treatment guidelines for acute coronary syndrome

Treatment Guidelines for Acute Coronary Syndrome

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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

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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.


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





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


ACUTE CORONARY SYNDROME

No ST Elevation ST Elevation

Myocardial Infarction

(-) markers

(+) markers

Unstable angina

NSTEMI

STEMI


ACS

Fibrinolysis Primary PCI

ST Elevation No ST Elevation

Early

Invasive Conservative

Early

Conservative Door to needle

<30 minutes

Door to balloon < 90 minutes


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




PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education

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


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


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





• 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


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


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


• 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






• 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


• CURE

• CREDO

• CAPRIE

• CHARISMA

• CURRENT-OASIS 7

• COMMIT

• ISAR-REACT-2


• 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


• 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





• 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


• 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


• 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


• 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





• 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


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.


• 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


• 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






• 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


• 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



• 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


• 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





• 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


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


• 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


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





• 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


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


• 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


• 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





• 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


Circulation 2011;124:544-554


• 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


• 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





• 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


• 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


• 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



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





• 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


• Emphasize the importance of secondary

preventive measures

– Lipids

– Blood pressure

– Weight

– Diabetes

– Exercise

– Influenza vaccine

50

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treatment guidelines for acute coronary syndrome

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