Acute Myocardial InfarctionWillis E. Godin, D.O.South Jersey Heart Group

Lourdes Cardiology Services

Acute Coronary Syndrome (ACS)Refers to the array of clinical signs and

symptoms produced by acute myocardial ischemia Unstable angina Non-ST-segment-elevation MI ST-segment-elevation MI

Each condition shares common pathophysiologic origins related to the instability and rupture of artherosclerotic vulnerable plaques

Unstable angina and NSTEMI

Differentiated one from the other by primarily by their severity

Whether the ischemia is prolonged enough to lead to structural myocardial damage and to the release of detectable markers of myocardial injury Troponin I (TnI) Troponin T (TnT) Creatine kinase (CK)-MB

Coronary heart disease

Major cause of morbidity and death in the United States

Affecting approximately 16 million Americans Someone in the US experiences a coronary

event every 25 seconds, and someone dies from a coronary event every minute.

More than 1.4 million hospitalizations for ACS in the US each year

Direct and indirect costs of CHD are estimated to be more than $165 billion in 2009 alone

Pathophysiology

Unstable angina and NSTEMI result from a disparity between myocardial oxygen delivery and demand, which usually presents as angina occurring with limited physical activity or at rest (a crescendo pattern).

Demand-and-delivery mismatch

Associated with UA/NSTEMI Can occur because of dynamic obstruction

from: Intense arterial spasm Progressive, severe, flow-limiting atherosclerosis

due to intimal hyperplasia or to lipid, calcium, and thrombus deposition, or to fibrointimal hyperplasia after PCI

Coronary artery dissection Conditions that alter myocardial oxygen demand

or supply, such as intense emotion, tachycardia, or uncontrolled systemic hypertension (secondary MI)

Pathophysiology

The most frequent mechanism of ischemia during limited physical activity or at rest is a primary reduction of the myocardial oxygen supply due to rupture or ulceration of a vulnerable atherosclerotic plaque

Results in endothelial injury and associated thrombosis and dynamic vasoconstriction

Pathophysiology

Plaque fissure or rupture exposes the highly thrombogenic subendothelium to circulating platelets and white blood cells, which in turn activates the coagulation cascade

The resultant platelet adhesion and aggregation at the site of plaque disruption leads to transient thrombosis or subtotal coronary artery occlusion with dynamic vasoconstriction

Activated platelets release powerful promoters of vasoconstriction and platelet aggregation, including thromboxane A2, serotonin, adenosine diphosphate, and platelet-activating factor

Plaque Rupture

Can occur in mildly or severely stenosed coronary arteries

Often occurs in arteries where the atherosclerotic lesions previously had caused only mild-to-moderate obstruction

Duration of ischemia

The duration of ischemia caused by the platelet-fibrin thrombi and severe dynamic vasoconstriction determines the overall clinical picture.

If ischemia is neither severe nor prolonged (usually <20min) and oftern occurs at rest, patients are given a diagnosis of UA

If ischemia lasts longer than 30 minutes and is associated with elevated cardiac markers, the diagnosis of MI is made

Further classification as STEMI or NSTEMI is made on the basis of electrocardiographic findings.

Pathophysiology

Patients with UA/NSTEMI remain at high risk for a new infarction and its sequelae, including sudden cardiac death, until the endothelial injury is repaired

UA, NSTEMI, and STEMI represent a pathophysiologic continuum

This concept has led to the development of effective pharmacologic therapies that, used in conjunction with careful and rapid risk-assessment strategies and catheter-based therapies, improve outcomes in UA/NSTEMI patients.

Atherosclerosis

Progressive in nature Chronic inflammatory and multifocal disease

involving medium- and large-sized arteries May begin in the subendothelium as early as

in the 1st decade of life Usually develops in lesion-prone vascular

areas that exhibit underlying endothelial dysfunction as a response to chronic, multifactorial injury to the arterial wall

Endothelial injury

Flow shear stress Hypertension Immune-complex deposition and complement

activation Smoking Diabetes mellitus Aging Substance abuse Infection Mechanical injury (coronary angioplasty, stent

placement, heart transplantation)

Endothelial Dysfunction

A process regarded as a precursor to the development of vascular disease

Characterized by disruption of vessel-wall homeostasis, which is signified by decreased vasodilation, increased vasoconstriction, increased oxidative stress and inflammation, deregulation of thrombosis and fibrinolysis, abnormal smooth-muscle-cell proliferation, and a deficient repair mechanism.

Diagnosis & Risk Stratification

Early risk stratification is vital in the timely diagnosis and treatment of ACS

Assessment of patients with suspected ACS should include: Clinical history Physical examination 12 lead ECG Biochemical marker measurement Noninvasive risk stratification

Clinical History

A thorough clinical history is of utmost importance in the initial evaluation and treatment of patients with suspected ACS

Typical symptoms of ACS include chest pain or discomfort that may or may not radiate to the arm, back, neck, jaw, or epigastrium

Women and elderly patients are more likely to present with atypical features, such as shortness of breath, weakness, diaphoresis, nausea, and lightheadness

Physical Examination

Findings of patients with suspected ACS are often normal

Attention must be paid to the presence of complications of ACS: Acute LV failure Hypotension S3 gallop New or worsening mitral regurgitation Pulmonary edema

Electrocardiography

Plays an important role in initial assessment, emergency treatment, prognostication, and subsequent decision-making regarding the definitive treatment of patients with suspected ACS

High specificity for diagnosing STEMIRemains test of 1st choice

Electrocardiography

Complete (>90%) occlusion of the coronary arteries alters the electrical potentials of the epicardial surface and usually manifests itself as ST-segment elevation in 2 or more adjacent leads

ST-segment depression associated with UA/NSTEMI is transient and dynamic. Its appearance is usually flat or down-sloping

Biochemical markers

When ischemia is prolonged enough to produce myocardial necrosis, the integrity of the myocytic membrane is lost

Cardiac enzymes and other substances then leak into the peripheral blood, and their elevated levels in the bloodstream are indicative of acute myocardial infarction (AMI)

Biochemical markers

Cardiac troponins: gold standard of biomarkers for establishing a diagnosis of AMI Previously, elevated levels of CK and its

cardiac-specific isoform CK-MB were used to make a diagnosis of AMI

Any elevation in the circulating levels of these biomarkers may provide a clinical distinction between UA and NSTEMI

Cardiac Troponins

Excellent independent markers of short-term and long-term prognoses

Risk of death within the first 42 days is directly proportional to cardiac troponin levels, and the prognostic information is independent of other clinical and electrocardiographic risk factors

Cardiac Troponins

Detectable in the serum 4-12 hours after onset of myocardial necrosis

Peak 12-48 hours from symptom onsetSerial sampling, including the

acquisition of a baseline sample and a follow-up sample 8-12 hours after symptom onset, is recommended

Risk Stratification

Clinical features, ECG, and cardiac troponin levels are fairly insensitive for immediately ruling out ACS

It is important to reliably stratify patients who are at high or low risk of an MI and who are likely to have adverse events in the near future TIMI score PURSUIT score GRACE score

TIMI risk score

TIMI IIB trialPrimary endpoint was the composite of

all-cause death, new or recurrent MI, or severe recurrent ischemia that prompts urgent revascularization by day 14

Simple 7-point score that can be calculated easily at the bedside

Treatment strategies

Initial treatment: Invasive vs. Conservative

Despite the debate, it is now widely accepted that the initial medical therapy for patients with suspected ACS should include relieving the ischemia and preventing further myocardial damage

Treatment strategies

How clinicians go about this is largely dictated by the initial risk assessment and continued patient monitoring in a controlled environment

Hemodynamically unstable patients with refractory ischemic pain are monitored in a critical care environment and are taken to the cardiac catheterization laboratory as soon as possible

Most patients’ conditions stabilize after a brief period of medical therapy at which time they can be further triaged according to ACS guidelines

Nitrates

Endothelium-independent vasodilatory effects on the coronary and peripheral vascular beds

Dilate venous capacitance vessels and peripheral arterioles

Decrease preload and afterload Lead to decrease in both myocardial wall

stress and oxygen demand Relieve coronary spasm in atherosclerotic

vessels and increase oxygen delivery to the subendocardial region that is supplied by the severely narrowed coronary artery

Nitrates

ISIS-4 and GISSI-3 studies No survival benefit or decrease in recurrent

myocardial infarction Should be used in patients who have refractory

ischemic discomfort Contraindicated:

Patients who have taken sildenafil, tadalafil, or vardenafil in the previous 24 hours

Systemic hypotension Marked tachycardia Severe aortic stenosis Right ventricular infarct

B-Adrenergic Blockers

Decrease sinus node rate and atrioventricular node conduction velocity, systolic blood pressure, and contractile responses at rest and during exercise

Decrease myocardial oxygen demand and increase the length of diastole

Good anti-ischemic agents

B-Blockers

Recommended that ACS patients without contraindications should receive their initial dose of an oral B-blocker within the first 24 hours of medical therapy

Overview of literature (1988) showed a 13% relative reduction in the risk of progression from UA to an MI

Pooled analysis of 5 trials (2003) showed a 50% reduction in mortality at 30 days and 6 months

Calcium channel blockers

Reduces myocardial contraction and relaxation of vascular smooth muscle, which increases coronary blood flow

Decrease afterload and heart rate, while relaxing the left ventricle and increasing arterial compliance

2 major classes: Dihydropyridine

Nifedipine, amlodipine Nondihydropyridine

Verapamil, diltiazem

Calcium channel blockers

Not routinely given to AMI patients due to lack of convincing evidence that they actually reduce death

CCBs can be used as 3rd-line anti-ischemic agents (after nitrates and B-blockers) in patients who have elevated blood pressure or angina at rest

Short acting nifedipine should be avoided due to increased adverse events

Antiplatelet therapy

Acetylsalicylic acid (Aspirin)Thienopyridines

Ticlopidine Clopidogrel Prasugrel

Aspirin

Causes irreversible acetylation of serine 529 of cyclooxygenase (COX-1) in platelets and the endothelium, thereby preventing thromboxane A2 (TXA2) production and resultant platelet aggregation

Aspirin

Reduces the risk of angina, death, or MI by approximately 30% in patients with CAD

1994 - the Antiplatelet Trialists’ Collaboration meta-analysis of 174 trials (70,000 pts)

2002 - meta-analysis of 287 studies (135,000 pts)

Thienopyridines

Block P2Y12 receptor signaling to prevent production of adenyl cyclase, thereby inhibiting platelet activation through adenosine diphosphate (ADP)

Limit ADP-mediated conversion of GPIIb/IIIa to its active form

Mechanism of action is independent of and complementary to that of aspirin

Ticlopidine

1st-generation thienopyridineIn combination with ASA, reduces rate

of vascular death and MI by 46% in NSTEMI patients

Used less frequently than the newer thienopyridines because of its potential for side effects: Rash, nausea, neutropenia,

thrombocytopenia

Clopidogrel

2nd-generation thienopyridineMost widely used and studied ADP-

receptor-blocking agentCAPRIE study (1996) : 19,185 ptsCURE trial (2001) : 12,562 ptsCHARISMA trial (2006)PCI-CURE trial (2001)

Clopidogrel

9% relative risk reduction in adverse cardiovascular events (vascular death, MI, or ischemic stroke) when compared to aspirin - (CAPRIE)

20% reduction in the primary composite endpoint (cardiovascular death, MI, or stroke) up to 12 months of f/u - (CURE)

31% reduction in cardiovascular death or MI in patients undergoing PCI - (PCI-CURE)

Glycoprotein IIb/IIIa Inhibitors

Platelets are activated through multiple pathways, however, the “final common pathway” of platelet activation and aggregation invloves a conformational change of the GPIIb/IIIa receptors from a resting state to an active state

Glycoprotein IIb/IIIa Inhibitors

AbciximabTirofibaneptifibatide

Glycoprotein IIb/IIIa Inhibitors

EPIC trial (1994) - 35% reduction in primary composite endpoint (death, MI, recurrent ischemia) in pts given abciximab vs placebo

CAPTURE trial (1997) - 30% relative reduction of death, MI, or recurrent ischemia in pts given abciximab

PRISM study (1998) - 32% reduction in death, MI, or recurrent ischemia in pts given tirofiban

PURSUIT trial (1998) - 10% reduction in the relative risk of death and MI in pts given eptifibatide

Anticoagulants

Unfractionated heparinLow-molecular-weight heparin

Enoxaparin dalteparin

Factor X inhibitors fondaparinux

Heparin

Anticoagulative effect by activating and accelerating the proteolytic activity of plasma cofactor antithrombin (AT)

Close and frequent monitoring of the activated partial thromboplastin time (PTT) is necessary to ensure that a safe therapeutic range is maintained

Heparin (UFH and LMWH)

FRISC trial (1997) - 63% relative risk reduction in death or MI in pts given dalteparin vs placebo

ESSENCE trial (1997) - the risk of death, MI, or recurrent angina was significantly lower in pts given enoxaparin vs UFH (16.6% vs 19.8%)

TIMI 11B trial (1999) - 14.3% risk reduction of death, MI, or need of urgent revascularization in pts given enoxaparin vs UFH

Early-Conservative and Early-Invasive StrategiesCoronary angiography aids in defining

the extent and location of CAD and in directing the definitive care strategy PCI/stenting CABG Medical management

Angiography is an invasive procedure and there is a small risk of serious complications (~1 in 1,000 cases)

Early-Conservative and Early-Invasive StrategiesIn the early-invasive strategy, all

patients without contraindications undergo coronary angiography with the intent to perform revascularization within 4 to 24 hours of hospital admission.

The early-conservative strategy consists of aggressive medical therapy for patients

TIMI-IIIB trial

Compared an early-invasive strategy to an early-conservative strategy in UA/NSTEMI pts (1994)

Primary endpoint: composite of death, MI, or abnormalities on a exercise stress test at 6 weeks

No significant difference in the occurrence of the composite endpoint between the groups.

However, the average length of initial hospitalization, the incidence of rehospitalization within 6 weeks, and the number of days of rehospitalization all were significantly lower in the early-invasive group

VANQUISH trial

Compared an early-conservative strategy to an early-invasive strategy (1998)

Combined endpoint of death and non-fatal MI occurred in 3.3% of pts in the early-conservative group and 7.7% of pts in the early-invasive group

(No benefit of early-invasive strategy)

FRISC-II trial

Compared an early-conservative strategy to an early-invasive strategy (1999)

Incidence of the composite endpoint of death or MI was 9.4% in the early-invasive group and 12.1% in the early-conservative group

Furthermore, angina symptoms and hospital readmissions were reduced by 50% with the use of the early-invasive strategy

Conclusions

ACS is associated with high rates of adverse cardiovascular events, despite recent therapeutic advances

Plaque composition and inflammation are more important in the pathogenesis of ACS than is the actual degree of stenosis

Conclusions

The cornerstone of contemporary treatment remains early risk stratification and aggressive medical therapy, supplemented by coronary angiography in appropriately selected patients

Conclusions

An early-invasive treatment strategy is of most benefit to high-risk patients

An early-conservative strategy is recommended for low-risk patients

Conclusions

Adjunctive medical therapy with ASA, clopidogrel, GPIIb/IIIa inhibitors, and either LMWH or UFH, in the appropriate setting, further reduces the risk of ischemic events secondary to thrombosis

Anticoagulation and short- and long-term inhibition of platelet aggregation should be achieved by appropriately evaluating the risk of bleeding complications in each patient

Our goal: enhance both short- and long-term event-free survival