ACUTE CORONARY SYNDROME

Dr. Rashidi AhmadMed USM, MMed USM (Emergency)

Consultant Emergency PhysicianIJN

Objectives

• Facts & figures• Classification of acute coronary syndromes • Pathophysiology of ACS• Risk stratification• Management of ACS

Anti-ischemic agents

Antithrombotic agents

Reperfusion therapy

Adjunctive therapies for AMI

ACS mortality

• Pre hospital – 52%

• 24H in hospital – 8%

• 48H in hospital – 19%

• 30 days – 21%

AHA statistical data + GUSTO trial data. Circulation, 1994; 90: 2658-65

Causes of death

• Arrythmias

• Cardiogenic shock

• LV rupture

• Delay in treatment

Incidence of VF

• Out-of-hospital- Br. Med J, 1983; 286: 1405-08: 4%- Br. Heart J, 981; 46: 351-7: 18%

• In-hospital- Circulation, 1994; 89: 998-1003: 5%

• GISSI - Early VF: 3.6%- Late VF: 0.69%

Risky time: VF occurs within 4H after Sx onset

Incidence of cardiac shock & rupture

• Leading cause of early & late mortality after AMI is LV dysfunction with CCF

• Incidence of cardiac rupture: 10%

AHA statistical data + GUSTO trial data. Circulation, 1994; 90: 2658-65

*Progressive increase in death of 1.6/1000 per hour of delay*Progressive increase in death of 1.6/1000 per hour of delay

Am J Cardiol 1998;82:259Am J Cardiol 1998;82:259

In-hospital delay

• Three time intervals of hospital delay1. Door to data (ECG)

• 21 min : Goal <10 min

2. Data to decision• 41 min : Goal <10 min

3. Decision to drug• 9 min : Goal <10 min

Cannon CP, et al. J Thromb Thrombolysis. 1994;1:27-34

In-hospital evaluation constitutes 25 – 33% of delay

(Am Heart J. 1999;138:1046-57; Circulation 2000;102:173-8)

Time to treatment remains poor

• GUSTO I 1990-93 n=41021 2.8h

• GUSTO II 1993-95 n=3053 2.9h

• GUSTO III 1995-97 n=15059 2.7h

• GUSTO V 1999-01 n=16588 2.7h

• InTIME II 1997-99 n=15060 2.9h

• ASSENT II 1997-98 n=16,949 2.8h

• ASSENT III 2000-01 n=6095 2.7h

Large Scale Trials (n:113825; mean: 2.8H)

Predictors of Door-to-Balloon Delay in Primary Angioplasty

Angeja BG, et al. Angeja BG, et al. Am J Cardiol Am J Cardiol 2002;89:1156-11612002;89:1156-1161

Door to balloon time & mortality

JAMA 2000;283:2941-7

Increased mortality if door to balloon > 2 H

Basis of ACS

Plaque features that predispose to rupture

Pathophysiology of ACS

After rupture of vulnerable plaque, its content is exposed to the passing blood stream.

Vulnerable plaques are laden with lipid & collagen & tissue factor (TF), resulting in activation of the coagulation cascade resulting in deposition of fibrin

Thrombin that is generated from activation of coagulation cascade is a PIVOTAL molecule – formation of fibrins & activation of platelets.

Pathophysiology of ACS

Micro-embolization

promotes occlusion / spasm in the microvasculature

Elevated Trop T/I

Spectrum of Clinical syndromes of CAD

Early outcomes in NSTEMI vs STEMI

Early & late outcome in NSTEMI vs STEMI

Risk stratification

• Directed therapy

• Avoid unnecessary therapy

• Avoid the potential adverse

consequences in pts at low risk

Risk stratification

Risk of death

Directed therapy

Mortality related to cardiac troponin I

The risk of subsequent death or MI is ~ 3x higher in patients with +ve troponin result than in those with a -ve result.

New criteria for AMI

Primary goals for patients with ACS

• Rapid defibrillation when VF occurs

• Prevention of major adverse cardiac events (death, non-fatal MI, & need for urgent revascularization)

• Reduction of myocardial necrosis in patients with ongoing infarction

PURSUIT trial

The greatest mortality & morbidity in those with ACS occurs in the first several days.

Rapid, efficient, & effective care Rapid, efficient, & effective care during this time frame.during this time frame.

30 min30 min

90 min90 min

Consider PCI capable hospital- CI to thrombolysis- PCI can be initiated promptly- High risk patients

Ideally…

Improving Time to Reperfusion

Cannon CP, et al. Cannon CP, et al. J Thromb Thrombolysis. J Thromb Thrombolysis. 1994;1:27-1994;1:27-3434.

Patient Transport Inhospital Drug Perfusion

Current

Target

A B C D

0 1 2 3 4

Methods of Speeding Time to ReperfusionA B C DMedia campaign 999 Expansion MI protocol Bolus fibrinolyticsPatient education Prehosp. Rx Prehosp. ECG

Hours from Onset of Pain

Door ReperfusionOnsetof MI

PatientResponse Data Decision Drug Started

2005 AHA Guidelines for ACS

MX of AMI

Therapeutic approach for ACS

Patient evaluation in ACS

Management of AMI

• Anti-ischemic agents

• Antithrombotic agents

- antiplatelets & anticoagulants

• Reperfusion therapy

• Adjunctive therapies for AMI

Improves SUPPLY and Reduces DEMAND

Oxygen

• Advantages: may limit ischemic myocardial injury & may reduce ST segment elevation

• Indications: overt pulmonary congestion OR arterial O2 saturation < 90%

• Reasonable: all pts with ACS for first 6 H of therapy

• Little justification for continuing its routine use beyond 6 H

• Disadvantages: Excess O2 may lead to systemic vasoconstriction. High flow rates may be harmful for COAD pts.

Nitrates

• ↓ preload & afterload

• Relaxation of epicardial coronary arteries

• Recurrent ischemia, nitrates are indicated in first 24-48 H

• IV GTN infusion at 5-20mcg/min

• Increase rate till SX are relieved, MAP by 10% of its

baseline in normotensive pts & 30% for HPT pts

• Nitrates should not be used if hypotension limits

administration of B-blockers, which improves survival.

Nitrates

• Pts with ongoing ischemic discomfort - sublingual nitroglycerin(0.4mg) every 5 min for total of 3 doses, then an assessment should be made about the need for IV nitroglycerin

• IV nitroglycerin is indicated in ongoing ischemic chest discomfort, control of HPT, STEMI a/w LV failure

• Nitrates should not be administered to pts

- SBP < 90 mmHg or ≥30 mmHg below baseline

- HR < 50 or >100 OR suspected RV infarction

- received a phosphodiesterase inhibitor within the last 24 hours

Analgesia

• AMI and pain contribute to ↑ sympathetic activity.

• Surges of catecholamines may contribute plaques

fissuring & thrombus propogation & ↓ threshold for VF.

• Titrating Morphine is analgesic of choice for continuing

pain unresponsive to nitrates.

• Cardiac pain is controlled with a combination of nitrates,

morphine, O2 & B-blockers.

Morphine

• ↓ restlessness & activity of the sympathetic nervous

system - ↓ heart’s metabolic demands.

• In pts with pulmonary oedema complicating MI,

morphine :

promotes peripheral arterial & venous dilatation,

promotes slowing of HR

Antiplatelet therapy

Aspirin

ASA reduce both mortality & the reinfarction rate in the acute phase of MI.

ASA also prevents reinfarction, stroke & death in patients with previous MI.

ASA reduce the risk for progression to infarction in patients with UA.

Aspirin

• ASA produces rapid clinical antithrombotic effect by immediate & near total inhibition of thromboxane A2 production

• Unlike fibrinolytic therapy, there is little evidence of time-dependent effect of ASA on early mortality

• ASA is the first choice of antiplatelet • Dose: 162-325mg & continued at daily dose 75-162mg• Chewable ASA is absorbed quicker than swallowed• Aspirin suppositories (300mg) are safe & can be

considered for pts with severe nausea, vomiting or disorders of upper GI tract.

B. Limitations of ASA as an anti-platelet agent

Weak antiplatelet agent

ADP, thrombin, collagen

Epinephrine platelet aggregation partially inhibited

No inhibition of platelet adhesion

Overcome by high shear stress and high epinephrine

ASA resistance

Associated with increased cardiovascular events

Clopidogrel

• Inhibits ADP-induced platelet aggregation

• Dose: 300mg loading dose

• Indications:

- NSTEMI (elevated cardiac markers or new ECG

changes consistent with ischemia)

- suspected of ACS (without ECG or cardiac marker

changes) who is unable to take aspirin because of

hypersensitivity or major GI intolerance

- STEMI (up to 75years of age who receive ASA, heparin

& fibrinolysis.

ACS algorithm 2005 guidelines

Ticlopidine

• ADP Inhibitor

• Delay to achieve full effect (benefit only after 2/52 of RX)

• Initial Rx with heparin & probably GP IIb/IIIa inhibitor is

required in UA/NSTEMI

• Adverse effects: Neutropenia (2.4%, severe in 0.8%) &

rarely TTP

• FBC (with differentials) monitoring every 2 weeks for 1st

3 months.

• Clopidogrel is preferred to ticlopidine but more rapidly

inhibits platelets & more favorably safety profile.

Reperfusion therapy

• All STEMI patients should undergo rapid evaluation for reperfusion therapy

• Prompt & complete restoration of flow in the infarct artery can be achieved by pharmacological means (fibrinolysis) or PCI (balloon angioplasty +/- stent, with support of pharmacological measures to prevent thrombosis).

• Expeditious restoration of flow in the obstructed infarct artery after onset of symptoms of STEMI is KEY DETERMIINANT of outcome, regardless of whether reperfusion is accomplished with PCI or fibrinolysis.

Fibrinolytic therapy

• The greatest benefit is when therapy is started within the

first 3 hours

• Indications:

- STEMI pts with onset of Sx ≤ 12 hours & ECG

findings of STEMI (ST elevation >0.1mV in 2 or

more contiguous precordial adjacent limb leads,

new or presumably LBBB)

- Reasonable to administer fibrinolytics to pts with

onset of Sx <12 hours & ECG findings of true

posterior MI

LBBB

• Direct PCI may be preferable to fibrinolytic therapy

• Pts with new or presumably new LBBB coupled with a

typical ischemic history should be approached with a

plan to rule in MI using 1 of 3 ECG criteria that provide

independent diagnostic value (Sgarbossa criteria)

LBBB

Sgarbossa criteria

• ST Elevation ≥ 1 mm & concordant with QRS complex• ST Depression ≥ 1 mm in V1, V2, V3• ST Elevation ≥ 5 mm and discordant with QRS complex

True posterior MI

• tall R waves in Right precordial leads & ST depression in V1-V4, especially when T waves are upright.

• Repeat ECG with incorporation of additional leads (V7-V9) are more specific for the detection of post infarct.

Fibrinolysis is Not recommended

Nor recommended: Pts presenting > 12 hours after onset of symptoms, although it may be considered if continuing ischemic pain is present with ST elevation >1mm in 2 or more contiguous precordial or adjacent limb leads

Should not be given to asymptomatic pts who presents > 24 hours after onset of Sx

Should not be given to pts who show ST-segment depression, unless true posterior MI suspecteD

Fibrinolytic agents

Source Gp C streptococci Recombinant human

Recombinant Recombinant

Advantages and disadvantages of thrombolytic therapy

ADVANTAGES DISADVANTAGES

Does not require access to catheterization laboratory facilities

May not be effective for hemodynamic instability

Treats the underlying problem of a central occluding thrombus

Early reperfusion rates range from 55&percnt;–80&percnt; depending on agent used

Documented efficacy in large, well-controlled trials

Achievement of TIMI-3 flow in ? 60&percnt; of patients even with newer agents

Reliable assessment of reperfusion often not possible

Residual stenosis

Efficacy has not been demonstrated in patients with prior CABG or non–ST-segmented elevation MI

Risk of life-threatening bleed

Mortality for fibrinolytic therapy vs control

Limitation of fibrinolytic therapy

• Despite adequate restoration of flow in the epicardial infarct artery, perfusion of the infarct zone may still be compromised by a combination of microvascular damage & reperfusion injury.

• Microvascular perfusion may be impaired despite achievemnt of TIMI 3 flow & < 50% coronary narrowing. Abnormal microperfusion has negative prognostic implications.

Assessment of reperfusion

• Relief of symptoms

• Maintenance or restoration of hemodynamic &

electrical stability

• Reduction of at least 50% of the initial ST-segment

elevation on follow up ECG at 60-90 min after

initiation of therapy – good indicator of myocardial

perfusion.

• In experienced centers, PCI has been shown to be superior to fibrinolysis

*Individuals who perform > 75 PCI procedures a year, in a lab that performs >200 PCI procedures per year, of which at least 36 are primary PCI for STEMI, and has cardiac surgical capability.

PCI in STEMI

PCI versus fibrinolysis

** PCI is preferred in high risk patients

Percutaneous coronary intervention for AMI

• Fibrinolytic-ineligible pts within 12 H of symptom onset

• Cardiogenic shock, heart failure (Killip class 3),

persistent angina

• In hosp without PCI facilities, rapid administration for

fibrinolytic agent & transfer the pt to a PCI facility centre

if low-output syndrome or ischemia continues.

• Preferable for RV infarction & LBBB.

• Should not be performed in asymptomatic pts > 12 H

after onset of STEMI if they are hemodynamically &

electrically stable

Recommendation for PCI in STEMI

Heparin in STEMI

• UFH is recommended for pts ≥ 75yo as ancillary therapy to fibrinolysis (Class IIa) & for any STEMI pts undergoing revascularization.

When UFH is used as adjunctive therapy with fibrin-specific fibrinolytics (alteplase/reteplase/tenecteplase) in STEMI, an IV bolus dose of 60U/kg is given followed by infusion at rate of 12U/kg/hr (max bolus 4000U & infusion 1000U/hr for pts >70kg).

Heparin in STEMI

• IV UFH should be given to pts treated with nonselective

fibrinolytic agents (streptokinase) who are at high risk for

systemic emboli (large or anterior MI, AF, previous embolus, known LV embolus).

• It may be reasonable to give IV UFH to pts undergoing reperfusion therapy with streptokinase.

• Aim aPTT of 50-70sec (1.5-2x control value).

Antithrombotic therapy in UA/ NSTEMI

LMWH

• Indication: UA/NSTEMI

• Enoxaparin is preferred to UFH in UA/NSTEMI, unless

CABG is planned within 24 hrs.

• LMWH (enoxaparin) is acceptable alternative to UFH in

the ED as ancillary therapy for pts < 75yo who are

receiving fibrinolytic therapy (tenecteplase), provided

that significant renal dysfunction (serum creatinine

>2.5mg/dL in men & 2mg/dL in women) is not present

and in pts with STEMI who are not receiving fibrinolysis

or revascularization, LMWH in the ED setting

LMWH vs UFH in UA

Direct antithrombins

Direct thrombin inhibitors very specifically block thrombin effects without the need of a cofactor such as ATIII.

Hirudin (Lepirudin - prototype direct thrombin inhibitor, a naturally occuring anticoagulant from medicinal leech) – is presently indicated only for anticoagulations in pts with heparin-

induced thrombocytopenia & for prophylaxis of DVT after hip replacement surgery.

– Superior to UFH in the reduction of death & MI in UA/MSTEMI.

Bivalirudin (synthetic analogue of hirudin, binds reversibly to thrombin) – could be considered as an alternative to heparin in pts with STEMI who is treated with streptokinase & who has heparin-induced thrombocytopenia (class IIa, LOE B).

Adjunctive therapy for AMI

• GP IIb/IIIa inhibitors

• B-adrenergic receptor blockers

• ACE inhibitor

• Statin therapy / CCB / Insulin

Summary

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