The medical letter on drugs and therapeutics october 27 2014

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

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IN THIS ISSUE

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Volume 56

Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE No

1454 Antithrombotic Drugs p 103

on Drugs and Therapeutics Objective Drug Reviews Since 1959

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IN THIS ISSUE

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Volume 56ISSUE No.1454 Antithrombotic Drugs

attack (TIA) or minor stroke in the previous 6 months found that a combination of extended-release dipyri-damole (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 prevent-ing 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 (Effi ent) 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thrombotic thrombocytopenic purpura; it has largely been replaced by clopidogrel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 clopi-dogrel 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 clopido-grel 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

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 fi brillation

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

per-cutaneous 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

15-25% 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,

di-pyridamole (Persantine, and generics) inhibits platelet

uptake of adenosine and blocks adenosine

diphos-phate (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

Related article(s) since publication

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 pri mary composite endpoint) had occurred in 9.3% of patients treated with vorapaxar and in 10.5% of those given placebo, a statistically signifi cant difference.12 The effi cacy of vorapaxar for treatment of ACS remains

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 signifi cantly 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

life-threatening 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 benefi t 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

Table 1 Some Antiplatelet Drugs for Acute Coronary Syndrome

(max 10 mcg/min) for 12 hrs

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 fi rst bolus dose.

12 Not an FDA-approved indication.

13 PT O'Gara et al J Am Coll Cardiol 2013; 61:e78.

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

glyco-protein IIb/IIIa receptor antagonists, which are

sometimes given IV for short periods for ACS or

PCI, prevent platelet aggregation by competing

with fi brinogen 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 affi nity

for platelets results in measurable platelet inhibition

for 24-48 hours, with low levels still detectable

after 15 days Eptifi batide (Integrilin) and tirofi ban

(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 heparin-induced 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

Table 2 Some Anticoagulants for Acute Coronary Syndrome

STEMI: 60 units/kg IV bolus, then 12 units/kg/h PCI: 70-100 units/kg IV bolus;

(50-70 units/kg IV bolus if

GP IIb/IIIa used; titrate to ACT 200-250 sec)

Low-Molecular-Weight Heparins

Direct Thrombin Inhibitor

dose to 1 mg/kg/h

Factor Xa Inhibitor

CrCl <30 mL/min:

do not use 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.

kidneys and therefore may be safer in patients with

renal insuffi ciency, and it directly inhibits the contact

activation pathway that is important in the formation

of thrombi in stents, fi lters, 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 signifi cantly fewer

pulmonary emboli and a lower risk of heparin-induced

thrombocytopenia.15

FONDAPARINUX — A synthetic analog of the

penta-saccharide sequence of heparin, fondaparinux (Arixtra,

and generics) binds antithrombin with high affi nity and inhibits factor Xa indirectly through antithrombin without neutralizing thrombin The drug has a long half-life 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 benefi t 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

Table 3 Some Anticoagulants for Venous Thromboembolism

Low-Molecular-Weight Heparins

Vitamin K Antagonist

Direct Thrombin Inhibitors

Factor Xa Inhibitors

1 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).

2 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.

3 Initial dose is 333 units/kg for unmonitored dosing regimen.

4 Dosage adjustments may be needed for renal impairment.

5 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).

6 Monitor daily and adjust dose until results in therapeutic range (INR 2-3) for ≥24 hours.

7 Avoid coadministration with P-glycoprotein inhibitors in patients with CrCl <50 mL/min.

8 Contraindicated in patients with CrCl <30 mL/min.

9 A dose of 220 mg (two 110-mg capsules) once daily is approved for VTE prophylaxis in Canada.

10 Use of desirudin has only been studied for up to 12 days.

11 Cost for 12 days' treatment.

12 5 mg if <50 kg, 7.5 mg if 50-100 kg, 10 mg if >100 kg.

13 Dose for adults ≥50 kg Contraindicated in patients weighing <50 kg.

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 signifi cantly

reduced the incidence of major bleeding compared to

UFH, but it did not provide a net benefi t in outcomes.20

In a meta-analysis of 16 randomized controlled trials

comparing bivalirudin-based regimens with

heparin-based 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

arthro-plasty 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

fi brillation 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 benefi ts 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 fi brillation 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 specifi c reversal agents are

in progress.26

Dabigatran – In a randomized trial (RE-LY) comparing

fi xed doses of the oral direct thrombin inhibitor

dabigatran (Pradaxa) with adjusted-dose warfarin for

a median of 2 years in patients with nonvalvular atrial

fi brillation considered at risk for stroke, the risk of

ischemic or hemorrhagic stroke was signifi cantly lower

with dabigatran 150 mg twice daily than with warfarin.27

For treatment of acute VTE, fi xed-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 antag onist for treatment of VTE and pulmonary embolism, with no increase in major bleeding.33,34 In a trial in patients with nonvalvular atrial fi brillation (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

Table 4 Oral Anticoagulants for Nonvalvular Atrial

Fibrillation

(Boehringer Ingelheim)

(BMS) inhibitor bid 5

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

with nonvalvular atrial fi brillation in preventing stroke

or systemic embolism, without signifi cantly 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 fi brillation, 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 effi cacy 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,

double-blind trial in 8240 patients with acute VTE first

treated with unfractionated heparin or LMWH,

once-daily 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 ■

that its anticoagulant effect may be reversed by prothrombin complex concentrate and clinical

APIXABAN (Eliquis) — Another factor Xa inhibitor,

patients with nonvalvular atrial fi brillation in preventing stroke or systemic embolism without signifi cantly increasing the risk of major bleeding

effective than warfarin in a randomized trial (ARISTOTLE) in preventing stroke or systemic embolism in patients with atrial fi brillation, with

a lower rate of major bleeding and hemorrhagic

apixaban was more effective than once-daily enoxaparin in preventing VTE after knee or hip replacement, without causing an increase in

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 effi cacy endpoint) Major bleeding, the primary safety outcome, occurred less frequently with

and rivaroxaban, apixaban has no FDA-approved antidote if bleeding occurs, but the results of some studies suggest that its anticoagulant effect may

be reversed by prothrombin complex concentrate and clinical studies of a reversal agent are

EDOXABAN — A fourth Xa inhibitor, edoxaban

(Daichii Sankyo), has not been approved to date by the FDA, but may soon be available for once-daily use in patients with non-valvular atrial fi brillation

or venous thromboembolism A randomized, dou-ble-blind trial in 21,105 patients with moderate to high risk atrial fi brillation found edoxaban non-in-ferior to warfarin in preventing stroke or systemic embolism, with signifi cantly lower risk of

double-blind trial in 8240 patients with acute VTE fi rst treated with unfractionated heparin or LMWH, once-daily edoxaban was non-inferior

to warfarin in preventing recurrent VTE or VTE-related death (the primary endpoint) Patients taking edoxaban had a signifi cantly lower rate of major or clinically relevant non-major bleeding

5 Drugs for peptic ulcer disease and GERD Treat Guidel Med Lett 2014; 12:25.

2009; 51:69.

7 MT Roe et al Prasugrel versus clopidogrel for acute coronary syndromes without revascularization N Engl J Med 2012; 367:1297.

8 Ticagrelor (Brilinta) – better than clopidogrel (Plavix)? Med Lett Drugs Ther 2011; 53:69.

9 L Wallentin et al Ticagrelor versus clopidogrel in patients with acute coronary syndromes N Engl J Med 2009; 361:1045.

10 KW Mahaffey et al Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Out-comes (PLATO) trial Circulation 2011; 124:544.

11 Vorapaxar (Zontivity) for prevention of thrombotic cardiovascu-lar events Med Lett Drugs Ther 2014; 56:85.

12 DA Morrow et al Vorapaxar in the secondary prevention of ath-erothrombotic events N Engl J Med 2012; 366:1404.

13 P Tricoci et al Thrombin-receptor antagonist vorapaxar in acute coronary syndromes N Engl J Med 2012; 366:20.

14 DJ Whellan et al Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) J Am Coll Cardiol 2014; 63:1048.

15 PROTECT Investigators Dalteparin versus unfractionated hep-arin in critically ill patients N Engl J Med 2011; 364:1305.

16 Y Falck-Ytter et al Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis,

clinical practice guidelines Chest 2012; 141:e278s.

17 TE Warkentin et al Prevalence and risk of preexisting heparin-induced thrombocytopenia antibodies in patients with acute VTE Chest 2011; 140:366.

18 H Jneid et al 2012 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines J Am Coll Cardiol 2012; 60:645.

19 S Yusuf et al Effects of fondaparinux on mortality and rein-farction in patients with acute ST-segment elevation myo-cardial infarction: the OASIS-6 randomized trial JAMA 2006; 295:1519.

20 G Patti et al Comparison of safety and effi cacy of bivalirudin versus unfractionated heparin in high-risk patients undergoing percutaneous coronary intervention (from the Anti-Thrombotic Strategy for Reduction of Myocardial Damage During Angioplasty-Bivalirudin vs Heparin study) Am J Cardiol 2012; 110:478.

21 MA Cavender and MS Sabatine Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials Lancet 2014; 384:599.

22 Desirudin (Iprivask) for DVT prevention Med Lett Drugs Ther 2010; 52:85.

23 Treatment of atrial fi brillation Treat Guidel Med Lett 2014; 56:53.

24 Choice of an oral anticoagulant in atrial fi brillation Med Lett Drugs Ther 2012; 54:79.

25 New oral anticoagulants for acute venous thromboembolism Med Lett Drugs Ther 2014; 56:3.

26 WI Gonsalves et al Management of bleeding complications in patients on new oral anticoagulants J Hematol Transfus 2014; 2:1015.

27 Dabigatran etexilate (Pradaxa) — a new oral anticoagulant Med Lett Drugs Ther 2010; 52:89.

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4 DM Roden and AR Shuldiner Responding to the clopidogrel

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treat-ment of acute venous thromboembolism N Engl J Med 2009;

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29 S Schulman et al Extended use of dabigatran, warfarin, or

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30 FDA drug safety communication: FDA study of Medicare

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gastrointestinal bleeding with Pradaxa (dabigatran) compared

to warfarin Available at www.fda.gov/Drugs/DrugSafety/ucm

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31 MR Southworth et al Dabigatran and postmarketing reports of

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double-blind trial Lancet 2010; 375:807.

40 MR Lassen et al Apixaban versus enoxaparin for

thrombopro-phylaxis 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 fi brillation 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.

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Issue 1454 Questions

(Correspond to questions #81-90 in Comprehensive Exam #71, available January 2015)

physician if she should be taking it You should tell her that:

anticoagulant effect

dabigatran compared with warfarin

approved by the FDA for prophylaxis of deep vein thrombosis after elective hip arthroplasty?

physician to recommend a treatment to reduce his risk of thromboembolic stroke You could tell him that:

INR monitoring

monitoring to maintain the INR within the therapeutic range

FDA-approved antidote to reverse its anticoagulant effect

10 Which of the following oral anticoagulants would be an appropriate choice for a patient with atrial fi brillation associated with a mechanical valve?

incidence of myocardial infarction and/or death by:

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?

3 The most common complication of glycoprotein IIb/IIIa receptor

antagonists is:

heparin:

infarction

6 Unlike heparins and fondaparinux, direct thrombin inhibitors

inhibit:

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

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