platelet function after stopping the drug is about twice as rapid with ticagrelor as it is with clopidogrel (RF Storey et al. J Thromb Haemost 2011; 9:1730).
8. Zontivity is available as 2.5-mg vorapaxar sulfate tablets, equivalent to 2.08 mg of vorapaxar.
9. FDA-approved only for patients with peripheral arterial disease or a history of myocardial infarction.
10. Vorapaxar’s long half-life makes it effectively irreversible.
11. For patients undergoing PCI, a second bolus dose should be administered 10 minutes after the first bolus dose.
12. Not an FDA-approved indication.
13. PT O'Gara et al. J Am Coll Cardiol 2013; 61:e78.

Prasugrel does not require CYP2C19 for activation. For
prevention of MI and stent thrombosis in patients with
ACS undergoing PCI, prasugrel plus aspirin has been
more effective than clopidogrel plus aspirin, but with
a higher incidence of major, life-threatening, and fatal
bleeding.6 In one trial in 7243 patients with UA/NSTEMI
who did not undergo revascularization, however,
prasugrel plus aspirin did not significantly reduce the
risk of cardiovascular death, MI, or stroke (the primary
endpoint), compared to clopidogrel plus aspirin, and
did not increase the risk of severe, major, or lifethreatening bleeding.7 Prasugrel is contraindicated in
patients with a history of stroke or transient ischemic
attack (TIA). It is not recommended for use in patients
≥75 years old unless they are at high risk (diabetes
or prior MI); the risk of bleeding is greater in older
patients, and the benefit is less clear.
TICAGRELOR — Ticagrelor (Brilinta) binds to the
same P2Y12 receptors as the thienopyridines.8 In
one trial (PLATO) in patients with ACS, ticagrelor
plus aspirin was more effective than clopidogrel plus

aspirin in preventing cardiovascular death, but was
104

associated with a higher rate of non-CABG-related
major bleeding and fatal intracranial bleeding.9 A
post-hoc subgroup analysis found that ticagrelor was
less effective in the US than in the rest of the world,
possibly because US patients took higher doses of
aspirin (median ≥300 mg/day) concomitantly.10
PAR-1 ANTAGONIST — Vorapaxar (Zontivity) blocks
protease-activated receptor-1, the major thrombin
receptor on platelets, inhibiting thrombin-induced
platelet aggregation.11 It has been approved by the
FDA for use with aspirin and/or clopidogrel to reduce
the risk of thrombotic cardiovascular events in
patients with peripheral arterial disease or a history of
MI. A double-blind trial (TRA 2°P-TIMI 50) randomized
26,449 patients with peripheral arterial disease or
a history of MI or ischemic stroke to receive either
vorapaxar or placebo, in addition to standard care. At 3
years, cardiovascular death, MI, or stroke (the primary
composite endpoint) had occurred in 9.3% of patients
treated with vorapaxar and in 10.5% of those given
placebo, a statistically significant difference.12 The
efficacy of vorapaxar for treatment of ACS remains


The Medical Letter

Vol. 56 (1454)

®

October 27, 2014

Table 2. Some Anticoagulants for Acute Coronary Syndrome
Drug

Usual Dosage

Unfractionated heparin –
generic

UA/NSTEMI: 60 units/kg IV bolus,
then 12 units/kg/h

Dosage Adjustment
for Renal Impairment

Reversibility of
Anticoagulant Effect

Cost1

None

Protamine can reverse
effects

$10.80

STEMI: 60 units/kg IV bolus,
then 12 units/kg/h
PCI: 70-100 units/kg IV bolus;
titrate to ACT 250-300 sec2
(50-70 units/kg IV bolus if
GP IIb/IIIa used; titrate to ACT
200-250 sec)
Low-Molecular-Weight Heparins
Enoxaparin – generic
Lovenox (Sanofi)

UA/NSTEMI: 1 mg/kg SC q12h
STEMI: 30 mg IV bolus plus
1 mg/kg SC, then 1 mg/kg
SC q12h3,4

CrCl <30 mL/min:
Protamine (max
UA/NSTEMI:
60% neutralized)
1 mg/kg SC once/d
STEMI:
30 mg IV bolus plus 1 mg/kg SC,
then 1 mg/kg SC once/d5

44.00
66.20

Dalteparin – Fragmin

(Eisai/Pfizer)

UA/NSTEMI: 120 IU/kg
(max 10,000 IU) SC q12h

CrCl <30 mL/min:
based on anti-Xa levels

Protamine (max
60-75% neutralized)

70.90

PCI: 0.75 mg/kg IV bolus,
then 1.75 mg/kg/h

CrCl <30 mL/min:
reduce maintenance
dose to 1 mg/kg/h

No antidote,
dialyzable

2.5 mg SC once/d7,8

CrCl 30-50 mL/min:
reduce dose by 50%9
CrCl <30 mL/min:
do not use

No antidote,
dialyzable

Direct Thrombin Inhibitor
Bivalirudin – Angiomax
(The Medicines Co.)

5344.80

Factor Xa Inhibitor
Fondaparinux6 – generic
Arixtra (GSK)

43.7010
50.6010

ACT = activated clotting time
1. Approximate wholesale acquisition cost (WAC) for 12 hours’ treatment for a 70-kg patient at the lowest usual maintenance dosage. Source: Analy$ource®
Monthly (Selected from FDB MedKnowledge™) October 5, 2014. Reprinted with permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/
policies/drug-pricing-policy. Actual retail prices may be higher.
2. With Hemotec device and 300-350 sec with Hemochron device.
3. Dose for patients <75 years old. For patients ≥75 years old, 0.75 mg/kg SC q12h (no bolus dose).
4. For PCI, no additional dosing is needed if the last SC administration was <8 hrs before balloon inflation. If ≥8 hrs, an IV bolus of 0.3 mg/kg should be given.
5. Dose for patients <75 years old. For patients ≥75 years old, 1 mg/kg SC once daily (no bolus dose).
6. Not an FDA-approved indication.
7. S Yusuf et al. JAMA 2006; 295:1519.
8. For STEMI, initial dose is given IV.
9. DA Garcia et al. Chest 2012; 141(2 suppl):e24s.
10. Cost of one 2.5 mg/0.5 mL syringe.

to be established.13,14 Because of an increased risk of
intracranial hemorrhage, vorapaxar is contraindicated
for use in patients with a history of stroke, TIA, or
intracranial hemorrhage.
GPIIb/IIIa RECEPTOR ANTAGONISTS — The glycoprotein IIb/IIIa receptor antagonists, which are
sometimes given IV for short periods for ACS or
PCI, prevent platelet aggregation by competing
with fibrinogen and von Willebrand factor for
platelet receptors. Abciximab (ReoPro) is the Fab
fragment of a chimeric monoclonal antibody to the
GPIIb/IIIa receptor that binds to both activated and
non-activated platelets. While the plasma half-life
of abciximab is only 30 minutes, its strong affinity
for platelets results in measurable platelet inhibition
for 24-48 hours, with low levels still detectable
after 15 days. Eptifibatide (Integrilin) and tirofiban
(Aggrastat) bind reversibly to the GPIIb/IIIa receptor

of activated platelets. Bleeding at arterial access sites
is the most common complication of these drugs.
GPIIb/IIIa inhibitors, particularly abciximab, can also
cause profound acute thrombocytopenia, even in the
absence of previous exposure.
PARENTERAL ANTICOAGULANTS
HEPARIN — Heparins act by combining with plasma
antithrombin to form a complex that is more active
than antithrombin alone in neutralizing thrombin and
factor Xa. Unfractionated heparin (UFH) has some
disadvantages compared to low-molecular-weight
heparin (LMWH): it is more likely to cause heparininduced thrombocytopenia and has a more variable

anticoagulant response that requires monitoring. It
also has advantages over LMWH, however, that have
kept it from becoming obsolete: its anticoagulant
effect can be rapidly reversed and is more completely
neutralized by protamine, it is not cleared by the
105


The Medical Letter

Vol. 56 (1454)

®

October 27, 2014

Table 3. Some Anticoagulants for Venous Thromboembolism
Drug

Dosage for Treatment

Dosage for Prophylaxis1

Cost2

Unfractionated heparin

Initial: 80 units/kg IV bolus, then 18 units/kg/hr
or 250 units/kg SC,3 then 250 units/kg q12h

5000 units SC q8-12h

$518.40

1 mg/kg SC bid or 1.5 mg/kg once/d
200 IU/kg SC once/d5

30 mg SC bid or
40 mg SC once/d
2500-5000 IU SC once/d

1980.00
2981.40
3190.50

2-10 mg PO once/d6

2-10 mg PO once/d6

150 mg PO bid7,8

150 mg PO bid7,8,9

No data

15 mg SC q12h10

5-10 mg12 SC once/d8

2.5 mg SC once/d8,13

15 mg PO bid x 3 weeks, then 20 mg once/d8
10 mg PO bid x 7 days, then 5 mg PO bid

10 mg PO once/d8
2.5 mg PO bid

Low-Molecular-Weight Heparins
Enoxaparin4 – generic
Lovenox (Sanofi)
Dalteparin4 – Fragmin (Eisai/Pfizer)
Vitamin K Antagonist
Warfarin – generic
Coumadin (BMS)
Direct Thrombin Inhibitors
Dabigatran etexilate4 –
Pradaxa (Boehringer Ingelheim)
Desirudin4 – Iprivask (Marathon)
Factor Xa Inhibitors
Fondaparinux4 – generic
Arixtra (GSK)
Rivaroxaban4 – Xarelto (Janssen)
Apixaban – Eliquis (BMS)
1.
2.
3.
4.
5.
6.
7.

8.
9.
10.
11.
12.
13.

291.70
3600.0011
1311.60
3926.10
286.40
291.70

Prophylaxis is recommended for a minimum of 10-14 days after elective hip or knee arthroplasty, and for up to 35 days after major orthopedic surgery
(Y Falck-Ytter et al. Chest 2012; 141:e278).
Approximate wholesale acquisition cost (WAC) for 30 days’ treatment of a 70-kg patient at the lowest usual maintenance dosage. Source: Analy$ource®
Monthly (Selected from FDB MedKnowledge™) October 5, 2014. Reprinted with permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/
policies/drug-pricing-policy. Actual retail prices may be higher.
Initial dose is 333 units/kg for unmonitored dosing regimen.
Dosage adjustments may be needed for renal impairment.
Dose only FDA-approved for cancer patients x 30 days, then 150 IU/kg SC daily x 5 months (not to exceed 18,000 IU/day).
Monitor daily and adjust dose until results in therapeutic range (INR 2-3) for ≥24 hours.
Avoid coadministration with P-glycoprotein inhibitors in patients with CrCl <50 mL/min.
Contraindicated in patients with CrCl <30 mL/min.
A dose of 220 mg (two 110-mg capsules) once daily is approved for VTE prophylaxis in Canada.
Use of desirudin has only been studied for up to 12 days.
Cost for 12 days' treatment.
5 mg if <50 kg, 7.5 mg if 50-100 kg, 10 mg if >100 kg.
Dose for adults ≥50 kg. Contraindicated in patients weighing <50 kg.

kidneys and therefore may be safer in patients with
renal insufficiency, and it directly inhibits the contact
activation pathway that is important in the formation
of thrombi in stents, filters, and catheter tips.
LMWH — Low-molecular-weight heparins, which are
produced by cleaving UFH into shorter chains, inhibit
factor Xa more than they inhibit thrombin. Compared
to UFH, LMWHs have longer half-lives that permit
fewer doses per day, and their greater bioavailability
leads to a more predictable anticoagulant response.
In clinical trials comparing them with UFH, LMWHs
have generally been at least as effective and as
safe. They are often used to prevent or treat venous
thromboembolism (VTE). For initial treatment of deep
vein thrombosis (DVT), LMWH is generally preferred
over UFH. In a controlled trial in patients in an ICU
(PROTECT), dalteparin was not superior to UFH in
preventing proximal leg DVT, the primary endpoint,
but dalteparin-treated patients had significantly fewer
pulmonary emboli and a lower risk of heparin-induced
thrombocytopenia.15

106

6.00
48.90

FONDAPARINUX — A synthetic analog of the pentasaccharide sequence of heparin, fondaparinux (Arixtra,
and generics) binds antithrombin with high affinity

and inhibits factor Xa indirectly through antithrombin
without neutralizing thrombin. The drug has a long halflife and requires injection only once daily. Fondaparinux
accumulates in patients with renal impairment, which
can be problematic in the elderly, and is contraindicated
in patients with a CrCl <30 mL/min.
Fondaparinux appears to be as effective and as
safe as UFH or LMWH for prophylaxis of DVT
and treatment of VTE, and it is much less likely
to cause heparin-induced thrombocytopenia.16,17
Fondaparinux can also be used as an alternative
to UFH or LMWH in UA/NSTEMI or STEMI, but in
patients who underwent PCI, it provided no benefit
compared to UFH and was associated with a higher
rate of catheter thrombosis.18,19
DIRECT THROMBIN INHIBITORS — Unlike heparins
and fondaparinux, direct thrombin inhibitors inhibit
clot-bound as well as circulating thrombin.


The Medical Letter

®

Bivalirudin (Angiomax), which is given IV and has
a short half-life, can be used instead of heparin in
patients undergoing PCI. In one controlled trial in
high-risk patients undergoing PCI, it significantly
reduced the incidence of major bleeding compared to
UFH, but it did not provide a net benefit in outcomes.20
In a meta-analysis of 16 randomized controlled trials

comparing bivalirudin-based regimens with heparinbased regimens in patients undergoing planned
PCI, bivalirudin increased the risk of MI and stent
thrombosis, but decreased the risk of bleeding.21
Desirudin (Iprivask) is a hirudin analog approved by
the FDA for prevention of DVT after elective hip arthroplasty. It appears to be more effective than enoxaparin
for this indication, but it must be injected twice daily
and can cause life-threatening allergic reactions.22
ORAL ANTICOAGULANTS
WARFARIN — Anticoagulation with warfarin
(Coumadin, and others) markedly reduces the risk
of thromboembolic stroke in patients with atrial
fibrillation or acute VTE. With an annual rate of major
bleeding of about 1-2% and an absolute increase
in the rate of intracranial hemorrhage of about
0.2%, the benefits of warfarin far surpass the risks.
Drawbacks of warfarin include the variability in dosage
requirements, dietary restrictions, and the need for
close monitoring to keep the international normalized
ratio in the therapeutic range (INR 2-3). Patients with
atrial fibrillation associated with a mechanical valve, a
bioprosthetic valve, prior mitral valve repair, or mitral
stenosis should take warfarin.23
NEW ORAL ANTICOAGULANTS — Three new oral
anticoagulants that do not require INR monitoring
and have a lower risk of intracranial bleeding are
now available in the US.24,25 Unlike warfarin, none
of them has an FDA-approved antidote that can
reverse their anticoagulant effect if bleeding occurs or
emergency surgery is needed, but the results of some
studies suggest that their anticoagulant effect may be

reversed by prothrombin complex concentrate, and
clinical studies of more specific reversal agents are
in progress.26
Dabigatran – In a randomized trial (RE-LY) comparing
fixed doses of the oral direct thrombin inhibitor
dabigatran (Pradaxa) with adjusted-dose warfarin for
a median of 2 years in patients with nonvalvular atrial
fibrillation considered at risk for stroke, the risk of
ischemic or hemorrhagic stroke was significantly lower
with dabigatran 150 mg twice daily than with warfarin.27

Vol. 56 (1454)

October 27, 2014

Table 4. Oral Anticoagulants for Nonvalvular Atrial
Fibrillation
Drug

Mechanism
of Action

Usual
Dosage

Cost1

Warfarin – generic
Coumadin (BMS)

Vitamin K
antagonist

2-10 mg
once/d2

$ 6.00
48.90

Dabigatran etexilate –
Pradaxa
(Boehringer Ingelheim)

Direct thrombin
inhibitor

150 mg
bid3

291.70

Rivaroxaban – Xarelto
(Janssen)

Direct factor Xa
inhibitor

20 mg
once/d4

286.40

Apixaban – Eliquis
(BMS)

Direct factor Xa
inhibitor

5 mg
bid5

291.70

Edoxaban6 – Savaysa
(Daichii Sankyo)

Direct factor Xa
inhibitor

30-60 mg
once/d7

N.A.

N.A. = cost not available
1. Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at
the lowest usual daily dosage. Source: Analy$ource® Monthly (Selected
from FDB MedKnowledge™) October 5, 2014. Reprinted with permission
by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/
drug-pricing-policy. Actual retail prices may be higher.

2. Monitor and maintain in therapeutic range (INR 2-3).
3. Dose is 75 mg bid for CrCl 15-30 mL/min, according to the US label. For
patients with a CrCl 30-50 mL/min, dose is 75 mg bid if co-administered
with dronedarone or ketoconazole. The American College of Chest
Physicians and Health Canada do not recommend use of the drug in
patients with a CrCl <30 mL/min.
4. Taken with the evening meal. Dose is 15 mg once daily for CrCl 15-50
mL/min. It is contraindicated in patients with a CrCl <15 mL/min.
5. Dose is 2.5 mg bid for patients with 2 or more of the following: ≥80 years
old, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.
6. Not FDA-approved to date.
7. RP Giuglianno et al. N Engl J Med 2013; 369:2093.

For treatment of acute VTE, fixed-dose dabigatran was
as effective and as safe as adjusted-dose warfarin in
preventing recurrent VTE.28 For extended treatment of
VTE, dabigatran was non-inferior to warfarin with a lower
risk of bleeding.29 Because of multiple spontaneous
reports of severe, sometimes fatal bleeding with
dabigatran, the FDA conducted a post-marketing study
in >134,000 Medicare patients ≥65 years old which found
that the risks of intracranial bleeding and ischemic and
thromboembolic stroke were lower with dabigatran
than with warfarin, but the risk of major gastrointestinal
bleeding was higher with dabigatran.30,31
Rivaroxaban – The oral direct factor Xa inhibitor
rivaroxaban (Xarelto) was more effective than
enoxaparin in preventing VTE and death after elective
hip or knee arthoplasty.32 It was non-inferior to
enoxaparin followed by a vitamin K antagonist for

treatment of VTE and pulmonary embolism, with no
increase in major bleeding.33,34 In a trial in patients with
nonvalvular atrial fibrillation (ROCKET AF), rivaroxaban
was non-inferior to warfarin for prevention of stroke or
systemic embolism and was associated with a lower
risk of intracranial and fatal bleeding.32,35
Apixaban – Another factor Xa inhibitor, apixaban
(Eliquis),36 was more effective than aspirin in patients
107


The Medical Letter

®

with nonvalvular atrial fibrillation in preventing stroke
or systemic embolism, without significantly increasing
the risk of major bleeding or intracranial hemorrhage.37
It was also more effective than warfarin in a randomized
trial (ARISTOTLE) in preventing stroke or systemic
embolism in patients with atrial fibrillation, with a
lower rate of major bleeding and hemorrhagic stroke.38
In 2 other randomized controlled trials, apixaban
was more effective than once-daily enoxaparin in
preventing VTE after knee or hip replacement, without
causing an increase in bleeding.39,40 A 6-month,
randomized, double-blind trial (AMPLIFY) in 5395
patients compared apixaban alone to enoxaparin
plus warfarin; twice-daily apixaban was non-inferior
in preventing recurrent VTE or VTE-related death (the

primary efficacy endpoint), and major bleeding, the
primary safety outcome, occurred less frequently with
apixaban (0.6% vs. 1.8%).41
Edoxaban – A fourth factor Xa inhibitor, edoxaban
(Savaysa), may soon be approved by the FDA for
once-daily use in patients with nonvalvular atrial
fibrillation or VTE. A randomized, double-blind
trial in 21,105 patients with moderate-to-high-risk
atrial fibrillation found edoxaban non-inferior to
warfarin in preventing stroke or systemic embolism,
with a significantly lower risk of bleeding and
cardiovascular death.42 In a randomized, doubleblind trial in 8240 patients with acute VTE first
treated with unfractionated heparin or LMWH, oncedaily edoxaban was non-inferior to warfarin in
preventing recurrent VTE or VTE-related death (the
primary endpoint) and patients taking edoxaban
had a significantly lower rate of major or clinically
relevant non-major bleeding.43 ■
1. US Preventive Services Task Force. Aspirin for the prevention
of cardiovascular disease: U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med 2009; 150:396.
2. Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the
primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849.
3. PJ Devereaux et al. Aspirin in patients undergoing noncardiac
surgery. N Engl J Med 2014; 370:1494.
3a. ESPIRIT Study Group et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT):
randomised controlled trial. Lancet 2006; 367:1665.
3b. RL Sacco et al. Aspirin and extended-release dipyridamole
versus clopidogrel for recurrent stroke. N Engl J Med 2008;
359:1238.
3c. WN Kernan et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for

healthcare professionals from the American Heart Association/
American Stroke Association. Stroke 2014; 45:2160.
4. DM Roden and AR Shuldiner. Responding to the clopidogrel
warning by the US Food and Drug Administration: real life is
complicated. Circulation 2010; 122:445.

108

Vol. 56 (1454)

October 27, 2014

that
its for
anticoagulant
effect
mayTreat
be Guidel
reversed
by
5. Drugs
peptic ulcer disease
and GERD.
Med Lett
2014; 12:25. complex concentrate and clinical
prothrombin
6. Prasugrel (Effient) vs. clopidogrel (Plavix). Med Lett Drugs
studies
of a reversal agent are underway.28a Ther

2009; 51:69.
7. MT Roe et al. Prasugrel versus clopidogrel for acute coronary
APIXABAN
(Eliquis) — Another factor Xa inhibitor,
syndromes without revascularization. N Engl J Med 2012;
34
apixaban,
367:1297. was more effective than aspirin in
8. Ticagrelorwith
(Brilinta)
– better than clopidogrel
Med Lett
patients
nonvalvular
atrial (Plavix)?
fibrillation
in
Drugs Ther 2011; 53:69.
preventing
stroke or systemic embolism without
9. L Wallentin et al. Ticagrelor versus clopidogrel in patients with
signifi
cantly
increasing
of2009;
major
bleeding
acute
coronary
syndromes. Nthe

Englrisk
J Med
361:1045.
34a
10. intracranial
KW Mahaffey et hemorrhage.
al. Ticagrelor compared
with clopidogrel
by
or
It was
also more
geographic
region
in
the
Platelet
Inhibition
and
Patient
Outeffective than warfarin in a randomized trial
comes (PLATO) trial. Circulation 2011; 124:544.
(ARISTOTLE)
in preventing
stroke
or cardiovascusystemic
11. Vorapaxar (Zontivity)
for prevention of
thrombotic
embolism

atrial
fibrillation, with
lar events. in
Medpatients
Lett Drugs with
Ther 2014;
56:85.
DA Morrow
al. Vorapaxar
in the secondary
of atha12.lower
rateetof
major bleeding
andprevention
hemorrhagic
erothrombotic
events. N Engl J Med 2012; 366:1404.
35
stroke.
In et2 al.
other
randomized
controlled
trials,
13. P Tricoci
Thrombin-receptor
antagonist
vorapaxar
in
apixaban

wassyndromes.
more effective
once-daily
acute coronary
N Engl J Medthan
2012; 366:20.
14. DJ Whellan etin
al. preventing
Vorapaxar in acute
coronary
syndrome
enoxaparin
VTE
after
knee patients
or hip
undergoing coronary artery bypass graft surgery: subgroup
replacement,
without
causing
an
increase
in
analysis from the TRACER trial (Thrombin Receptor Antagonist
36,37
bleeding.
AReduction
6-month,
randomized,
doublefor Clinical Event

in Acute
Coronary Syndrome).
J Am
Colltrial
Cardiol
2014; 63:1048.in 5395 patients compared
blind
(AMPLIFY)
15. PROTECT Investigators. Dalteparin versus unfractionated hepapixaban
alone to enoxaparin plus warfarin; twicearin in critically ill patients. N Engl J Med 2011; 364:1305.
daily
apixaban
was
non-inferior
in preventing
16. Y Falck-Ytter
et al.
Prevention
of VTE in orthopedic
surgery
patients: VTE
antithrombotic
therapy and prevention
of thrombosis,
recurrent
or VTE-related
death (the
primary
9th ed: American College of Chest Physicians evidence-based
efficacy

endpoint). Major bleeding, the primary
clinical practice guidelines. Chest 2012; 141:e278s.
safety
outcome,
occurred
with
17. TE Warkentin et al. Prevalence
andless
risk of frequently
preexisting heparin38
induced thrombocytopenia
antibodies
patients
with acute
apixaban
(0.6% vs. 1.8%).
As inwith
dabigatran
Chest 2011; 140:366.
andVTE.
rivaroxaban,
apixaban has no FDA-approved
18. H Jneid et al. 2012 ACCF/AHA focused update of the guidelines
antidote
if bleedingofoccurs,
the results
of some
for the management
patients but
with unstable

angina/non-STelevation
myocardial
infarction
(updating the 2007effect
guidelinemay
and
studies
suggest
that
its anticoagulant
replacing theby
2011
focused update):
a report of
the American
be reversed
prothrombin
complex
concentrate
College of Cardiology Foundation/American Heart Association
andtaskclinical
studies
of aJ Amreversal
are
force on practice
guidelines.
Coll Cardiol agent
2012; 60:645.
28a
underway.

19. S Yusuf et
al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction:
OASIS-6Xa
randomized
trial. JAMA
2006;
EDOXABAN
— Athefourth
inhibitor,
edoxaban
295:1519.
(Daichii
Sankyo), has not been approved to date by
20. G Patti et al. Comparison of safety and efficacy of bivalirudin
theversus
FDA, unfractionated
but may soon
beinavailable
for once-daily
heparin
high-risk patients
undergoing
usepercutaneous
in patients
with
non-valvular
atrial
fibrillation
coronary intervention (from the Anti-Thrombotic
Strategy thromboembolism.

for Reduction of Myocardial
Damage During
or venous
A randomized,
douAngioplasty-Bivalirudin vs Heparin study). Am J Cardiol 2012;
ble-blind
trial
in
21,105
patients
with
moderate
to
110:478.
high
atrialand
fibrillation
found
edoxaban
non-in21. MArisk
Cavender
MS Sabatine.
Bivalirudin
versus heparin
in
patients
planned for
intervention:
a
ferior

to warfarin
in percutaneous
preventing coronary
stroke or
systemic
meta-analysis of randomised controlled trials. Lancet 2014;
embolism,
with significantly lower risk of bleed384:599.
39
ing
and cardiovascular
a randomized,
22. Desirudin
(Iprivask) for DVT death.
prevention.In
Med
Lett Drugs Ther
2010; 52:85. trial in 8240 patients with acute
double-blind
23. Treatment
of atrial with
fibrillation.
Treat Guidel Med
Lett 2014;
VTE
first treated
unfractionated
heparin
or
56:53.

LMWH,
edoxaban
was
non-inferior
24. Choice once-daily
of an oral anticoagulant
in atrial
fibrillation.
Med Lett
to warfarin
in preventing
recurrent VTE or VTEDrugs Ther 2012;
54:79.
25. New oral
anticoagulants
for acute venous
thromboembolism.
related
death
(the primary
endpoint).
Patients
Med Lett Drugs Ther 2014; 56:3.
taking
edoxaban
had
a
signifi
cantly
lower

rate of
26. WI Gonsalves et al. Management of bleeding complications in
major
or on
clinically
relevant non-major
bleeding
patients
new oral anticoagulants.
J Hematol Transfus
2014;
2:1015.
(8.5%
vs. 10.3%).40
27. Dabigatran etexilate (Pradaxa) — a new oral anticoagulant. Med
Lett Drugs Ther 2010; 52:89.


The Medical Letter

®

28. S Schulman et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;
361:2342.
29. S Schulman et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368:709.
30. FDA drug safety communication: FDA study of Medicare
patients finds risks lower for stroke and death but higher for
gastrointestinal bleeding with Pradaxa (dabigatran) compared
to warfarin. Available at www.fda.gov/Drugs/DrugSafety/ucm
396470.htm. Accessed October 16, 2014.

31. MR Southworth et al. Dabigatran and postmarketing reports of
bleeding. N Engl J Med 2013; 368:1272.
32. Rivaroxaban (Xarelto) – a new oral anticoagulant. Med Lett
Drugs Ther 2011; 53:65.
33. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499.
34. EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment
of symptomatic pulmonary embolism. N Engl J Med 2012;
366:1287.
35. MR Patel et al. Rivaroxaban versus warfarin in nonvalvular atrial
fibrillation. N Engl J Med 2011; 365:883.
36. Apixaban (Eliquis) – a new oral anticoagulant for atrial fibrillation. Med Lett Drugs Ther 2013; 55:9.
37. SJ Connolly et al. Apixaban in patients with atrial fibrillation. N
Engl J Med 2011; 364:806.
38. CB Granger et al. Apixaban versus warfarin in patients with
atrial fibrillation. N Engl J Med 2011; 365:981.
39. MR Lassen et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised
double-blind trial. Lancet 2010; 375:807.
40. MR Lassen et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363:2487.
41. G Agnelli et al. Oral apixaban for the treatment of acute venous
thromboembolism. N Engl J Med 2013; 369:799.
42. RP Giugliano et al. Edoxaban versus warfarin in patients with
atrial fibrillation. N Engl J Med 2013; 369:2093.
43. Hokusai-VTE Investigators. Edoxaban versus warfarin for the
treatment of symptomatic venous thromboembolism. N Engl J
Med 2013; 369:1406.

Vol. 56 (1454)

October 27, 2014

The Medical Letter

®

Continuing Medical Education Program
medicalletter.org/cme
Earn Up To 52 Credits Per Year
Choose CME from The Medical Letter in the format that’s right for you!
▶ Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 78 question test enables you to earn 13 credits immediately
upon successful completion of the test. A score of 70% or greater is required to pass the exam. Our comprehensive exams allow you to test at your
own pace in the comfort of your home or office. Comprehensive tests are offered every January and July enabling you to earn up to 26 credits per
year. Starting with our January 2015 comprehensive exam, there will be 130 questions, enabling you to earn 26 credits upon successful completion
of the test (or up to 52 credits if also taking the July 2015 exam). $49/exam.
▶ Free Individual Exams – Free to active subscribers of The Medical Letter. Answer 10 questions per issue and submit answers online. Earn two credits/exam.
▶ Paid Individual Exams – Available to non-subscribers. Answer 10 questions per issue and submit answers online. Earn two credits/exam. $12/exam.

ACCREDITATION INFORMATION:
ACCME: The Medical Letter is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Medical
Letter designates this enduring material for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their
participation in the activity. This CME activity was planned and produced in accordance with the ACCME Essentials and Policies.
AAFP : This enduring material activity, The Medical Letter Continuing Medical Education Program, has been reviewed and is acceptable for up to 39 Prescribed credits by the
American Academy of Family Physicians. AAFP certification begins January 1, 2014. Term of approval is for one year from this date with the option of yearly renewal. Credit
may be claimed for one year from the date of each issue. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
ACPE: The Medical Letter is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This exam is acceptable
for 2.0 hour(s) of knowledge-based continuing education credit (0.2 CEU).
The American Academy of Nurse Practitioners (AANP) and the American Academy of Physician Assistants (AAPA) accept AMA Category 1 credit for the Physician’s
Recognition Award from organizations accredited by the ACCME.
This activity, being ACCME (AMA) approved, is acceptable for Category 2-B credit by the American Osteopathic Association (AOA).
Physician Assistants: The National Commission on Certification of Physician Assistants (NCCPA) accepts AMA PRA Category 1 Credit(s)™ from organizations accredited by

ACCME. NCCPA also accepts AAFP Prescribed credits for recertification. The Medical Letter is accredited by both ACCME and AAFP.
Physicians in Canada: Members of The College of Family Physicians of Canada are eligible to receive Mainpro-M1 credits (equivalent to AAFP Prescribed credits) as per our
reciprocal agreement with the American Academy of Family Physicians.
MISSION:
The mission of The Medical Letter’s Continuing Medical Education Program is to support the professional development of healthcare providers including physicians, nurse
practitioners, pharmacists, and physician assistants by providing independent, unbiased drug information and prescribing recommendations that are free of industry influence.
The program content includes current information and unbiased reviews of FDA-approved and off-label uses of drugs, their mechanisms of action, clinical trials, dosage and
administration, adverse effects, and drug interactions. The Medical Letter delivers educational content in the form of self-study material.
The expected outcome of the CME program is to increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in
materials contained in The Medical Letter.
The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities. The Medical Letter aims to be a leader in
supporting the professional development of healthcare providers through Core Competencies by providing continuing medical education that is unbiased and free of industry
influence. The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations.
GOAL:
Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and timely educational content that they will use to make
independent and informed therapeutic choices in their practice.
LEARNING OBJECTIVES:
Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities. Activity participants will be
able to select and prescribe, or confirm the appropriateness of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with
specific attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient management. Activity participants will make
independent and informed therapeutic choices in their practice.
Upon completion of this program, the participant will be able to:
1.
Explain the current approach to the management of a patient with arterial or venous thromboses.
2.
Discuss the pharmacologic options available for prevention or treatment of arterial or venous thromboses and compare them based on their efficacy, dosage and
administration, potential adverse effects, and drug interactions.
Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy. We do not sell any of your information. Secure server software (SSL) is used
for commerce transactions through VeriSign, Inc. No credit card information is stored.
IT Requirements: Windows XP/Vista/7/8, Mac OS X+; current versions of Microsoft IE, Mozilla Firefox, Google Chrome, Safari or any other compatible web browser. High-speed

connection.
Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at:

Questions start on next page


The Medical Letter

®

Online Continuing Medical Education
DO NOT FAX OR MAIL THIS EXAM
To take CME exams and earn credit, go to:

medicalletter.org/CMEstatus

Issue 1454 Questions

(Correspond to questions #81-90 in Comprehensive Exam #71, available January 2015)
1. In patients with acute coronary syndrome, aspirin reduces the
incidence of myocardial infarction and/or death by:
a. 5-10%
b. 15-25%
c. 30-40%
d. 50-60%
2. A 70-year-old man taking clopidogrel for acute coronary
syndrome has recently been diagnosed with erosive esophagitis
and asks his physician which proton pump inhibitor he should
take. Which of the following would be the most appropriate choice
for this patient?

a. omeprazole
b. esomeprazole
c. pantoprazole
d. none of the above
3. The most common complication of glycoprotein IIb/IIIa receptor
antagonists is:
a. bleeding at arterial access sites
b. leukopenia
c. intracranial hemmorhage
d. all of the above
4. Compared to unfractionated heparin, low-molecular-weight
heparin:
a. is more likely to cause heparin-induced thrombocytopenia
b. has a more predictable anticoagulant response
c. is more completely neutralized by protamine
d. may be safer in patients with renal impairment
5. Fondaparinux can be used:
a. for prophylaxis of deep vein thrombosis
b. for treatment of venous thromboembolism
c. for unstable angina/non-ST segment elevation myocardial
infarction
d. all of the above

7. A 72-year-old woman undergoing knee replacement surgery
who recently saw an advertisement for Pradaxa asks her
physician if she should be taking it. You should tell her that:
a. there is no FDA-approved antidote to reverse its
anticoagulant effect
b. the risk of major gastrointestinal bleeding is higher with
dabigatran compared with warfarin

c. dabigatran should be taken twice daily
d. all of the above
8. Which of the following anticoagulants is a hirudin analog
approved by the FDA for prophylaxis of deep vein thrombosis
after elective hip arthroplasty?
a. dabigatran
b. apixaban
c. desirudin
d. bivalirudin
9. A 55-year-old man with nonvalvular atrial fibrillation asks his
physician to recommend a treatment to reduce his risk of
thromboembolic stroke. You could tell him that:
a. rivaroxaban is non-inferior to warfarin and does not require
INR monitoring
b. apixaban is more effective than warfarin, but requires
monitoring to maintain the INR within the therapeutic range
c. dabigatran is more effective than warfarin and has an FDAapproved antidote to reverse its anticoagulant effect
d. all of the above
10. Which of the following oral anticoagulants would be an
appropriate choice for a patient with atrial fibrillation associated
with a mechanical valve?
a. warfarin
b. apixaban
c. rivaroxaban
d. dabigatran

6. Unlike heparins and fondaparinux, direct thrombin inhibitors
inhibit:
a. clot-bound and circulating thrombin
b. factor Xa

c. P2Y12
d. protease-activated receptor-1
ACPE UPN: Per Issue Exam: 0379-0000-14-454-H01-P; Release: October 27, 2014, Expire: October 27, 2015
Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016
EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H.,
Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R.,
Weill Medical College of Cornell University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino;
VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without
prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage
resulting from any error, inaccuracy, or omission.

Subscription Services
Address:
The Medical Letter, Inc.
145 Huguenot St. Ste. 312
New Rochelle, NY 10801-7537
www.medicalletter.org

Customer Service:
Call: 800-211-2769 or 914-235-0500
Fax: 914-632-1733
E-mail:

Permissions:
To reproduce any portion of this issue,
please e-mail your request to:


Copyright 2014. ISSN 1523-2859

Subscriptions (US):
1 year - $98; 2 years - $189;
3 years - $279. $49 per year
for students, interns, residents, and
fellows in the US and Canada.
Reprints - $12 each.

Site License Inquiries:
E-mail:
Call: 800-211-2769 ext. 315
Special rates available for bulk
subscriptions.