treatment guidelines for acute coronary syndrome
TRANSCRIPT
Treatment Guidelines for Acute Coronary Syndrome
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Reproduction in whole or in part without permission is prohibited.
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This activity is supported by an educational grant from AstraZeneca
Accreditation Pharmacists: 0798-0000-12-025-L01-P Nurses: N-748
Faculty
Jean Nappi, PharmD, FCCP, BCPS Professor Medical University of South Carolina College of Pharmacy
CE Credit(s) 1.25 contact hour(s)
Faculty Disclosure Dr. Nappi has no actual or potential conflicts of interest in relation to this program.
Learning Objectives •Describe the evidence and guideline-based role of antiplatelet therapy in the prevention of coronary attacks in patients with acute coronary syndromes (ACS) •Compare and contrast the safety and efficacy of oral antiplatelet therapies for long-term prevention of coronary attacks in ACS patients to include bleeding risks associated with antiplatelet therapy •Describe the pharmacist’s role in counseling patients to increase understanding of treatment guidelines and medication adherence as a critical component of long-term maintenance of ACS patients
Legal Disclaimer The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity.
Treatment Guidelines for Acute Coronary Syndrome
This activity is supported by an educational grant from AstraZeneca
PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education
• Describe the evidence and guideline-based role of antiplatelet therapy in the prevention of coronary attacks in patients with acute coronary syndromes (ACS).
• Compare and contrast the safety and efficacy of oral antiplatelet therapies for long-term prevention of coronary attacks in ACS patients to include bleeding risks associated with antiplatelet therapy.
• Describe the pharmacist’s role in counseling patients to increase the understanding of treatment guidelines and medication adherence as a critical component of long-term maintenance of ACS patients.
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2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline). Published on-line March 28, 2011
AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2011 Update. Published on-line November 3, 2011
2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. Published on-line November 7, 2011
Treatment Guidelines for Acute Coronary Syndrome
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
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Chest pain consistent with coronary ischemia
Within 10 minutes • 12 lead ECG, continuous ECG monitoring
• IV with D5W • Aspirin 325mg (chewed) • IV NTG
• Blood for baseline serum cardiac markers
Therapeutic/Diagnostic tracking according to 12-lead ECG
Not diagnostic/normal ECG ECG suggestive of ischemia
T wave inversion or ST depression
ST segment elevation or new bundle branch block
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ACUTE CORONARY SYNDROME
No ST Elevation ST Elevation
Myocardial Infarction
(-) markers
(+) markers
Unstable angina
NSTEMI
STEMI
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ACS
Fibrinolysis Primary PCI
ST Elevation No ST Elevation
Early
Invasive Conservative
Early
Conservative Door to needle
<30 minutes
Door to balloon < 90 minutes
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Tissue factor
Plasma clotting
cascade
Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombus
Platelet aggregation
Conformational activation of GPIIb/IIIa
Collagen
Thromboxane A2
ADP
AT
Aspirin
Clopidogrel
Prasugrel
Ticagrelor
GPIIb/IIIa
inhibitors
Bivalirudin
Lepirudin
Argatroban
Factor
Xa
LMWH
Heparin
Fibrinolytics
AT
Fondaparinux Rivaroxaban
Treatment Guidelines for Acute Coronary Syndrome
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
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Vessel Wall Injury
Inflammation
• High dose statin
Thrombin Generation
• Indirect thrombin inhibitors
Unfractionated heparin
LMWH
• Direct thrombin inhibitors
Bivalirudin, Argatroban
Platelet Activation
• Aspirin
• P2Y12 antagonists
• GP IIb/IIIa inhibitor
Tissue Factor
Adhesion Molecules
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No clopidogrel
pretreatment
Clopidogrel
pretreatment
STEMI
Class IIa
LOE:A
Class IIa
LOE:C
UA/NSTEMI
Class I
LOE:A
Class IIa
LOE:B
Stable IHD
Class IIa
LOE:B
Class IIb
LOE:B
2011 PCI guidelines. Circulation 2011;124:2574-2609
2011 Focused Update for NSTEMI/UA. Circulation 2011;123:2022-2060
Class IIb recommendation For UA/NSTEMI patients in whom a conservative (non-invasive strategy) is selected, it may be reasonable to add eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy. LOE:B
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Abciximab (Reopro)
Tirofiban (Aggrastat)
Eptifibatide (Integrilin)
Indication PCI ACS + PCI ACS + PCI
Size Large Small Small
GP IIb/IIIa receptor specificity
No Yes Yes
Duration of effect Long Short Short
Reversible with platelets
Yes No No
Dosing
0.25 mg/kg bolus prior to PCI then
0.125 mcg/kg/min x 12 hours
0.4 mcg/kg/min x 30 min (or 10 mcg/kg
bolus) then 0.1 mcg/kg/min for 12-24
hr after PCI
180 mcg/kg bolus (max 22.6 mg), then 2
mcg/kg/min (max 15 mg/hr) x 18-24hrs. Repeat bolus after 10 minutes for
PCI.
Adverse effects Thrombocytopenia and bleeding
Adjust dose No Decrease infusion by
50% with CrCl <30
Decrease infusion by 50% with CrCl <50
Treatment Guidelines for Acute Coronary Syndrome
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
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• Anti-thrombotic Agents • Anticoagulants
• Heparin • Low Molecular Weight Heparin • Direct thrombin inhibitors
• Antiplatelet agents • ASA +/or clopidogrel or prasugrel or ticagrelor • GP IIb/IIIa receptor antagonists
• Anti-ischemic Agents
• Nitroglycerin • Beta-blockers
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ASPIRIN
• Class I Recommendations:
• Patients already taking daily aspirin should take 81 to 325 mg before PCI (LOE:B)
• Patients not on aspirin should be given non-enteric aspirin 325 mg before PCI (LOE:B)
• After PCI, continue aspirin indefinitely (LOE:A)
• Class IIa Recommendations: • It is reasonable to use aspirin 81 mg daily in preference to
higher maintenance doses (LOE:B)
2011 PCI Guidelines
Levine et al. Circulation 2011;124:2574-2609
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P2Y12 receptor inhibitor
• Class I Recommendations • A loading dose of a P2Y12 receptor inhibitor is
recommended for patients for whom PCI is planned. (LOE:A)
• Clopidogrel 600 mg for ACS and non-ACS patients (LOE:B)
• Clopidogrel 300 mg within 24 hrs and 600 mg > 24 hrs of fibrinolytic therapy (LOE:C)
• Prasugrel 60 mg for ACS patients (LOE:B)
• Ticagrelor 180 mg for ACS patients (LOE:B)
2011 PCI Guidelines
Levine et al. Circulation 2011:124;e574-e651
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• Class I recommendations
– Patients receiving a stent (BMS or DES) for ACS • Dual antiplatelet therapy x 12 months (clopidogrel, prasugrel or ticagrelor
(LOE:B)
– Patients receiving a DES for non-ACS indication • Clopidogrel 75 mg daily for at least 12 months if not at high risk of
bleeding (LOE:B)
– Patients receiving a BMS for a non-ACS indication • Clopidogrel 75 mg daily for a minimum of one month and ideally up to 12
months but should be given for a minimum of 2 weeks in patients at high risk of bleeding (LOE:B)
2011 PCI Guidelines
Levine et al. Circulation 2011:124;e574-e651
Treatment Guidelines for Acute Coronary Syndrome
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
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• Indication
• ACS patients managed medically or with PCI
• Recent MI or stroke
• Peripheral arterial disease
• Dosing
• 600 mg loading dose then 75 mg once daily
• 300 mg loading dose if within 24 hrs of thrombolytic
• Metabolism
• CYP2C19, CYP3A, CYP2B6, CYP1A2
Plavix. [package insert]. Bridgewater, NJ: Bristol-Meyers Squibb/Sanofi Pharmaceuticals Partnership; 2011
2011 PCI guidelines
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• CURE
• CREDO
• CAPRIE
• CHARISMA
• CURRENT-OASIS 7
• COMMIT
• ISAR-REACT-2
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• Current issues and controversy
– “Plavix resistance”
• Genetic polymorphisms
– Decreased effectiveness in CYP2C19 poor metabolizers
• Drug interactions
– PPIs
» Avoid the concomitant use of clopidogrel and
omeprazole
– VerifyNow assay
• PRU >235 associated with increased CV events
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• Dual antiplatelet therapy not routinely recommended for patients with prior ischemic stroke
• Patients with prior GI bleed are at highest risk for bleeding
• Consider other factors: age, concurrent use of anticoagulants or NSAIDS, and H pylori infection
• PPIs are recommended for patients with a hx of upper GI bleed and may be appropriate for patients with multiple risk factors
• PPIs and H2 antagonists are not recommended for routine use in patients at low risk
ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump
Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus
Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use
Circulation 2010;122:2619-2633
Treatment Guidelines for Acute Coronary Syndrome
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
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• Thienopyridine approved 2009
• Pharmacokinetics
– Pro-drug
– Onset of action 0.5-1 hour
– Half-life 7 hours
– Metabolism primarily by CYP 3A4 and 2B6
• Side effect
– Major bleeding
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• Indication
• ACS managed with PCI
• Dosing • 60 mg load, 10 mg daily
• Contraindicated in patients with a previous TIA or stroke
• Not used in elective PCI
• Not recommended for patients >75 years of age, unless patient is high risk (DM or prior MI)
• Consider a reduced dose (5 mg instead of 10 mg) in patients < 60 kg
• Discontinue 7 days prior to surgery
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• TRITON – TIMI 38 – Prasugrel vs. clopidogrel
• Prasugrel - 60 mg LD then 10 mg daily • Clopidogrel - 300 mg LD then 75 mg daily
– 13,608 patients with ACS managed with PCI – Significant reduction in composite of CV death,
nonfatal MI or nonfatal stroke • Driven by decrease in nonfatal MIs • Due to reduced-metabolizer status or PPI use
with clopidogrel patients (?) – Significantly higher rates of bleeding in prasugrel
group
Wiviott et al. New Engl J Med 2007;357:2001-2015
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• Not a thienopyridine (different from ticlopidine, clopidogrel,
prasugrel)
• Approved 2011
• Reversible, concentration dependent inhibition of the P2Y12
receptor
• Not a prodrug
• Rapidly absorbed, one active metabolite (similar potency)
• Max Cp and platelet inhibition 1-3 hrs post dose
• Plasma half-life = 6-13 hours, given BID
• Functional recovery of circulating platelets within ~48 hours
Wallentin L. European Heart J 2009;30(16):1964-1977
Treatment Guidelines for Acute Coronary Syndrome
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
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• Indication
– ACS who are managed medically or with PCI
• Dosing:
– 180 mg LD then 90 mg twice daily
• Major Side Effects
– Bleeding
– Dyspnea
• Metabolism
– CYP3A4, 2B6, 2C9, 2D6
Brilinta. [package insert]. Wilmington, DE: AstraZeneca; 2011
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Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
N Engl J Med, 2009, 361(11):1045-57.
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• Study Objective
– To determine if ticagrelor is superior to clopidogrel for the prevention of CV events and death in a broad population of patients presenting with ACS (NSTEMI and STEMI)
• Study Design
– Multicenter, randomized, double-blind, double-dummy, parallel-group, event-driven, international trial
Wallentin et al. N Engl J Med, 2009, 361:1045-57
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• 18,624 patients recruited from 862 centers in 43 countries
• Patients randomized in a 1:1 ratio to receive ticagrelor or clopidogrel (prior or open label clopidogrel allowed)
• Ticagrelor: 180 mg LD then 90 mg BID
• Clopidogrel: 300 mg LD then 75 mg daily
• Could receive additional 300 mg LD if PCI
• Randomization took place within 24 hours of onset of ACS symptoms
• Treatment continued 6 to 12 months
• Median follow-up: 11 months
Wallentin et al. N Engl J Med, 2009, 361:1045-57
Treatment Guidelines for Acute Coronary Syndrome
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
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• Inclusion Criteria: – Hospitalized for potential ACS
– ACS onset within previous 24 hours
– Cardiac ischemic symptoms of ≥10 minutes duration at rest
– ≥ 2 of the following:
• ST segment changes on ECG
• Positive biomarkers greater than ULN
• One of the following:
– >60 y/o, previous MI, stroke, TIA or CABG
– CAD, DM, PAD, chronic renal dysfunction
– Or persistent ST segment elevation Wallentin et al. N Engl J Med, 2009, 361:1045-57
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• Exclusion Criteria:
– Drug Related: • Contraindication to study drug
• Oral anticoagulation therapy that cannot be stopped
• Fibrinolytic therapy planned or within the previous 24 hours
• Concomitant administration of CYP3A inhibitors, inducers or substrates
– Treatment Related: • Event due to PCI complication
– Medical • ↑ risk of bradycardic event
• Thrombocytopenia, anemia
Wallentin et al. N Engl J Med, 2009, 361:1045-57
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• Efficacy
• Primary • Time to first occurrence of composite of death from vascular
causes, MI or stroke
• Secondary • Time to first occurrence of composite of death from vascular
causes, MI or stroke in the subgroup of patients for whom invasive management was planned at randomization
• Composite of death from any cause, MI or stroke
• Composite of death from vascular causes, MI, stroke, severe recurrent cardiac ischemia, TIA or other arterial thrombotic events
• MI alone
• Stroke alone
• Death from any cause
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• Safety
– Primary • First occurrence of any major bleeding event
– Two definitions used
– Secondary • Minor bleeding
• Dyspnea
• Bradyarrhythmia
• Any other clinical adverse event
• Results of laboratory safety tests
• Endpoints were explored in 25 pre-specified subgroups and 8 post hoc subgroups
Treatment Guidelines for Acute Coronary Syndrome
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• Efficacy
– Death from vascular causes, MI or stroke
• Primary efficacy endpoint
• Occurred significantly less often in the ticagrelor group vs. clopidogrel group
• 9.8% of patients vs. 11.7% at 12 months (P < 0.001)
• Findings same for 28 of the 31 subgroups
– The 3 exceptions:
» Patients weighing less than the median weight for their sex
» Patients not taking lipid-lowering drugs at randomization
» Patients enrolled in study in North America
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End Point Ticagrelor Clopidogrel P Value
Death from any cause, MI or stroke 901/9333 (10.2%) 1065/9291 (12.3%) <0.001
Death from vascular causes, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA or
other arterial thrombotic event
1290/9333 (14.6%) 1456/9291 (16.7%) <0.001
MI 504/9333 (5.8%) 593/9291 (6.9%) 0.005
Death from vascular causes 353/9333 (4.0%) 442/9291 (5.1%) 0.001
Stroke 125/9333 (1.5%) 106/9291 (1.3%) 0.22
Death from any cause 399/9333 (4.5%) 506/9291 (5.9%) <0.001
Death from causes other than vascular causes 46/9333 (0.5%) 64/9291 (0.8%) 0.08
Severe recurrent ischemia 302/9333 (3.5%) 345/9291 (4.0%) 0.22
Recurrent ischemia 500/9333 (5.8%) 536/9291 (6.2%) 0.22
TIA 18/9333 (0.2%) 23/9291 (0.3%) 0.42
Other arterial thrombotic event 19/9333 (0.2%) 31/9291 (0.4%) 0.09
Death from vascular causes, MI or stroke in patients w/ invasive treatment planned
569/6732 (8.9%) 668/6676 (10.6%) 0.003
Definite stent thrombosis 71/5640 (1.3%) 106/5649 (1.9%) 0.009
Probable or definite stent thrombosis 118/5640 (2.2%) 158/5649 (2.9%) 0.02
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• Safety
– First occurrence of major bleeding event
End Point Ticagrelor Group Clopidogrel Group P Value
Major bleeding (study criteria)
961/9235 (11.6%) 929/9186 (11.2%) 0.43
Major bleeding (TIMI criteria)
657/9235 (7.9%) 638/9186 (7.7%) 0.57
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End Point Ticagrelor Clopidogrel P
Value
Bleeding requiring RBC transfusion 818/9235 (8.9%) 809/9186 (8.9%) 0.96
Life-threatening or fatal bleeding 491/9235 (5.8%) 480/9186 (5.8%) 0.70
Non-intracranial fatal bleeding 9/9235 (0.1%) 21/9186 (0.3%) 0.03
Fatal intracranial bleeding 11/9235 (0.1%) 1/9186 (0.01%) 0.02
Non-CABG-related major bleeding 362/9235 (4.5%) 306/9186 (3.8%) 0.03
CABG-related major bleeding 619/9235 (7.4%) 654/9186 (7.9%) 0.32
Major or minor bleeding, study criteria 1339/9235 (16.1%) 1215/9186 (14.6%) 0.008
Major or minor bleeding, TIMI criteria 946/9235 (11.4%) 906/9186 (10.9%) 0.33
Dyspnea 1270/9235 (13.8%) 721/9186 (7.8%) <0.001
Bradycardia 409/9235 (4.4%) 378/9186 (4.0%) 0.21
Ventricular pauses ≥ 3 sec. during 1st wk 84/1451 (5.8%) 51/1415 (3.6%) 0.01
Ventricular pauses ≥ 3 sec. at 30 days 21/985 (2.1%) 17/1006 (1.7%) 0.52
Treatment Guidelines for Acute Coronary Syndrome
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
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• In patients with ACS, ticagrelor significantly reduced the rates of
death from vascular causes, MI or stroke
• Ticagrelor inhibited P2Y12 receptor more intensely
– May contribute to primary end point outcome
– Intensity similar to prasugrel
– Without the increased risk of major bleeding
– Increased risk of non-procedure-related bleeding
• Primary end point results differed in North American subgroup
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Mahaffey KW, Wojdyla DM, Carroll D, Becker RC et al.
Ticagrelor compared with clopidogrel by geographic region in the platelet inhibiton and patient outcomes (PLATO) trial.
Circulation. 2011 Aug 2; 124(5):544-554
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• North American subgroup results
– HR = 1.25 vs. overall HR in PLATO = 0.84
• Aspirin protocol in PLATO
– Single loading dose
• ≤325 mg preferred
– Daily dose
• 75 to 100 mg daily
• 325 mg daily permitted for ≤ 6 months
– Only after coronary stenting
• Regional interaction driven by patients from U.S.
– Canadian patients grouped into rest of the world Circulation 2011;124:544-554
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• Systematic errors analysis
– No difference in trial conduct
• Patients in the United States less adherent
• Discontinuation higher in the United States
Circulation 2011;124:544-554
Treatment Guidelines for Acute Coronary Syndrome
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
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• Aspirin median maintenance dose
– Could account for 80-100% of the regional interaction
Region ASA dose
(mg)
Ticagrelor
Events/#pts
Clopidogrel
Events/#pts
HR (95% CI)
U.S. ≥ 300 40/324 27/352 1.62 (0.99 - 2.64)
>100- <300 2/22 2/16 **
≤100 19/284 24/263 0.73 (0.40 - 1.33)
Non-U.S. ≥300 28/140 23/140 1.23 (0.71 - 2.14)
>100- <300 62/503 63/511 1.00 (0.71 - 1.42)
≤ 100 546/7449 699/7443 0.78 (0.69 - 0.87)
Circulation 2011;124:544-554
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Circulation 2011;124:544-554
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• Aspirin dose only factor to significantly ↑ treatment by region interaction
• 61% of patients in U.S. treated with high-dose aspirin after day 2
– Versus 4% of patient in the rest of the world
• Worse outcomes noted in ticagrelor patients treated with high-dose aspirin in both regional groups versus clopidogrel patients
• Clopidogrel group outcomes did not vary by aspirin dose at any landmark date
• Low-dose aspirin use with ticagrelor associated with better outcomes at all landmark dates
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• Limitations
– Only 1413 patients enrolled in U.S.
– Only 676 patients in U.S. and 280 in rest-of-the world took high-dose maintenance aspirin
– Analysis of United States - post hoc
Circulation 2011;124:544-554
Treatment Guidelines for Acute Coronary Syndrome
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• Bleeding Risk
– Do not use in patients with active bleed or history of intracranial hemorrhage
– Do not use in patients who will undergo urgent CABG
– Manage bleeding without discontinuing ticagrelor
• Aspirin Use
– Should only be taken with <100 mg of aspirin daily
Brilinta. [package insert]. Wilmington, DE: AstraZeneca; 2011
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• Who?
• Left main disease >50%
• 3 (major) vessel disease >70%
• Advantages
• Bypass occluded vessel completely
• Disadvantages
• Invasive
• Infection
• Stop P2Y12 inhibitors • Prasugrel
• 7 days prior to surgery
• Clopidogrel and Ticagrelor • 5 days prior to surgery
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• Prasugrel has not been studied in elective PCI.
– No recommendations are made regarding its use in this
setting.
• Ticagrelor has not been studied in elective PCI or in
patients who have received thrombolytics.
– No recommendations are made regarding its use in
these settings.
2011 PCI Guidelines
Levine et al. Circulation 2011:124;e574-e651
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Clinical Differences
Clopidogrel Prasugrel Ticagrelor
Receptor binding Irreversible Irreversible
Reversible
Activation Prodrug limited by metabolism
Prodrug not limited by metabolism
Active drug
Interpatient variability
High CYP 2C19
Low Low
Onset of action 2-6 hours 0.5 hours 0.5 to 2 hours
Dose 600 mg load 75 mg daily
60 mg load 10 mg daily
180 mg load 90 mg bid
Indication ACS, Elective
Stent/PCI,CVA, PAD
Only for ACS treated with PCI
ACS
Other Contraindicated with
hx CVA/TIA Avoid doses of ASA
>100 mg
Treatment Guidelines for Acute Coronary Syndrome
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Reproduction in whole or in part without permission is prohibited.
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• Helping patients understand the importance of
adherence to dual antiplatelet therapy following
stent implantation
– Withdrawal of these agents prematurely has been
associated with increased CV events
• Patients receiving ticagrelor take low dose aspirin
• Ticagrelor: dyspnea is transient
• Monitor for bleeding complications
49
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• Emphasize the importance of secondary
preventive measures
– Lipids
– Blood pressure
– Weight
– Diabetes
– Exercise
– Influenza vaccine
50
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