Acute Coronary Syndromes

*CHAIRMAN QMMC INTERNAL MEDICINE CHAIRMAN CLINICAL CARDIOLOGY DIVIISION, PHILIPPINE HEART CENTER

Kurt Glenn C. Jacoba*, MD, MHSA FPCP, FPCC, FPSCCII, FACC, FAHA

Acute Coronary Syndromes

Unstable angina (UA) Coronary arterial thrombosis

Non-ST-elevation myocardial infarction (MI)

ST-elevation MI

15-20%

Chase SL, et.al.: Pharmacological Considerations In Acute Coronary Syndrome (ACS): An Expert Debate. Pharmacy and Therapeutics Vol 32(3):Suppl 1; March 2007

Endothelium

A Model of Risk Stratification Based on a Representative Panel of Molecular and Genetic Factors
Platelet Fn Inflammatory State Atherosclerotic Plaque Gene Profile Adipocyte Products

vWF Circulating EPCs Endothelial Cells CD40/CD40L P-Selectin CRP/CD40 MPO IL-18 MMPs/?PAPP-A FLAP/LTA4 Adinopectin TNF- VEGF PAI-1 IL-6

ACS

Endothelial Dysfunction

Endothelial + Dysfunction

Inflammation

Plaque Morphology/ Stability

vWF = Von Wille-brand factor fn = platelet function EPC = endothelial progenitor C-reactive protein CRP = cell

MPO = myeloperoxidase IL = interleukin TNF- = tumor necrosis factor alpha FLAP = 5-lipoxygenase activating proteinendothelial growth factor MMP = matrix metalloproteinases VEGF = vascular pathway PAPP-A = pregnancy-associated LTA4 = leukotriene A4 pathway plasminogen activator inhibitor PAI-1 = plasma protein A

Endothelial Proinflammatory/ + Dysfunction Prothrombotic State

Anwaruddin, S et al, Redefining Risk in Acute Coronary Syndromes Using Molecular Medicine. J Am Coll Cardiol 2007; 49:279-89

Acute Coronary Syndromes

WBC Foam cell Blood clot

25%

75%

Antman EM, et al.: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). 2004.

Factors that lead to ACS ENVIRONMENTAL FACTORS Occupation, income, lifestyle Medical care availability

NATURAL HISTORY OF ACUTE CORONARY SYNDROME ASYMPTOMATIC Natural Course of ACS PHASE 50 years Death STEMI Non-STEMI Unstable angina Elevated/ Not elevated markers of myocardial necrosis Acute cardiac ischaemia with or w/o ST segment elevation Thrombus formation with or w/o embolisation

HOST FACTORS Age men: >45y women: >55 y Familial disposition History of Coronary Artery Disease Genetic predisposition Concomittant medical illness

Above mentioned factors occurring singly or in combination can cause ACS

Plaque disruption

Early Pathogenesis

Progression of the disease

Convalescence or death

PREPATHOGENESIS PERIOD

PERIOD OF PATHOGENESIS

PREPATHOGENESIS PERIOD Health Promotion Awareness Right nutrition Lifestyle modification

SPECIFIC PROTECTION

PERIOD OF PATHOGENESIS
EARLY DIAGNOSIS & TREATMENT DISABILITY LIMITATION REHABILITATION

Genetic counseling Drug use prevention Health care promotion

Medical Therapy

Continuous medical therapy

Cardiac rehabilitation Manageable exercise regimen

Mechanopharmacolgical Lifestyle modification approaches Thrombolytics Percutaneous Coronary Intervention Coronary Artery Bypass Graft

Primary Prevention

Secondary Prevention

Tertiary

Typical Chest Pain

UA
Thrombus Non-occlusive

NSTEMI

STEMI

Partial occlusion, Complete occlusion sufficient to cause tissue damage & mild myocardial necrosis ST depression +/- T wave inversion No Q wave Elevated ST-elevation New LBBB Q wave Elevated

ECG

Non-specific

Cardiac markers

Normal

UNSTABLE ANGINA and NSTEMI

Timing of Release of Various Biomarkers After Acute Myocardial Infarction

Anderson JL, et al.. ACC/AHA 2007 guidelines for the management of patients with unstable angina/nonST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/NonST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2007;50:e1157.

Troponin I Levels to Predict the Risk of Mortality in Acute Coronary Syndromes

Anderson JL, et al.. ACC/AHA 2007 guidelines for the management of patients with unstable angina/nonST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/NonST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2007;50:e1157.

Selection of Initial Treatment Strategy: Invasive Versus Conservative Strategy

Preferred strategy Invasive Patient Characteristics Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy Elevated cardiac biomarkers (TnT or TnI) New or presumably new ST-segment depression Signs and symptoms of HF or new or worsening mitral regurgitation High-risk findings from noninvasive testing Hemodynamic instability Sustained ventricular tachycardia PCI within 6 months Prior CABG High risk score (e.g., TIMI, GRACE) Reduced left ventricular function (LVEF less than 40 %) Low risk score (e.g., TIMI, GRACE) Patient or physician preference in the absence of high-risk features

Conservative

CABG = coronary artery bypass graft surgery; GRACE = Global Registry of Acute Coronary Events; HF = heart failure; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TIMI = Thrombolysis In Myocardial Infarction; TnI = troponin I; TnT = troponin T
Anderson JL, et al.. ACC/AHA 2007 guidelines for the management of patients with unstable angina/nonST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/NonST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2007;50:e1157.

Algorithm for the management of patients with unstable angina or non-ST elevation myocardial infarction.
UA/NSTEMI ASA, enoxaparin or heparin, -block., nitrates, clopidogrel Risk stratify Low risk

High or intermediate risk

Lower risk Stress test High risk Not high risk Negative

Coronary arteriography High-risk pathway

STATIN, ACEI, outpatient Rx

Consider alternative diagnosis

High/Intermediate risk Coronary arteriography LMCD, 3VD + LV dysfunction or diabetes mellitus CABG 1 or 2 VD, suitable for PCI IIb/IIIa inhibitors PCI Discharge on ASA, clopidogrel, statin, ACE-I Normal Consider alternative diagnosis

Older Trials of Antiplatelet and Anticoagulant Therapy in UA/NSTEMI

ATACS = Antithrombotic Therapy in Acute Coronary Syndromes CAPTURE = c73e Fab AntiPlatelet Therapy in Unstable REfractory angina FRISC = FRagmin and fast Revascularization during InStability in Coronary artery disease PARAGON = Platelet IIb-IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network PRISM = Platelet Receptor inhibition in Ischemic Syndrome Management PRISM-PLUS = Platelet Receptor inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms PURSUIT = Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy RISC = Research on InStability in Coronary artery disease

0.005 0.012 0.0005

0.018 0.001 0.0005 0.003 0.034 0.042 0.0022

SYNERGY Primary Outcomes at 30 d

Superior Yield of the New strategy of Enoxaparin, Revasculariation and Glycoprotein IIb/IIIa inhibitors

ACUITY Clinical Outcomes at 30 d

Acute Catheterization and Urgent Intervention Triage strategy

OASIS 5 Cumulative Risks of Death, MI, or Refractory Ischemia

Fifth Organization to Assess Strategies for Ischemic Syndromes

Kaplan-Meier Curves Showing Cumulative Incidence of Death or MI

Kaplan-Meier Curves Showing Cumulative Incidence of Death or MI

Cumulative Risk of Death or Myocardial Infarction (top) or Death (bottom) in RITA-3

Relative Risk of Outcomes With Early Invasive Versus Conservative Therapy in UA/NSTEMI
FRISC-II = FRagmin and fast Revascularization during InStability in Coronary artery disease ICTUS = Invasive versus Conservative Treatment in Unstable coronary Syndromes ISAR-COOL = Intracoronary Stenting with Antithrombotic Regimen COOLing-off study RITA-3 = Third Randomized Intervention Treatment of Angina trial TIMI-18 = Thrombolysis In Myocardial Infarction-18 TRUCS = Treatment of Refractory Unstable angina in geographically isolated areas without Cardiac Surgery VINO = Value of first day angiography/angioplasty in evolving Non-ST segment elevation myocardial infarction

Relative Risk of All-Cause Mortality for Early Invasive Therapy Compared With Conservative Therapy at a mean follow-up of 2 years

Relative Risk of Recurrent Nonfatal Myocardial Infarction for Early Invasive Therapy Compared With Conservative Therapy at a mean follow-up of 2 years

Relative Risk of Recurrent Unstable Angina Resulting in Hospitalization for Early Invasive Therapy Compared With Conservative Therapy at a mean follow-up of 13 months

TIMI III B 1 year (p = 0.42)

VANQWISH 1 year (p = 0.025)

MATE 2 years (p = 0.6)

FRISC II 1 year (p = 0.005)

TACTICSTIMI 18 6 months (p = 0.0498)

VINO 6 months (p < 0.001)

RITA-3 1 year (p < 0.007)

ICTUS 1 year nonfatal MI (p = 0.005) death (p = 0.97)

Weaver WD and Block P: Is There a Conservative Strategy for NSTEMI? American College of Cardiology. February 2006.

TRIAL

Population 1473 2457

Thrombolysis In Myocardial Ischemia trial, phase IIIB

Circulation 1994;89:1545-56

Fragmin and fast Revascularization during InStability in Coronary artery disease II

Lancet 1999;354:708-715

Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Ischemia 18
NEJM 2001;344:1879-1887

2220

Value of first day angiography/angioplasty In evolving Non-ST segment elevation myocardial infarction, an Open multicenter randomized trial
European Heart Journal 2002;23:230-238

131

Randomized Intervention Trial of unstable Angina-3

Lancet 2002;360:743-751

1810

TRIAL

Population 920 201 1200

Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital

NEJM 1998;338:1785-92

Medicine versus Angiography in Thrombolytic Exclusion trial

JACC 1998; 32:596-605

Invasive versus Conservative Treatment in Unstable Coronary Syndromes

NEJM 2005;353:1095-104

Clinical Outcomes Utilizing Revascularization and AGgressive drug Evaluation

NEJM 2007;356:1-14

2287

TRIAL TIMI IIIB

Death

Endpoints

INV (%) 2.4 5.1 8.6 16.2 7.8 9.4 7.8 1.9

CONS (%) 2.5 5.7 10.0 18.1 14.1 12.1 10.1 2.9

p 0.78 0.78 0.78 0.33 <0.001 0.031 0.045 0.10

Nonfatal MI 6-wk exercise tolerance test Total (primary end point) No. of patients rehospitalized within 6 wk
Positive After

FRISC II

or MI MI alone Death

6 months composite endpoint of death

TACTICS-TIMI 18

At 6 months Primary endpoint Death or nonfatal MI Death Fatal or nonfatal MI Rehospitalization for ACS At 6 months Primary endpoint (death/reinfarction) at 6 months Mortality in the first day angiography group Non-fatal Reinfarction At 4 months Death, MI, or refractory angina At 1 year

15.9 7.3 3.3 4.8 11.0 6.2 3.1 3.1

19.4 9.5 3.5 6.9 13.7 22.3 13.4 14.9

0.025 <0.05 0.74 0.029 0.054 <0.001 <0.03 <0.02

VINO

RITA-3

9.6

14.5

0.001

TRIAL

Endpoints

INV (%) 24.0 12.6 13 14

CONS (%) 18.6 7.9 34 12

VANQWISH At 1 year Primary endpoint Death MATE

Composite

0.05 0.025 0.0002 0.6

of All Recurrent Ischemic Events or Death Composite of Repeat MI or Reinfarction or Death

Primary Death MI

ICTUS

endpoint for ACS

Rehospitalization

22.7 2.5 15.0 7.4 19.0 20.0 12.4 13.2

21.2 2.5 10.0 10.9 18.5 19.5 11.8 12.3

0.33 0.005 0.04 0.62 0.62 0.56 0.33

COURAGE

At 4.6 year Primary-event Composite of Death, MI and stroke Hospitalization for ACS MI

STEMI

Cardiac biomarkers in ST-elevation myocardial infarction (STEMI)

Major components of time delay between onset of symptoms from ST-elevation MI and restoration of flow in the infarct artery.

Antman EM, et al.: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). 2004.

or transportation of patients with STEMI and initial reperfusion t

Hospital fibrinolysis: Door-to-Needle within 30 min

1 -1l 9 st l Ca ll fa Ca

Not PCI capable

l ita sp ho er- sfer Int ran T

Onset of symptoms of STEMI

911 EMS Dispatch

EMS on-scene EMS Encourage12-lead ECGs Triage Consider prehospital fibrinolytic if Plan capableand EMS-to-needle within 30 min

Goals
Patient 5 min after symptom onset Dispatch 1 min EMS on scene Within 8 min

PCI capable EMS transport: EMS-toBalloon within 90 min

EMS transport
Prehospital fibrinolysis: EMS-to-Neddle within 30 min

Patient self-transport: Hospital Door-to-Balloon within 30 min

Total ischemic time: Within120 min* *Golden hour = First 60 minutes

Antman EM, et al.: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). 2004.

or transportation of patients with STEMI and initial reperfusion t

Fibrinolysis

Noninv Risk Stratification

driven Ischemia

Rescue

Not PCI capable PCI capable

Late Hosp Care & Secondary Prev

Receiving Hospital

PCI or CABG

Primary PCI

Antman EM, et al.: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). 2004.

Noninvasive Risk Stratificationrate) High risk (>3% annual mortality

Severe resting LV dysfunction (LVEF <0.35) 2. High-risk treadmill score (score -11) 3. Severe LV dysfunction (exercise LVEF <0.35) 4. Stress-induced large perfusion defect (particularly if anterior) 5. Stress-induced multiple perfusion defects of moderate size 6. Large, fixed perfusion defect with LV dilation or increased lung uptake (thallium-201) 7. Stress-induced moderate perfusion defect with LV dilation or increased lung uptake (thallium-201) 8. Echocardiographic wall motion abnormality (involving > 2 segements) developing at a low dose of dobutamine ( 10 mgkg-1min-1) or at a low heart rate (<120 bpm) Braunwald E, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and nonST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice 9. Stress echocardiographic evidence of extensive Guidelines (Committee on the Management of Patients With Unstable Angina). 2002.
1.

Intermediate risk (1-3% annual mortality rate)

1.

Noninvasive Risk Stratification

2.

3.

4.

Braunwald E, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non ST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina).

Mild/moderate resting LV dysfunction (LVEF 0.35-0.49) Intermediate-risk treadmill score (-11 < score <5) Stress-induced moderate perfusion defect without LV dilation or increased lung intake (thallium-201) Limited stress echocardiographic ischemia with a wall motion abnomality only at higher doses of dobutamine

Noninvasive Risk Stratification

Low risk (<1% annual mortality rate)
1. 2.

3.

Braunwald E, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non ST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina).

Low-risk treadmill score (score 5) Normal or small myocardial perfusion defect at rest or with stress Normal stress echocardiographic wall motion or no change of limited resting wall motion abnormalities during stress

Assessment of Reperfusion Options for STEMI Patients

STEP 1: STEP 2: Assess time and risk Determine if fibrinolysis or invasive strategy is preferred

Fibrinolysis generally preferred if:

Early Presentation Invasive Strategy is not an option Delay to Invasive Strategy

Prolonged transport (Door-to-Balloon)-(Door-to-Needle) >1hr Medical contact-to-balloon or door-toballoon >90min

Absolute contraindications Prior intracranial hemorrhage Structural cerebral vascular lesion Malignant intracranial neoplasm Ischemic stroke w/in 3 mo. EXCEPT acute ischemic stroke w/in 3 h Suspected aortic dissection Active bleeding or bleeding diathesis Significant closed head or facial trauma w/in 3 mo.

Contraindications and Cautions for Fibrinolytic Use in STEMI

Effect of fibrinolytic therapy on mortality according to admission electrocardiogram

Lives Saved per Thousand
60 50 40 30 20 10 0 -10 -20

4 9 3 7

-1 4
BBB ANT ST Elevation INF ST Elevation ST DEP

BBB=bundle-branch block; ANT ST Elevation=anterior ST-segment elevation; INF ST Elevation=Inferior STsegment elevation; ST DEP= ST-segment depression
Antman EM, et al.: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). 2004.

Invasive Strategy preferred if:

Skilled PCI lab available

Medical contact-to-balloon or door-toballoon <90 min (Door-to-Balloon)-(Door-to-Needle) <1 hr

High risk from STEMI Contraindications to fibrinolysis including risk of bleeding and ICH Late presentation Diagnosis of STEMI is in doubt

Primary Angioplasty Strategy

Provides a greater chance for restoring blood flow and stabilization of the infarct artery compared to thrombolysis The expanded latitude of temporal benefit may mitigate the logical constraints Stents enhance the durability of the procedure The promise for evolution of the science of microcirculatory and

Comparison of Revascularization Strategies in Multivessel Disease

Advantages Percutaneous Coronary Intervention Less invasive Shorter hospital stay Lower initial cost Easily repeated Effective in relieving symptoms Restenosis High incidence of incomplete revascularization Relative inefficacy in patients with severe left ventricular dysfunction Less favorable outcome in diabetics Limited to specific anatomical subsets Disadvantages

Coronary Artery Bypass Graft Surgery Effective in relieving symptoms Improved survival in certain subsets Ability to achieve complete revascularization Wider applicability (anatomical Cost Morbidity

PCI VS CABG
TRIAL N Endpoints PCI (%) 73.8 90 42 26.7 CABG (%) 87.8 79 21 6.6 p Arterial Revascularization 1205 At 1 year Rate of event-free survival Therapy Study Rate of freedom from angina Use of antianginal medications At 3 years Repeat revascularization OCTOSTENT 280 At 1 year Event-free survival Total mortality Cardiac death 988 At median follow-up of 2 years Required additional revascularization Death or QWMI Death 450 First 30 days Major adverse cardiac events: Death, Q-wave MI, repeat revascularization or stroke Mean follow-up 18.5 months Survival rate Free from MI Repeat revascularization <0.001 <0.001 <0.001 0.0001

85.5 0 0 21 9 5

91.5 1.4 2.8 6 10 2

NS NS <0.0001 0.80 0.01

Stent or Surgery

ERACI II

3.6

12.3

0.002

96.9 97.7 16.8

92.5 93.4 4.8

<0.017 <0.017 <0.002

Percutaneous coronary intervention (PCI) versus fibrinolysis

Short-term clinical outcomes of patients in 23 randomized trials of primary angioplasty versus thrombolysis
20

15

For every 1,000 patients treated, PTCA compared with lytic therapy: 20 lives saved 43 re-MI prevented 13 ICH prevented
P = 0.0003

P < 0.0001

Percentage

10

P = 0.0003

P < 0.0001

P = 0.0004 P < 0.0001

0 Death Death (exclude SHO CK trial) Reinfarction Stroke

Angioplasty Thrombolysis

Hemorrhagic stroke Death, reinfarction, stroke