Acute Coronary Syndrome

Steven R. Bruhl MD, MS 3rd Year Cardiology Fellow Internal Medicine Didactics July 14, 2010

Goals and Objectives

Discuss the definition & pathophysiology of ACS Recognize the clinical features of low, intermediate and high risk ACS Be able to identify and treat patients appropriate for a conservative or invasive strategy Discuss new and controversial pharmacological treatments

Gold Standard for Treatment of ACS

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/NonST-Elevation Myocardial Infarction

http://circ.ahajournals.org/cgi/content/full/102/10/1193

Algorithm for evaluation and management of patients suspected of having ACS. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1e157, Figure 2.

ACS Overview

Overview of ACS Assessment of Likelihood of ACS Early Risk Stratification Invasive vs Conservative Strategy Pharmacotherapy Long-term Therapy/Secondary Prevention

Scope of the Problem

5 million ER visits nationwide for CP

800,000 experience an MI each year

213,000 die from their event

of those die before reaching the ER

Pre-CCU, mortality for MI was >30%

Fell to 15% with CCU

With current interventions, in hospital mortality of STEMI is 6-7%

Overview of ACS
Acute Coronary Syndromes*
1.57 Million Hospital Admissions - ACS
UA/NSTEMI

STEMI

1.24 million
Admissions per year

0.33 million
Admissions per year

*Primary and secondary diagnoses. About 0.57 million NSTEMI and 0.67 million UA. Heart Disease and Stroke Statistics 2007 Update. Circulation 2007; 115:69 171.

Acute Coronary Syndrome (ACS)

Definition: The spectrum of acute ischemia related syndromes ranging from UA to MI with or without ST elevation that are secondary to acute plaque rupture or plaque erosion.
[----UA---------NSTEMI----------STEMI----]

Pathophysiology of Stable Angina and ACS

Pathophysiology Decreased O2 Supply
Flow- limiting stenosis Anemia

ACS

Plaque rupture/clot

Asymptomatic

Increased O2 Demand
O2 supply/demand mismatchIschemia Myocardial ischemianecrosis

Angina

Pathophysiology of ACS Evolution of Coronary Thrombosis

Unstable Angina
Non occlusive thrombus

NSTEMI
Non-occlusive thrombus sufficient to cause tissue damage & mild myocardial necrosis ST depression +/T wave inversion on ECG Elevated cardiac enzymes

STEMI
Complete thrombus occlusion ST elevations on ECG or new LBBB Elevated cardiac enzymes More severe symptoms

Non specific ECG

Normal cardiac enzymes

STEMI

Name 3 situations in which you cannot diagnose STEMI

STEMI

Name 3 situations in which you cannot diagnose STEMI

Left Ventricular Hypertrophy Chronic or Rate Dependent LBBB Paced Rhythm

Cardiac Catheterization

Name the only 3 situations that demand emergent cardiac catheterization.

Cardiac Catheterization

Name the only 3 situations that demand emergent cardiac catheterization.

STEMI or new LBBB ACS with hemodynamic or electrical instability despite optimal medical management Uncontrolled CP despite optimal medical management

Diagnosis of ACS

At least 2 of the following

History ( angina or angina equivalent) Acute ischemic ECG changes Typical rise and fall of cardiac markers Absence of another identifiable etiology

Initial Evaluation and management of Non ST-elevation ACS

Initial Evaluation and Management History and Physical ECG Cardiac Biomarkers

Establish the Likelihood that Clinical Presentation Represents an ACS Secondary to CAD

Risk Stratify for Short-term Adverse Outcomes

Likelihood of ACS by Hx/PE

History/Examination

Suggesting AMI
LR 2.7
LR 2.9 (1.4-6.0) LR 2.3 (1.7-3.1) LR 7.1 (3.6-14.2) LR 2.0 (1.9-2.2) LR 3.2 (1.6-6.5) LR 3.1 (1.8-5.2) LR 2.1 (1.4-3.1)

Pain in Chest or Left Arm CP Radiation Right Shoulder Left Arm Both Left & Right Arm Diaphoresis 3rd Heart Sound SBP < 80 mm Hg Pulmonary Crackles

Panju AA. JAMA. 1998;280:1256.

Likelihood of ACS by Hx/PE

Clinical Examination Pleuritic Chest Pain Sharp or Stabbing Pain Positional Chest Pain Reproducible Chest Pain

Against AMI LR 0.2 (0.2-0.3) LR 0.3 (0.2-0.5) LR 0.3 (0.2-0.4) LR 0.2-0.4

Panju AA. JAMA. 1998;280:1256.

Risk Stratification by ECG

Simple, quick, noninvasive tool Universally available, cheap Correlates with risk and prognosis Guides treatment decisions Can identify alternative causes

Risk Stratification by ECG

ECG Findings and Associated LR for AMI

New ST-E > 1mm New Q waves Any ST-E New Conduction Defect New ST-D

LR 5.7-53.9 LR 5.3-24.8 LR 11.2 (7.1-17.8) LR 6.3 ( 2.5-15.7) LR 3.0-5.2

NORMAL ECG
Panju AA. JAMA. 1998;280:1256.

LR 0.1-0.4

Risk Stratification by ECG

CAVEATS

1-8% AMI have a normal ECG

Only Approx 50% of AMI patients have diagnostic changes on their initial ECG
Peter J. Zimetbaum, M.D., N Engl J Med 2003;348:933-40.

Risk Stratification by ECG

CAVEATS cont. 1 ECG cannot exclude AMI

Brief sample of a dynamic process

Small regions of ischemia or infarction may be missed

Peter J. Zimetbaum, M.D., N Engl J Med 2003;348:933-40.

How Sensitive is the ECG Alone?

How Predictive is NTG response?

Timing of Release of Various Biomarkers After Acute Myocardial Infarction

Shapiro BP, Jaffe AS. Cardiac biomarkers. In: Murphy JG, Lloyd MA, editors. Mayo Clinic Cardiology: Concise Textbook. 3 rd ed. Rochester, MN: Mayo Clinic Scientific Press and New York: Informa Healthcare USA, 2007:77380. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1e157, Figure 5.

Risk Stratification by Troponin

8
Mortality at 42 Days

7.5 % 6.0 % 3.7 %

7 6 5 4 3 2 1 0

3.4 % 1.0 %
831

1.7 %
174 148 134 50 67
9.0

0 to <0.4 0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0 Cardiac troponin I (ng/ml)

Non ACS causes of Troponin Elevation

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

17.
18. 19. 20. 21.

Trauma (including contusion; ablation; pacing; ICD firings,, endomyocardial biopsy, cardiac surgery, after-interventional closure of ASDs) Congestive heart failure (acute and chronic) Aortic valve disease and HOCM with significant LVH Hypertension Hypotension, often with arrhythmias Noncardiac surgery Renal failure Critically ill patients, especially with diabetes, respiratory failure Drug toxicity (eg, adriamycin, 5 FU, herceptin, snake venoms) Hypothyroidism Coronary vasospasm, including apical ballooning syndrome Inflammatory diseases (eg, myocarditis, Kawasaki disease, smallpox vaccination, Post-PCI Pulmonary embolism, severe pulmonary hypertension Sepsis Burns, especially if TBSA greater than 30% Infiltrative diseases: amyloidosis, hemachromatosis, sarcoidosis, and scleroderma Acute neurologic disease, including CVA, subarchnoid bleeds Rhabdomyolysis with cardiac injury Transplant vasculopathy Vital exhaustion

Modified from Apple FS, et al Heart J. 2002;144:981-986.

Combined Sensitivities for ACS

Early Invasive

Conservative

Unstable angina/NSTEMI cardiac care

Evaluate for conservative vs. invasive strategy based upon:

Likelihood

of actual ACS Risk stratification by TIMI risk score ACS risk categories per AHA guidelines

Low
Intermediate

High

TIMI Risk Score

Predicts risk of death, new/recurrent MI, need for urgent revascularization within 14 days

TIMI Risk Score

T: Troponin elevation (or CK-MB elevation) H: History or CAD (>50% Stenosis) R: Risk Factors: > 3 (HTN, Hyperlipidemia, Family Hx, DM II, Active Smoker) E: EKG changes: ST elevation or depression 0.5 mm concordant leads A2:Aspirin use within the past 7 days; Age over 65 T: Two or more episodes of CP within 2 hours

Deciding between Early Invasive vs a Conservative Strategies

Definitive/Possible ACS Initiate ASA, BB, Nitrates, Anticoagulants, Telemetry

Early Invasive Strategy

TIMI Risk Score >3
New ST segment deviation Positive biomarkers Hemodynamic instability Elecrical instability Refractory angina PCI in past 6 months CABG EF <40%

Conservative Strategy
TIMI Risk Score <3 (Esp. Women) No ST segment deviation Negative Biomarkers

Coronary angiography (24-48 hours)

Recurrent Signs/Symptoms Heart failure Arrhythmias

Remains Stable Assess EF and/or Stress Testing EF<40% OR Positive stress Go to Angiography

Specifics of Early Hospital Care

Anti-Ischemic

Therapy Anti-Platelet Therapy Anticoagulant Therapy

Early Hospital Care Anti-Ischemic Therapy

Class I

Bed/Chair rest and Telemetry Oxygen (maintain saturation >90%) Nitrates (SLx3 Oral/topical. IV for ongoing iscemia, heart failure, hypertension) Oral B-blockers in First 24-hours if no contraindications. (IV B-blockers class IIa indication) Non-dihydropyridine Ca-channel blockers for those with contraindication fo B-blockers ACE inhibitors in first 24-hours for heart failure or EF<40% (Class IIa for all other pts) (ARBs for those intolerant) Statins

Early Hospital Care Anti-Ischemic Therapy

Class III

Nitrates if BP<90 mmHg or RV infarction Nitrates within 24-hrs of Sildenafil or 48 hrs of Tadalafil Immediate release dihydropyradine Ca-blockers in the absence of B-Blocker therapy IV ACE-inhibitors IV B-blockers in patients with acute HF, Low output state or cardiogenic shock, PR interval >0.24 sec, 2nd or 3rd degree heart block, active asthma, or reactive airway disease NSAIDS and Cox-2 inhibitors

Early Hospital Care Anti-Platelet Therapy

Class I
Aspirin (162-325 mg), non enteric coated Clopidogrel for those with Aspirin allergy/intolerance (300-600 mg load and 75 mg/d) GI prophylaxis if a Hx of GI bleed GP IIb/IIIa inhibitors should be evaluated based on whether an invasive or conservative strategy is used GP IIb/IIIa inhibitors recommended for all diabetics and all patient in early invasive arm

Early Hospital Care Anticoagulant Therapy

Class I
Unfractionated Heparin Enoxaparin Bivalarudin Fondaparinux

Relative choice depends on invasive vs conservative strategy and bleeding risk

Early Hospital Care Statin Therapy

MIRACL Trial Inclusion Criteria

3086 patients with Non ST ACS Total cholesterol <270 mg/dl No planned PCI Randomized to Atorvastatin vs Placebo Drug started at 24-96 hours

Statin Evidence: MIRACL Study

Primary Efficacy Measure

Placebo
15

17.4% 14.8%

Cumulative Incidence (%)

Atorvastatin
10 Time to first occurrence of: Death (any cause) Nonfatal MI Resuscitated cardiac arrest Worsening angina with new objective evidence and urgent rehospitalization 0 4 8

Relative risk = 0.84 P = .048 95% CI 0.701-0.999

12 16

Time Since Randomization (weeks)

Schwartz GG, et al. JAMA. 2001;285:1711-1718.

Statin Evidence: MIRACL Study

Fatal and Nonfatal Stroke
2

Cumulative Incidence (%)

1.5

Placebo

Atorvastatin
Relative risk = 0.49 P = .04 95% CI 0.24-0.98
0 4 8 12 16

0.5

Time Since Randomization (weeks)

Waters DD, et al. Circulation. 2002;106:1690-1695.

S24

PROVE-IT Trial
All-Cause Death or Major CV Events in All Randomized Subjects 30 25 20

Pravastatin 40mg (26.3%)

% with 15 Event
10 5 0 0 3 6 9 12

Atorvastatin 80mg (22.4%)

16% RR (P = 0.005)

15

18

21

24

27

30

Months of Follow-up

Summary of PROVE-IT Results

In

patients recently hospitalized within 10 days for an acute coronary syndrome:

Intensive high-dose LDL-C lowering (median LDL-C 62 mg/dL) compared to moderate standard-dose lipid-lowering therapy (median LDL-C 95 mg/dL) reduced the risk of all cause mortality or major cardiac events by 16% (p=0.005) Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-up Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups

Invasive vs Conservative Strategies

Invasive vs Conservative Strategy Clinical Trials

ISARCOOL VANQWISH (98) ICTUS (05) MATE
TIMI IIIB (94)

RITA-3 (02) VINO TRUCS TACTICSTIMI 18 (01)

Weight of the evidence

FRISC II (99) Invasive Strategy Favored N=7,018

Conservative Strategy Favored N=920

No difference N=2,874

How Early is Early?

Secondary Prevention Class I Indications

Aspirin Beta-blockers: (all pts, slow titration with moderate to severe failure ACE-Inhibitors: CHF, EF<40%, HTN, DM (All pts-Class IIa) ARB when intolerant to ACE. (Class IIa as alternative to ACEI) Aldosterone blockade: An ACEI, CHF with either EF<40% or DM and if CrCl>30 ml/min and K<5.0 mEq/L Statins Standard Risk Factor Management

Long-Term Antithrombotic Therapy at Hospital Discharge after UA/NSTEMI

New
UA/NSTEMI Patient Groups at Discharge

Medical Therapy without Stent ASA 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d at least 1 month (Class I, LOE: A) and up to 1 year (Class I, LOE: B)

Bare Metal Stent Group

Drug Eluting Stent Group

ASA 162 to 325 mg/d for at least 1 month, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 month and up to 1 year (Class I, LOE:B)

ASA 162 to 325 mg/d for at least 3 to 6 months, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 year (Class I, LOE: B)

Indication for Anticoagulation?

Ye s No

Add: Warfarin (INR 2.0 to 2.5) (Class IIb, LOE: B)

Continue with dual antiplatelet therapy as above

Anderson JL, et al. J Am Coll Cardiol 2007;50:e1e157, Figure 11. INR = international normalized ratio; LOE = level of evidence.

Secondary Prevention Class III

Hormone Replacement Therapy Antioxidants (Vit C, Vit E) Folic Acid

New and Controversial Drug Therapies

Early Treatment with Clopidogrel

Shortcomings of the CURE Trial

Conducted primarily at centers without routine use of early invasive strategy Only 462 (3.7%) patients enrolled from the U.S. 44% had catheterization during index hospitalization Adverse event reduced only in nonfatal MI set Major Bleeding rate of 9.6% among patients who were administered clopidogrel within 5 days of CABG

Clopidogrel Bleeding Risk and CABG

In hospitals in which patients with UA/NSTEMI undergo rapid diagnostic catheterization within 24 hours of admission, clopidogrel is not started until it is clear that CABG will not be scheduled within the next several days. However, unstable patients should receive clopidogrel or be take for immediate angiography.

Clopidogrel vs. Prasugrel

Prasugrel-Key Facts

Contraindicated in pts with prior TIA/Stroke Not recommended for patients >75 years 5 mg maintenance dose suggested in patients <60 Kg, though this dose has not been studied

Summary

ACS includes UA, NSTEMI, and STEMI Management guideline focus

Immediate assessment/intervention (MONA+BAH) Risk stratification (UA/NSTEMI vs. STEMI) RAPID reperfusion for STEMI (PCI vs.

Thrombolytics)

Conservative vs Invasive therapy for UA/NSTEMI

Aggressive attention to secondary prevention initiatives for ACS patients

Beta blocker, ASA, ACE-I, Statin

Questions?