Acute Coronary Syndrome

Dr.A.S.Mannoun

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Worldwide Statistics

Each year:

• > 4 million patients are admitted with unstable angina and acute MI

• > 900,000 patients undergo PTCA with or without stent

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Myocardial Ischemia

• Spectrum of presentation– silent ischemia– exertion-induced angina– unstable angina– acute myocardial infarction

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Cumulative 6-month mortality from ischemic heart disease

0 1 2 3 4 5 6

5

10

0

15

20

25

Months after hospital admission

Dea

ths

/ 100

pts

/ m

onth

Acute MIUnstable anginaStable angina

Duke Cardiovascular Database

N = 21,761; 1985-1992Diagnosis on adm to hosp

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Ischemic Heart Diseaseevaluation

• Based on the patient’s– history / physical exam– electrocardiogram

• Patients are categorized into 3 groups– non-cardiac chest pain– unstable angina– myocardial infarction

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Acute Coronary Syndrome

Ischemic DiscomfortUnstable Symptoms

No ST-segmentelevation

ST-segmentelevation

Unstable Non-Q Q-Waveangina AMI AMI

ECG

AcuteReperfusion

HistoryPhysical Exam

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Acute Coronary Syndrome

• The spectrum of clinical conditions ranging from:– unstable angina– non-Q wave MI– Q-wave MI

• characterized by the common pathophysiology of a disrupted atheroslerotic plaque

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Unstable Angina - Definition

• angina at rest (> 20 minutes)

• new-onset (< 2 months) exertional angina (at least CCSC III in severity)

• recent (< 2 months) acceleration of angina (increase in severity of at least one CCSC class to at least CCSC class III)

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Unstable AnginaLikelihood of CAD

• Previous history of CAD

• presence of risk factors

• older age

• ST-T wave ischemic ECG changes

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Unstable Anginaprecipitating factors

• Inappropriate tachycardia– anemia, fever, hypoxia, tachyarrhythmias,

thyrotoxicosis• High afterload

– aortic valve stenosis, LVH• High preload

– high cardiac output, chamber dilatation• Inotropic state

– sympathomimetic drugs, cocaine intoxication

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Unstable Anginaprognostic indicators

• Presence of ST-T-wave changes with pain• Hemodynamic deterioration

– pulmonary edema, new mitral regurgitation,– 3rd heart sound, hypotension

• Other predictors– left ventricular dysfunction, extensive CAD,

age, comorbid conditions (diabetes mellitus, obstructive pulmonary disease, renal failure, malignancy)

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Unstable Anginapathogenesis

• Plaque disruption

• Acute thrombosis

• Vasoconstriction

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Unstable Anginapathogenesis

• Plaque disruption– Passive plaque disruption

soft plaque with high concentration of cholesteryl esters and a thin fibrous cap

– Active plaque disruptionmacrophage-rich area with enzymes that may degrade and weaken the fibrous cap; predisposing it to rupture

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Unstable Anginapathogenesis

• Acute Thrombosis– Vulnerable plaque

• disrupted plaque with ulceration• occurring in 2/3 of unstable patients• the exposed lipid-rich core abundant in

cholesteryl ester is highly thrombogenic

– Systemic Hypercoagulable State• disrupted plaque with erosion• occurring in 1/3 of unstable patients

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Unstable Anginapathogenesis

• Vasoconstriction– the culprit lesion in response to deep

arterial damage or plaque disruption– area of dysfunctional endothelium near

the culprit lesion– platelet-dependent and thrombin-

dependent vasoconstriction, mediated by serotonin and thromboxane A2

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Acute Coronary Syndrome

• Process of resolution– spontaneous thrombolysis– vasoconstriction resolution– presence of collateral circulation

• Delayed or absence of resolution may lead to non-Q-wave or Q-wave myocardial infarction

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Non-Q-Wave MIclues to diagnosis

• Prolonged chest pain

• Associated symptoms from the autonomic nervous system– nausea, vomiting, diaphoresis

• Persistent ST-segment depression after resolution of chest pain

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Prinzmetal’s Anginaclues to diagnosis

• Transient ST-segment elevation during chest pain

• Intermittent chest pain– often repetitive– usually at rest– typically in the early morning hours– rapidly relieved by nitroglycerine

• Syncope (rare), Raynaud’s, migrainedasmannoun.com

Unstable AnginaRisk Stratification

Low Risk• new-onset exertional angina• minor chest pain during exercise• pain relieved promptly by nitroglycerine

Management• can be managed safely as an outpatient

(assuming close follow-up and rapid investigation)

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Unstable AnginaRisk Stratification

Intermediate Risk• prolonged chest pain• diagnosis of rule-out MI

Management• observe in the ER or Chest Pain Unit• monitor clinical status and ECG• obtain cardiac enzymes (troponin T or I)

every 8 to 12 hours

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Unstable AnginaRisk Stratification

High Risk• recurrent chest pain• ST-segment change• hemodynamic compromise• elevation in cardiac enzymes

Management• monitor in the Coronary Care Unit

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Risk Stratification by ECG

The risk of death or MI at 30 days is strongly related to the ECG at the time of chest pain.

• ST depression 10%• T-wave inversion 5%• No ECG changes 1-2%

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Unstable AnginaTherapeutic Goals

Therapeutic Goals• Reduce myocardial ischemia • Control of symptoms • Prevention of MI and death

Medical Management• Anti-ischemic therapy• Anti-thrombotic therapy

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Unstable AnginaMedical Therapy

• Anti-ischemic therapy– nitrates, beta blockers, calcium antagonists

• Anti-thrombotic therapy– Anti-platelet therapy

• aspirin, ticlopidine, clopidogrel, GP IIb/IIIa inhibitors

– Anti-coagulant therapy

• heparin, low molecular weight heparin (LMWH), warfarin, hirudin, hirulog

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Unstable AnginaAnti-ischemic Therapy

• restrict activities• morphine• oxygen• nitroglycerine

– pain relief, prevent silent ischemia, control hypertension, improve ventricular dysfunction

– nitrate free period recommended after the first 24-48 hours

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Unstable AnginaAnti-ischemic Therapy

• beta-blockers– lowering angina threshold– prevent ischemia and death after MI– particularly useful during high sympathetic tone

• calcium antagonists– particularly the rate-limiting agents– nifedipine is not recommended without

concomitant ß-blockade

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Unstable AnginaAnti-thrombotic Therapy

• Thrombolytics are not indicated• “lytic agents may stimulate the

thrombogenic process and result in paradoxical aggravation of ischemia and myocardial infarction”

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Platelets in Acute Coronary Syndromes

• Platelets play a key role in ACS• Sources of platelet activation (triggers)

– thromboxane A2 (TXA2)

– ADP– epinephrine– collagen– thrombin

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Unstable AnginaAnti-platelet Therapy

• aspirin is the “gold standard”– irreversible inhibition of the cyclooxygenase

pathway in platelets, blocking formation of thromboxane A2, and platelet aggregation

– in AMI, ASA reduced the risk of death by 20-25%– in UA, ASA reduced the risk of fatal or nonfatal

MI by 71% during the acute phase, 60% at 3 months, and 52% at 2 years

– bolus dose of 160-325 mg, followed by maintenance dose of 80-160 mg/d

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GP IIb/IIIa ReceptorFinal Pathway to Platelet Aggregation

• Platelet activation and aggregation are early events in the development of coronary thrombosis

• GP IIb/IIIa receptors on activated platelets undergo a conformational change allowing recognition and binding of fibrinogen

• Fibrinogen “acts like glue”, bridging GP IIb/IIIa receptors on adjacent platelets, leading to platelet aggregation

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GP IIb/IIIa ReceptorKVGFFGR

• There are approximately 50,000 GP IIb/IIIa receptors on each platelet

• KVGFFGR is a specific region within GP IIb/IIIa receptor that is thought to be involved in platelet activation

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Incidence of Ischemic Events

0

2

4

6

8

10

12

14

16

No aspirin(early 1980s)

Aspirin

16%

12%

9%

Incidence of death and MI

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Unstable AnginaAnti-platelet Therapy

• Thienopyridines– ticlopidine (Ticlid; Hoffmann-La Roche)– clopidogrel (Plavix; Bristol-Myers Squibb)

block platelet aggregation induced by ADP and the transformation of GP IIb/IIIa into its high affinity state

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Unstable AnginaAnti-platelet Therapy

• Ticlopidine– in an open-label, randomized study in patients

with unstable angina– ticlopidine 250 mg bid vs. placebo reduced the

risk of fatal or nonfatal MI by 46% at 6 months– benefit not seen at 7 days, but became apparent

after 10 days of therapy (the time required for full antiplatelet activity)

– an alternative for patient with aspirin intolerance

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Unstable AnginaAnti-platelet Therapy

• Clopidogrel– CAPRIE (Clopidogrel versus Aspirin in Patients

at Risk of Ischemic Events)– 19,000 patients randomly assigned to

clopidogrel (75 mg/d) or to aspirin (325 mg/d)– there was an 8.7% reduction in the combined

incidence of stroke, MI, or death (P=.043)– patients with MI did better with aspirin– patients with PVD or stroke did better with

clopidogrel

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Unstable AnginaAnti-platelet Therapy

• GP IIb/IIIa inhibitors– abciximab (monoclonal antibody)– eptifibatide (peptidic inhibitor)– lamifiban and tirofiban (non-peptides)

direct occupancy of the GP IIb/IIIa receptor by a monoclonal antibody or by synthetic compounds mimicking the RGD sequence for fibrinogen binding prevents platelet aggregation

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Unstable AnginaAnti-platelet Therapy

• Abciximab (Reo-Pro)– EPIC Trial

effective in preventing death, MI, and abrupt closure associated with coronary angioplasty (see also EPIC slides)

– EPISTENT Trial(unpublished - see MedSlides News)

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Unstable AnginaAnti-platelet Therapy

• Abciximab (Reo-Pro)– CAPTURE (Chimeric 7E3 Antiplatelet in

Unstable Angina Refractory to Standard Treatment)

– 1,000 patients with angiographically documented unstable angina, not responding to ASA, nitrates, heparin,and other anti-anginals, received either abciximab or placebo within 18-24 hours

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Unstable AnginaAnti-platelet Therapy

• Abciximab (ReoPro; Centocor)– CAPTURE – At 30 days, there was a 29% reduction in the

primary composite endpoint of death, MI, or urgent revascularization in the abciximab group

– At 6 months, this benefit was not evident

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Unstable AnginaAnti-platelet Therapy

• Lamifiban– PARAGON (Platelet IIb/IIIa Antagonist for

the Reduction of Acute Coronary Syndrome Events in a Global Organization Network)

– 2000 patients received two different doses of lamifiban compared with placebo + heparin

– at 6 months, there was a lower event rate (12.6% vs 17.9%) with low dose lamifiban

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Unstable AnginaAnti-platelet Therapy

• Tirofiban (Aggrastat; Merk & Co.)– PRISM (Platelet Receptor Inhibition for

Ischemic Syndrome Management)– 3,200 patients with unstable angina were

treated with either heparin or tirofiban– At 48 hours, there was significant risk

reduction (5.9% to 3.6%) in the rate of death, MI, or refractory ischemia. The benefit was lost at 30 days.

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Unstable AnginaAnti-platelet Therapy

• Tirofiban– PRISM -PLUS (Platelet Receptor Inhibition

for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms)

– randomized 1,915 patients with UA and non-Q-MI to tirofiban alone, heparin alone, or a combination of the two (all received aspirin)

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Unstable AnginaAnti-platelet Therapy

• Tirofiban– PRISM -PLUS – angiography was performed after 48 hr of

initial medical therapy – combination therapy (tirofiban, aspirin, and

heparin) reduced the risk of death and MI at 48 hr from 2.6% to 0.9%, and at 30 days from 11.9% to 8.7%

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Unstable AnginaAnti-platelet Therapy

• Tirofiban– RESTORE (Randomized Efficacy Study of

Tirfiban for Outcomes and Restenosis) – evaluate the impact of tirofiban on

angioplasty for acute coronary syndromes– tirofiban reduced the frequency of events

associated with intervention in ACS

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Unstable AnginaAnti-platelet Therapy

• Eptifibatide (Integrilin; Cor/Schering)– PURSUIT (Platelet IIb/IIIa Underpinning the

Receptor for Suppression of Unstable Ischemia Trial)

– ~11,000 patients admitted with unstable angina or non-Q-wave myocardial infarction

– a broad-based trial encompassing a variety of clinical practices and practice styles

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Unstable AnginaAnti-platelet Therapy

• Eptifibatide (Integrilin; Cor/Schering)PURSUIT– randomized to eptifibatide or placebo; all

patients received aspirin and heparin – significantly reduced the risk of death and MI

at 30 days from 15.7% to 14.2%, a 9% risk reduction

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Platelet Inhibition and Bleeding Time

IMPACT II PURSUIT

135 / 0.5 180 / 2.0

Inhibition of platelet aggregation

15 minutes after bolus 69% 84%

at steady state 40-50% >90%

4h after infusion discontinuation <30% <50%

Bleeding-time prolongation

at steady state <5x <5x

6h after infusion discontinuation 1x 1.4x

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Fibanincidence of intracranial bleeding

Treatment (%)

Study Compound Placebo Active Heparin

RESTORE Tirofiban 0.3 0.1

EPIC Abciximab 0.3 0.1

0.4

EPILOG Abciximab 0.0 0.1

IMPACT II Integrelin 0.07 0.07 0.15

Bolus

Low dose

High dose

Bolus + Infusion

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Unstable AnginaAnti-platelet Therapy

• Summary – the four “P trials” (PRISM, PRISM-PLUS,

PARAGON, PURSUIT)– all show reduction of death rate between

1.3% and 3.4% - in addition to the benefit of aspirin

– useful in the management of patients with unstable angina and MI without ST elevation

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Unstable AnginaAnti-platelet Therapy

• Summary

The question is no longer“Is there a reason to use GP IIb/IIIa inhibitors?” but “Is there a reason not to use them?”

Eric Topol, MD

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Unstable AnginaAnti-coagulant Therapy

• Heparin– recommendation is based on documented

efficacy in many trials of moderate size– meta-analyses (1,2) of six trials showed a

33% risk reduction in MI and death, but with a two fold increase in major bleeding

– titrate PTT to 2x the upper limits of normal

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Unstable AnginaAnti-coagulant Therapy

• Low-molecular-weight heparinadvantages over heparin:– better bio-availability– higher ratio (3:1) of anti-Xa to anti-IIa activity– longer anti-Xa activity, avoid rebound– induces less platelet activation– ease of use (subcutaneous - qd or bid)– no need for monitoring

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Unstable Angina Anti-coagulant Therapy

• Low-molecular-weight heparin– ESSENCE Trial (Efficacy and Safety of

Subcutaneous Enoxaparin in non-Q-Wave Coronary Events Study)

– at 30days, there was a relative risk reduction of 15% -16% in the rate of death, MI, or refractory ischemia as compared to standard heparin

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ESSENCE Trialincidence of death, MI, or recurrent angina

0

5

10

15

20

25

0

5

10

15

20

25

heparin Lovenox heparin Lovenox

n=1564 n=1607 n=1564 n=1607

19.8%

16.6%P=0.019

23.3%

19.8%P=0.016

Day 14 Day 30

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Unstable Angina Coronary Interventions

• TIMI 3B – early intervention vs conservative strategy

(coronary angiography within 24-48 hrs, followed by angioplasty or bypass surgery)

– 1473 patients with UA or non-Q-wave MI were randomized, there were no difference between the groups in the rates of death or MI at 1 year

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Unstable Angina Coronary Interventions

• VANQWISH (Veteran Affairs non-Q-Wave Infarction Strategies in Hospital)– better outcome with initial conservative

therapy with lower rates of death and MI

medical invasiveHosp discharge 3% 8%One year 18.5% 24%

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Unstable Angina role of non-ionic contrast

• Ionic contrast media seem to perform better in ACS

• prospective, randomized control trial of 211 patient

• a much greater need for CABG was seen in the non-ionic contrast medium group

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Trials Underway

• GUSTO-IV (abciximab vs placebo)

• EXCITE ( Eval of Oral Xemilofiban in Controlling Thrombotic Events)

• OPUS (Orofiban in Patients with Unstable Coronary Syndromes)

• SYMPHONY (Sibrafiban vs Aspirin to Yield Maximum Protection from Ischemic Events Post ACS)

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