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Practical Approaches to Managing Antiplatelet Therapy in

Acute Coronary Syndrome

Presented as a Live Webinar

Wednesday, September 17, 2014 Tuesday, October 7, 2014

1:00 p.m. – 2:00 p.m. ET

www.ashpadvantage.com/acs

Planned and conducted by ASHP Advantage and supported by an educational grant from The Medicines Company.

http://www.ashpadvantage.com/acs

Practical Approaches to Managing Antiplatelet Therapy in Acute Coronary Syndrome

Activity Overview

In the United States, acute coronary syndrome (ACS) accounts for more than 1.4 million hospital admissions per year. Between 9% and 19% of persons with ACS die in the first six months after diagnosis. Appropriate management of ACS is essential to optimizing patient outcomes. During this activity, faculty will summarize treatment guidelines for ACS, focusing on antiplatelet therapy. Patient cases will be used to illustrate practical approaches to clinical challenges encountered managing ACS patients throughout the continuum of care, especially during the periprocedural period.

Learning Objectives

At the conclusion of this application-based educational activity, participants should be able to • Summarize current published treatment guidelines on the management of patients with acute coronary

syndrome (ACS), focusing on antiplatelet therapy. • Evaluate evolving clinical evidence on the use of antiplatelet therapy in the management of ACS and

potential impact on recommendations from published treatment guidelines. • Discuss practical approaches to managing challenges in antiplatelet therapy for ACS patients at different

points in the continuum of care.

Continuing Education Accreditation

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0 hour (0.1 CEU – no partial credit) of continuing pharmacy education credit (ACPE activity #0204-

0000-14-494-L01-P for the live activity and ACPE activity #0204-0000-14-494-H01-P for the on-demand activity).

Participants will process CPE credit online at http://elearning.ashp.org/my-activities, with the option of printing a CE certificate. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home study activity.

Webinar Information

Visit http://www.ashpadvantage.com/acs to find: • Webinar registration link• Group viewing information and technical requirements• CPE webinar processing information

Additional Educational Activities in this Initiative This live activity will be archived and offered as web-based on-demand learning at

www.ashpadvantage.com/acs

http://elearning.ashp.org/my-activities




Activity Faculty

Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology) Associate Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology), is Associate Professor of Pharmacy Practice at the University of Nebraska Medical Center in Omaha, Nebraska. Dr. Dobesh earned both his Bachelor of Science in pharmacy and Doctor of Pharmacy degrees from South Dakota State University. He completed a specialty residency in internal medicine at the University of Texas at Austin at Brackenridge Hospital, and he is a board-certified pharmacotherapy specialist with added qualifications in cardiology.

Dr. Dobesh’s current responsibilities at the University of Nebraska Medical Center (UNMC) include clinical practice in both internal medicine and cardiology services. He is responsible for teaching pharmacy and medical students, as well as pharmacy and medical residents. His main lecture topics include ischemic heart disease, antithrombotic therapy, and other cardiology and critical care topics. Dr. Dobesh recently received the UNMC College of Pharmacy Distinguished Educator of the Year Award for 2012, an award he has received three times within the last seven years. In 2013, he received the UNMC campus wide Outstanding Educator Award.

Dr. Dobesh has conducted research on antiplatelet and antithrombotic therapy, focusing on the real-world use of these therapies and health-care economics. He has also published book chapters and several manuscripts in this field.

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Toby C. Trujillo, Pharm.D., FCCP, FAHA, BCPS (AQ Cardiology) Associate Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Clinical Specialist-Anticoagulation/Cardiology University of Colorado Hospital Aurora, Colorado Toby C. Trujillo, Pharm.D., FCCP, FAHA, BCPS (AQ Cardiology), is Associate Professor of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences in Aurora, Colorado. He also serves as Clinical Specialist in cardiovascular pharmacotherapy and anticoagulation at University of Colorado Hospital. Dr. Trujillo earned his Bachelor of Science degree in biochemistry from the University of California, Davis and his Doctor of Pharmacy degree from the University of California, San Francisco, where he also completed a residency in pharmacy practice. Dr. Trujillo completed a fellowship in cardiovascular pharmacotherapy at The University of Arizona, and he is a board-certified pharmacotherapy specialist with added qualifications in cardiology. Dr. Trujillo’s current responsibilities at University of Colorado Hospital include providing clinical pharmacy services to cardiology, as well as directing the inpatient anticoagulation program. He also serves as co-chair of the anticoagulation subcommittee of the P&T committee. Dr. Trujillo currently serves as a preceptor to both pharmacy students and residents. His lectures at the School of Pharmacy focus on ischemic heart disease, antithrombotic therapy, and other cardiology and critical care topics. Dr. Trujillo has served in several capacities within the American Heart Association and the Society of Critical Care Medicine. He has also served a number of committees within the American College of Clinical Pharmacy, served as a speaker on numerous occasions on a national level, and authored several articles and book chapters in the area of cardiovascular pharmacotherapy. Dr. Trujillo is a member of the American Society of Health-System Pharmacists, and he helped develop current standards for postgraduate year 2 (PGY2) cardiology residency training programs.

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Disclosure Statement

In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support and the Accreditation Council for Pharmacy Education’s Guidelines for Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A commercial interest is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on presentations.

All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an educational activity.

• Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology), declares that he served as a consultant for AstraZeneca; Bristol-Myers Squibb/Pfizer; Daiichi Sankyo, Inc.; Gilead Sciences, Inc.; and Janssen Pharmaceuticals,Inc.; and also received research grants from AstraZeneca and Daiichi Sankyo, Inc. and Eli Lilly and Companyalliance.

• All other faculty and planners report no financial relationships relevant to this activity.

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Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology)Associate Professor of Pharmacy PracticeCollege of Pharmacy

University of Nebraska Medical Center

Omaha, Nebraska

Toby C. Trujillo, Pharm.D., FCCP, FAHA, BCPS (AQ Cardiology)Associate ProfessorUniversity of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences

Clinical Specialist-Anticoagulation/CardiologyUniversity of Colorado Hospital

Aurora, Colorado

Planned and conducted by ASHP Advantage and supported by an educational grant from The Medicines Company.

• Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology), declares that he served as a consultant for Astra Zeneca; Bristol-Myers Squibb/Pfizer; Daiichi Sankyo, Inc.; Gilead Sciences, Inc.; and Janssen Pharmaceuticals, Inc.; and also received research grants from AstraZeneca and Daiichi Sankyo, Inc. and Eli Lilly and Company alliance.

• All other faculty and planners report no financialrelationships relevant to this activity

Disclosures

Learning ObjectivesAt the conclusion of this educational activity, participants should be able to• Summarize current published treatment guidelines on the

management of patients with acute coronary syndrome (ACS), focusing on antiplatelet therapy

• Evaluate evolving clinical evidence on the use of antiplatelet therapy in the management of ACS and potential impact on recommendations from published treatment guidelines

• Discuss practical approaches to managing challenges in antiplatelet therapy for ACS patients at different points in the continuum of care

Platelet Cascade in ACSAdhesion1

Platelets

LipidCore

CollagenGP la/lla Bind

von WillebrandFactor/GP lb Bind

Activation2

Thrombin

ADP

5 HT

TXA2

Aggregation3

FibrinogenActivatedGP llb/llla

Platelet Plug4

Acute Coronary Syndrome

non-ST elevation(UA / NSTEMI)

ST elevation(STEMI)

FibrinolysisPCI +/-Stent

MedicalTherapy

Start and continue indefinitely aspirin 75 to 162 mg/d in all patients unless contraindicated

Aspirin allergic patients with ACS treated medically (without stenting) use clopidogrel or ticagrelor indefinitely

In post-PCI-stented patients, it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses.

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

Smith SC Jr. et al. Circulation. 2011;124:2458-73.

Aspirin Recommendations

6

Antiplatelet Trialists’ Collaboration: Meta-analysis

*Odds reduction in serious vascular events Treatment effect p<0.0001

0 0.5 1.0 1.5 2.0

500-1500 mg 34 19

160-325 mg 19 26

75-150 mg 12 32

<75 mg 3 13

Any aspirin 65 23

Antiplatelet Better Antiplatelet Worse

Aspirin Dose # Trials OR* (%) Odds Ratio

Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.

Relationship Between Major Bleeding and ASA Dose in ACS Patients

Peters RJG et al. Circulation. 2003; 108:16827.ASA dose (range 75-325 mg)

0

1.0

2.0

3.0

4.0

5.0

Inci

den

ce o

f M

ajo

r B

leed

ing

(%

)

1.9%

3.0% 2.8%

3.4%

3.7%

4.9%

101–199 mg

(N=3109)

≥200 mg

(N=4110)

≤100 mg (N=5320)

PlaceboClopidogrel

(Post-hoc analysis from CURE)

Clopidogrel 75 mg/d for patients allergic or intolerant to aspirin.

P2Y12 inhibitors for post ACS or post PCI with stent placement patients for up to 12 months

Clopidogrel 75 mg dailyPrasugrel 10 mg dailyTicagrelor 90 mg twice daily

Smith SC Jr. et al. Circulation 2011;124:2458-73.

P2Y12 Receptor Inhibitor Recommendations

Used with permission. Schomig A. N Engl J Med. 2009;361:1108-11.

Biotransformation and Mode of ActionClopidogrel, Prasugrel, and Ticagrelor

Clopidogrel 75 mg QD + ASA 75-325 mg QD

(6259 patients)

Placebo + ASA 75-325 mg QD(6303 patients)

Patients withAcute Coronary

Syndrome

(unstable angina or non–ST-segment

elevation MI)

R

Yusuf S et al. N Engl J Med. 2001;345:494-502.

CURE Study Design

3 months double-blind treatment 12 months

Clopidogrel 300 mg loading dose

Primary Endpoint: MI/Stroke/CV Death

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Cu

mu

lati

ve H

azar

d R

ate

Clopidogrel + ASA

3 6 9

Placebo + ASA

Months of Follow-Up

p = 0.00009n = 12,562

0 12

20%RRR

CURE Study

Yusuf S et al. N Engl J Med 2001;345:494-502.

7

Clopidogrel in ACS• STEMI

– CLARITY (n=3,491)• Patients age 18-75 within 12

hours – Clopidogrel 300 mg/75 mg– Placebo

• Significant reductions in occluded vessel, death, MI by angiography and up to 30 days

– COMMIT (n=45,852)• Patients within 24 hours of

suspected MI– Clopidogrel 75 mg– Placebo

• 9% reduction in death/MI/stroke over treatment period

• NSTE ACS– CURE (n=12,562)

• 300/75 vs. placebo within 24 hours of symptom onset

• Significant reductions in death, MI and stroke

– PCI-CURE (n=2,658)• 31% Relative risk

reduction in CV death/MI

– CREDO (n=2,116)• 300/75 vs placebo 3-24 h before

PCI, 75 mg vs placebo after 28 days• 27% RRR MI/ stroke/ death 1 year• 18.5% RRR in Death, MI, UTVR• Benefit only seen if load > 6 hours

prior to PCI

– ACUITY (n=13,819)• Benefit with bivalirudin

monotherapy contingent on clopidogrel loading pre-PCI

Yusuf S et al. N Engl J Med. 2001;345:494-502.Mehta SR et al. Lancet. 2001;358:527-33.

Steinhubl S. JAMA. 2002;288:2411-20.Stone GW et al. N Engl J Med. 2006;355:2203-16.

CLARITY. N Engl J Med. 2005;352:1179-89. COMMIT. Lancet. 2005;366:1607-21.

Clinical Issues with Clopidogrel• Variability of platelet inhibition

– Drug – drug interactions (PPIs)

– Up to 40% of patients are “nonresponsive”

– Role of platelet function testing?

– What to do with the results?

• Genetic polymorphisms in metabolism– Prodrug that must undergo two CYP450

enzyme conversion steps

– CYP 2C19 loss-of-function alleles• Heterozygous vs. homozygous

• Connection with clinical outcomes debated

Biotransformation and Mode of ActionClopidogrel, Prasugrel, and Ticagrelor

Used with permission. Schomig A. N Engl J Med. 2009;361:1108-11.

TRITON TIMI-38ACS (STEMI or UA/NSTEMI) & planned PCI

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, stroke2o endpoints: CV death, MI, stroke, rehosp-recurr. ischemia

CV death, MI, UTVRStent thrombosis (definite/probable)

Safety endpoints: TIMI major bleeds, life-threatening bleeds

Median duration of therapy - 12 months

Wiviott SD et al. N Engl J Med. 2007;357:2001-15.

n = 13,608

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138events

35events

TRITON TIMI-38 Trial - Results

CV Death / MI / Stroke

TIMI Major Non-CABG Bleeds

NNT = 46

NNH = 167

Wiviott SD et al. N Engl J Med 2007;357:2001-15.

Pri

mar

y E

nd

po

int

(%)

0

2

4

6

8

0 1 2 3 30 6090 180 270 360 450

HR 0.82p=0.01

HR 0.80p=0.003

5.6%

4.7%

6.9%

5.6%

Days

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Loading Dose Maintenance DoseWiviott SD et al. N Engl J Med. 2007;357:2001-15.

TRITON – TIMI 38 TrialTiming of Benefit

8

PLATO study design

Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding

ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;

Ticagrelor180 mg loading dose, then

90 mg bid maintenance;(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;

randomized within 24 hours of index event

Wallentin L et al. N Engl J Med. 2009;361:1045-57.

n=18,624

PLATO TrialPrimary Endpoint Results

Days after randomization0 60 120 180 240 300 360

12

10

8

6

4

2

0Cu

mu

lati

ve in

cid

ence

(%

)

9.8

11.7Clopidogrel

Ticagrelor

p<0.001HR 0.84 (95% CI 0.77 to 0.92)

NNT=53


5.3%

6.6%

0 10 20 30

8

6

4

2

0

Cu

mu

lati

ve i

nci

den

ce (

%)

Clopidogrel

Ticagrelor

4.8%5.4%

HR 0.88 p=0.045

Days after randomization

31 90 150 210 270 330

8

6

4

2

0

Clopidogrel

Ticagrelor

Days after randomization

HR 0.80p<0.001C

um

ula

tive

in

cid

ence

(%

)

*Composite of CV death, MI, or stroke

PLATO TrialTiming of Benefit*

Days 1 - 30 Days 30 – 365


PLATO Results – Major BleedingNon-CABG and CABG Related

Total PLATO major bleeding: 11.6% Ticagrelor vs. 11.2% Clopidogrel; p=0.43Total TIMI major bleeding: 7.9% Ticagrelor vs. 7.7% Clopidogrel; p=0.57

p=0.026

p=0.025

p=NS

p=NS

% o

f P

atie

nts


Evolving Evidence and Applications for Antiplatelet

Therapy in CV Disease

Case Study 1• PD is a 56 year-old male with a PMhx of HTN, DM,

CAD (s/p MI x 2, PCI x1 with DES placement 2 years ago) presenting to the hospital ED with a 6 hour history of chest squeezing and tightness

• PE: BP 148/92 mm Hg, HR 88 bpm; Ht 72 in, Wt 90 kg, afebrile 3 cm JVD, lungs rales; regular S1, S2, -S3, -S4, no

murmur Abdomen obese, soft, with mild epigastric tenderness;

-FOBT Extremities without edema, pulses 1-2+ throughout

9

Case Study 1

• ECG: 2 mm ST depression, Leads V4-V6 with symmetrical T wave inversion

• CXR: heart failure • Labs:

Hct 45, WBC 8.7, Plts 238K Na 138, K 4.2 BUN 41, SCr 1.82 mg/dL Gluc 142 Est CrCl 58 mL/min (CG) CK-MB 6 (ULN <6) TnT 3.80 (ULN <0.10) LDL 130 mg/dL, HDL 32 mg/dL, TGs 149 mg/dL

Case Study 1

• Medications taken prior to admission

Aspirin 81 mg daily

Clopidogrel 75 mg daily

Metformin 1 g twice daily

Ramipril 10 mg daily

Metoprolol 50 mg twice daily

Amlodipine 10 mg daily

SL NTG 0.4 mg prn chest pain

Case Study 1PD is managed with an invasive strategy for his recurrent MI, recovers quickly, and is discharged home. He returns for follow-up with his cardiologist 2 weeks later. As the clinical pharmacist in the cardiology clinic, you are asked if there are any improvements that can be made in the antithrombotic regimen. You recommend which of the following?

1) Aspirin 81 mg, plus prasugrel 10 mg daily

2) Aspirin 81 mg, plus ticagrelor 90 mg twice daily

3) Aspirin 81 mg, plus clopidogrel 150 mg twice daily

4) Aspirin 81 mg, plus clopidogrel 75 mg, plus vorapaxar 2.5 mg daily

TBX A2

Vorapaxar

Chackalamannil S. J Med Chem. 2006;49:5389-403.

Platelet

PAR-4

TBXA2-R

Thrombin

Anionicphospholipidsurfaces

GP IIb/IIIa

ADP P2Y12

PAR-1

Clopidogrel

Prasugrel

Ticagrelor

Cangrelor

Aspirin

Vorapaxar• Protease-activated receptor-

1 (PAR-1) antagonist

• Indicated for reduction of CV events in patients with previous MI or PAD

• 1 tablet daily (2.08 mg)

• Boxed warning – do NOT use in history of stroke, TIA, ICH, or active bleeding

• CYP 3A4 metabolism – avoid strong inhibitors, inducers

• No adjustment for renal impairment

• Terminal elimination half-life (t½) = 8 days

TRA 2P – TIMI 50: Trial DesignStable atherosclerosis: History of MI, stroke, or PAD

Receiving standard of care

Vorapaxar 2.5 mg dailyPlacebo

Primary Efficacy Endpoint: CV death, MI, stroke, recurrent ischemia leading to revascularizationPrimary Bleeding Endpoint: GUSTO moderate or severe bleeding

n=26,449

Morrow DA et al. N Engl J Med. 2012;366:1404-13.

Median treatment duration of 30 monthsAt 2 years, study halted in the ischemic stroke group due to in risk of ICH

Key exclusion criteria: planned revascularization, history of bleeding diathesis, recent abnormal bleeding, warfarin, hepatobiliary disease

TRA 2P – TIMI 50: Efficacy ResultsAll Patients

Used with permission. Morrow DA et al. N Engl J Med. 2012;366:1404-13.

Eve

nt

Rat

e (%

)

CV Death, MI, Stroke, or Recurrent Ischemia Leading to Urgent

Coronary Revascularization (UCR)CV Death, MI, or Stroke

HR 0.87 (95% CI, 0.80 – 0.94)

p<0.001

HR 0.88(95% CI, 0.82 – 0.95)

p=0.001

Days Since Randomization Days Since Randomization

10

TRA 2P – TIMI 50: Efficacy ResultsPatients Without a History of Stroke or TIA

Morrow DA et al. N Engl J Med. 2012;366:1404-13.Zontivity Prescribing Information, May 2014.

EndpointsPlacebo

(n=10,090)

Vorapaxar

(n=10,080)

Hazard Ratio

(95% CI)p-

value

1° Endpoint: CV death, MI, stroke, UCR (%)

10.6 8.9 0.83 (0.76 – 0.90) <0.001

CV death, MI, Stroke (%) 8.4 6.8 0.80 (0.73 – 0.89) <0.001

CV death (%) 2.4 2.0 0.86 (0.71 – 1.03)

MI (%) 5.6 4.7 0.82 (0.73 – 0.93)

Stroke (%) 1.4 1.0 0.67 (0.52 – 0.87)

UCR (%) 2.8 2.5 0.88 (0.74 – 1.04)

TRA 2P – TIMI 50: Safety ResultsPatients Without a History of Stroke or TIA

Morrow DA et al. N Engl J Med. 2012;366:1404-13.Zontivity Prescribing Information, May 2014.

GUSTO Bleeding (%)Placebo

(n=10,049)

Vorapaxar

(n=10,059)

Hazard Ratio

(95% CI)

Severe 0.8 1.0 1.24 (0.92 – 1.66)

Moderate or severe 2.0 3.0 1.55 ( 1.30 -1.86)

Any (severe/mod/mild) 17.6 25.0 1.52 (1.43 – 1.61)

Fatal bleeding 0.1 0.2 1.15 (0.56 – 2.36)

Intracranial hemorrhage 0.3 0.4 1.46 (0.92 – 2.31)

Clinically significant bleeding (TIMI)

9.5 13.4 1.47 (1.35 – 1.60)

Gastrointestinal bleeding 3.0 4.0 1.37 (1.18 – 1.59)

Case Study 1PD is managed with an invasive strategy for his recurrent MI, recovers quickly, and is discharged home. He returns for follow-up with his cardiologist 2 weeks later. As the clinical pharmacist in the cardiology clinic, you are asked if there are any improvements that can be made in the antithrombotic regimen. You recommend which of the following?

A.Aspirin 81 mg, plus prasugrel 10 mg daily

B.Aspirin 81 mg, plus ticagrelor 90 mg twice daily

C.Aspirin 81 mg, plus clopidogrel 150 mg twice daily

D.Aspirin 81 mg, plus clopidogrel 75 mg, plus vorapaxar 2.5 mg daily

Case Study 2PD is switched to aspirin plus ticagrelor for dual antiplatelet therapy.

6 months later, he requires surgery for removal of a parotid neoplasm (adenocarcinoma).

The cardiologist following PD comes to you for advice on how his antiplatelet regimen should be managed around the procedure.

Case Study 2Which of the following would you recommend?

A. Stop ASA and ticagrelor 7-10 days pre-op and resume both drugs 1-2 days post-op.

B. Stop ASA and ticagrelor 7-10 days pre-op and administer bridging with SC low-molecular-weight heparin or IV heparin, and resume both drugs 1-2 days post-op.

C. Continue ASA pre-/post-op and stop ticagrelor 7-10 days pre-op, and resume ticagrelor 1-2 days post-op.

D. Continue ASA + ticagrelor pre-/post-op.

E. Stop ASA and ticagrelor 7-10 days pre-op and administer GP IIa/IIIb inhibitor around the time of surgery, and resume both drugs 1-2 days post-op.

Peri-Operative Management of Antiplatelet Therapy

• Perioperative Management of Antithrombotic Therapy (Douketis JD et al. CHEST. 2012; 141(Suppl 2): e326S–e350S.)

• Expert Position Paper on the Management of Antiplatelet Therapy in Patients Undergoing CABG (Sousa-Uva M et al. Eur Heart J. 2014: 35;1510-4.)

• Management of Antiplatelet Therapy in Patients with CAD Requiring Cardiac and Noncardiac Surgery (Capodanno D et al. Circulation. 2013;128:2785-98.)

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Considerations in Perioperative Management of Antiplatelet Therapy

• Avoid Unnecessary Revascularization and Stent Placement

• Ischemic Risk– Underlying pathophysiology

– Stent placement, type of stent used

• Bleeding Risk– Procedure type

• Consequences of ischemia/bleeding– Stent thrombosis

– Low-risk bleed risk, but severe consequences (pacemaker placement)

Multidisciplinary Discussion Should be Undertaken to Formulate Plan

ACCP Guideline Recommendations

• In patients who are receiving aspirin for the secondary prevention of cardiovascular disease and are having minor dental or dermatologic procedures or cataract surgery, we suggest continuing aspirin around the time of the procedure instead of stopping ASA 7 to 10 days before the procedure (Grade 2C)

• In patients at moderate to high risk for cardiovascular events who are receiving aspirin therapy and require noncardiac surgery, we suggest continuing aspirin around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C)

Douketis JD et al. CHEST. 2012;141(Suppl 2):e326S–e350S.


• In patients at low risk for cardiovascular events who are receiving aspirin therapy, we suggest stopping aspirin 7 to 10 days before surgery instead of continuation of aspirin (Grade 2C).

• In patients who are receiving aspirin and require CABG surgery, we suggest continuing aspirin around the time of surgery instead of stopping aspirin 7 to 10 days before surgery (Grade 2C).



• In patients who are receiving dual antiplatelet drug therapy and require CABG surgery, we suggest continuing aspirin around the time of surgery and stopping clopidogrel/prasugrel 5 days before surgery instead of continuing dual antiplatelet therapy around the time of surgery (Grade 2C).

• In patients with a coronary stent who are receiving dual antiplatelet therapy and require surgery, we recommend deferring surgery for at least 6 weeks after placement of a bare-metal stent and for at least 6 months after placement of a drug-eluting stent instead of undertaking surgery within these time periods (Grade 1C).



• In patients who require surgery within 6 weeks of placement of a bare-metal stent or within 6 months of placement of a drug-eluting stent, we suggest continuing dual antiplatelet therapy around the time of surgery instead of stopping dual antiplatelet therapy 7-10 days before surgery (Grade 2C).


Examples of Surgery that May Require Thienopyridine Discontinuation

• Major cardiac or thoracic surgery

• Neurosurgical procedures (may require aspirin discontinuation as well)

• Major orthopedic surgery

• Urologic procedures

• General abdominal surgery

Capodanno D et al. Circulation. 2013;128:2785-98.

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Role of Bridging Therapy?

• GP IIb/IIIa receptor antagonists– Limited clinical trial information to validate

the efficacy and safety of use for bridging of thienopyridines around surgery

• Small case series all continued aspirin therapy

• Tirofiban or eptifibatide used at standard doses– Thienopyridines stopped 5-7 days pre-op

– GP IIb/IIIa receptor antagonists started Day 3 pre-op and continued up to 4-6 hours prior to surgery

– Restart oral agent post-op when deemed safe

Capodanno D et al. Circulation. 2013;128:2785-98.

Bridging with a GP IIb/IIIa Receptor Antagonist

Used with permission. Capodanno D et al. Circulation. 2013;128:2785-98.

N N

N N

NH

SCF3

OHOH

OO

PO

OPP

OO

OClCl

OO

O

S

4Na+

Future Options for Bridging?Cangrelor

• Intravenous ADP–P2Y12 receptor antagonist – Rapid acting: quick onset, quick offset

– Plasma half-life of 3 – 6 minutes

– 60 minutes for return to normal platelet function

Meadows TA et al. Circ Res. 2007;100:1261-75.Akers W. J Clin Pharmacol. 2010;50:27-35.

Steinhubl S. Thromb Res. 2008;121:527-34.

BRIDGE Trial DesignRandomized, Double-Blind, Placebo-Controlled

Treat per Standard of Care

(CABG rule-in)

0

100

200

300

400

-1 0 1 2 3 4 5-7Elapsed Days

PR

U

CABGCABG

Thru Hospital Discharge

Demonstrate that cangrelor infusion maintains PRU< 240

Cangrelor/Placebo InfusionDose Determined in Stage I :

0.75 µg/kg/min

• Patients with an ACS or treated with a coronary stent (BMS or DES) on a thienopyridine (ticlopidine, clopidogrel or prasugrel) awaiting CABG.

• After thienopyridine discontinuation (<72 hours), patients were administered cangrelor/placebo for at least 48 hours and up to 7 days, which was discontinued 1-6 hours prior to CABG.

• Objective: demonstrate that cangrelor would maintain levels of platelet reactivity <240 P2Y12 Reaction Units (PRU) throughout the pre-operative period as measured by the VerifyNow™ P2Y12 test.

Clopidogrel or prasugrel

Angiolillo DJ et al. JAMA. 2012;307:265-74.

BRIDGE Trial Primary EndpointPercent of patients with PRU<240

for all on-treatment samples:

p<0.0001

OR (95% CI)353 (45.6-2728)


0

50

100

150

200

250

300

350

400

Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Last on-infusion

sample

Pre-CABGsample

Time Point

n=80n=70

n=55 n=33n=7

n=1

n=6

n=85

n=84

n=78

Cangrelor Placebo

Ver

ifyN

ow

PR

U

BRIDGE TrialPlatelet Reactivity by Day

n=76n=73

n=57 n=34 n=24

n=14n=86

n=2n=84

n=75


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BRIDGE Trial Bleeding EndpointExcessive CABG-related bleeding

(primary safety endpoint)*

*Excessive CABG-related bleeding is defined as the occurrence of one or more of the following 3 components during the CABG procedure or post-operative hospitalization: Surgical re-exploration, 24 hour chest tube output > 1.5 liters, Incidence of PRBC transfusion > 4 units.

p=0.76


BRIDGE Trial Pre-Operative* Bleeding

Parameter* Cangrelor(n= 106)

Placebo(n= 101)

Odds Ratio(95% CI)

p-value

ACUITY Bleeding (%)

Major 2.8 1.0 2.91 (0.30 – 28.5) 0.358

Minor 17.9 9.9 1.99 (0.88 – 4.51) 0.101

GUSTO Bleeding (%)

Severe/Life threatening 0 0 NA NA

Moderate 1.9 1.0 1.92 (0.17 – 21.5) 0.596

Mild 17.9 9.9 1.99 (0.88 – 4.51) 0.101

TIMI Bleeding (%)

Major 0.9 0 NA NA

Minor 0.9 0 NA NA

Angiolillo DJ et al. JAMA. 2012;307:265-74.* From randomization until surgical incision

BRIDGE Trial Ischemic Events

*Ischemic events not adjudicated; site reported† Ischemia-driven revascularization

Parameter* Cangrelor(N= 106)

Placebo(N= 101)

Incidence of Pre-Procedure Ischemic endpoints (randomization to surgery) (%)

Death/MI/IDR†/Stroke 2.8 4.0

Death 0.9 3.0

MI 1.9 0

IDR† 0.9 0

Stroke 0 0

Incidence of Post-Surgery Ischemic endpoints (through 30 days) (%)

Death/MI/IDR†/Stroke 3.9 4.2

Death 1.0 2.1

MI 2.0 1.0

IDR† 2.5 0


Potential Bridging Strategy with Cangrelor

Used with permission. Capodanno D et al. Circulation. 2013;128:2785-98.

Case Study 2Which of the following would you recommend?

A. Stop ASA and ticagrelor 7-10 days pre-op and resume both drugs 1-2 days post-op.

B. Stop ASA and ticagrelor 7-10 days pre-op and administer bridging with SC low-molecular-weight heparin or IV heparin, and resume both drugs 1-2 days post-op.

C. Continue ASA pre-/post-op and stop ticagrelor 7-10 days pre-op, and resume ticagrelor 1-2 days post-op.

D. Continue ASA + clopidogrel pre-/post-op.

E. Stop ASA and ticagrelor 7-10 days pre-op and administer GP IIa/IIIb inhibitor around the time of surgery, and resume both drugs 1-2 days post-op.

Learning ObjectivesAt the conclusion of this educational activity, participants should be able to• Summarize current published treatment guidelines on the

management of patients with acute coronary syndrome (ACS), focusing on antiplatelet therapy

• Evaluate evolving clinical evidence on the use of antiplatelet therapy in the management of ACS and potential impact on recommendations from published treatment guidelines

• Discuss practical approaches to managing challenges in antiplatelet therapy for ACS patients at different points in the continuum of care

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Self‐assessment Questions

The presentation self‐assessment questions are listed here for your convenience. Note the correct answers for future reference. 1. PD is managed with an invasive strategy for his recurrent MI, recovers quickly, and is discharged home. He

returns for follow‐up with his cardiologist 2 weeks later. As the clinical pharmacist in the cardiology clinic, you are asked if there are any improvements that can be made in the antithrombotic regimen. You recommend which of the following?

a. Aspirin 81 mg, plus prasugrel 10 mg daily b. Aspirin 81 mg, plus ticagrelor 90 mg twice daily c. Aspirin 81 mg, plus clopidogrel 150 mg twice daily d. Aspirin 81 mg, plus clopidogrel 75 mg, plus vorapaxar 2.5 mg daily

2. PD is switched to aspirin plus ticagrelor for dual antiplatelet therapy. 6 months later, he requires surgery for removal of a parotid neoplasm (adenocarcinoma). The cardiologist following PD comes to you for advice on how his antiplatelet regimen should be managed around the procedure. Which of the following would you recommend?

a. Stop ASA and ticagrelor 7‐10 days pre‐op and resume both drugs 1‐2 days post‐op. b. Stop ASA and ticagrelor 7‐10 days pre‐op and administer bridging with SC low‐molecular‐weight

heparin or IV heparin, and resume both drugs 1‐2 days post‐op. c. Continue ASA pre‐/post‐op and stop ticagrelor 7‐10 days pre‐op, and resume ticagrelor 1‐2 days

post‐op. d. Continue ASA + ticagrelor pre‐/post‐op. e. Stop ASA and ticagrelor 7‐10 days pre‐op and administer GP IIa/IIIb inhibitor around the time of

surgery, and resume both drugs 1‐2 days post‐op.

Answers

1. No one correct answer. Options a, b, and d are all acceptable 2. Option c is best answer, but option e is acceptable

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