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CORONARY ARTERY DISEASE
General Coronary Artery Disease and Stable Exertional Angina
GENERAL PRINCIPLES
Definition
  • Coronary artery disease (CAD) is most commonly defined as a >50% luminal stenosis of any epicardial coronary artery.
  • Chronic stable angina is the typical manifestation of ischemic heart disease in nearly half of patients with CAD.
Epidemiology
  • CAD is the leading cause of morbidity and mortality in Western Society.
  • Prevalence of CAD in the United States was 7.6% as of 2006 (American Heart Association, Heart Disease and Stroke Statistics 2009 Update).
  • Of the 16.8 million individuals in the United States carrying a diagnosis of CAD, 7.9 million presented as MI and 9.8 million as angina pectoris.
  • CAD was responsible for 35.3% of all U.S. deaths in 2005.
  • An estimated 785,000 Americans will have a first MI and 470,000 will have a recurrent MI in 2009. Another 195,000 will have a silent MI.
Etiology
  • CAD most commonly results from luminal obstruction by atheromatous plaque.
  • Other causes include congenital coronary abnormalities, myocardial bridging, vasculitis, prior radiation therapy, cocaine use, aortic stenosis, hypertrophic cardiomyopathy, coronary vasospasm, spontaneous coronary dissection, and syndrome X.
Pathophysiology
  • CAD manifestations include stable angina, ACS, CHF, sudden cardiac death, and silent ischemia.
  • ACS represents a continuum of clinical presentations ranging from UA to ST-segment elevation MI (STEMI). ACS most often results from acute thrombosis of a coronary artery at the site of atheromatous plaque rupture or ulceration.
  • Stable angina most often results from fixed coronary lesions that produce a mismatch between myocardial oxygen supply and demand. This mismatch is accentuated by increasing cardiac workload.
  • Anginal symptoms usually develop when a fixed stenosis reaches 70% or greater. In the setting of increased myocardial demand or diminished oxygen supply, the fixed stenosis does not permit adequate distal perfusion and ischemia results, manifesting itself as angina.
Risk Factors
  • Hypertension
  • Diabetes mellitus: The incidence of CAD in patients with diabetes is two to four times that of the general population. Insulin resistance, such as that seen with the metabolic syndrome, is associated with increased risk of CAD.
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  • Obesity increases the risk of CAD and is associated with additional cardiac risk factors, including hypertension, diabetes, and lipid abnormalities. A body mass index of >25 kg/m2 is considered overweight and >30 kg/m2 is obese.
  • Dyslipidemia: Elevated LDL, low HDL, and elevated triglycerides are independent risk factors for CAD.
  • Family history of premature CAD: Defined as first-degree male relative with CAD before age 55 or female relative before age 65.
  • Tobacco use is associated with a marked increase in risk of CAD. The risk is reversible and smoking cessation restores the risk of CAD to that of a nonsmoker within approximately 15 years (Arch Intern Med 1994 Jan 24;154(2):169-175).
Prevention
  • Aspirin (75 to 162 mg/d) should be considered in patients at higher risk of cardiovascular events (>10% risk of stroke or MI over 10 years). The U.S. Preventative Services Task Force recommends aspirin be used for men aged 45 to 79 and women aged 55 to 79 (http://www.ahrq.gov/clinic/USpstf/uspsasmi.htm#related).
  • Regular cardiovascular risk assessment commencing at age 20 and recurring every 5 years. The Framingham Risk Score is a commonly used algorithm for estimating risk of CAD (http://hp2010.nhlbihin.net/ATPiii/calculator.asp?usertype=prof).
  • Risk factor modification including tobacco cessation, treatment of hypertension, diabetes, obesity, and lipid control.
  • Initiation of statin therapy may limit the risk of developing CAD in addition to subsequent MI and cardiac mortality in select patients who have an elevated CRP (NEJM 2008;359:2195).
  • Current exercise guidelines recommend a minimum of 30 minutes of moderateintensity aerobic physical activity 5 days per week in addition to activities of daily living (Circulation 2007;116:1081-1093).
  • Hormone replacement therapy is not indicated for either primary or secondary CAD prevention in postmenopausal women.
Associated Conditions
  • Stable angina
  • Unstable angina
  • Non-ST-segment elevation MI (NSTEMI)
  • ST-segment elevation MI
  • Congestive heart failure
DIAGNOSIS
Clinical Presentation
History
  • Angina: Typical angina has three features: (i) substernal chest discomfort or heaviness with a characteristic quality and duration that is (ii) precipitated by stress and (iii) relieved by rest or nitroglycerin (NTG).
    • Atypical angina has two of these three features.
    • Noncardiac chest pain meets one or none of these characteristics.
  • The severity of angina may be quantified using the Canadian Cardiovascular Society (CCS) classification system (Table 16).
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  • Associated symptoms may include dyspnea, diaphoresis, nausea, vomiting, and dizziness.
  • Female patients and those with diabetes or chronic kidney disease may have minimal or atypical symptoms that serve as anginal equivalents. Such symptoms include dyspnea, epigastric pain, and nausea.
  • A careful history usually provides sufficient information to establish an appropriate pretest probability of CAD. For instance, in men and older women, the presence of typical angina in association with other cardiac risk factors is strongly predictive of CAD (Table 17).
Table 16 Canadian Cardiovascular Society Classification System

Class

Definition

CCS 1

Angina with strenuous activity

CCS 2

Angina with moderate activity (walking greater than two blocks or one flight of stairs)

CCS 3

Angina with mild activity (walking less than two blocks or one flight of stairs)

CCS 4

Angina that occurs with any activity or at rest

Anginal symptoms may include typical chest discomfort or anginal equivalents. CCS, Canadian Cardiovascular Society.

From Coronary Artery Dis 2004;15:111, with permission.

Physical Examination
  • Clinical exam should include measurement of BP, heart rate, and arterial pulses.
  • Cardiac exam findings including murmurs and gallops are of high importance.
  • Clinical stigmata of hyperlipidemia such as corneal arcus and xanthelasmas should be noted.
  • Signs of heart failure including an S3 gallop, rales on lung exam, elevated jugular venous pulsation, and peripheral edema may also be present.
Table 17 Pretest Probability of Coronary Disease (%)

Nonanginal Chest Pain

Atypical Angina

Typical Angina

Age (yr)

Men

Women

Men

Women

Men

Women

30-39

4

2

34

12

76

26

40-49

13

3

51

22

87

55

50-59

20

7

65

31

93

73

60-69

27

14

72

51

94

86

Pretest probability of CAD in Symptomatic Patients According to Age and Sex (Combined Diamond/Forrester and CASS Data). ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina.

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Diagnostic Criteria
Angina is primarily a clinical diagnosis that is made based on history, clinical presentation and known risk of coronary artery disease. This diagnosis is often supported by diagnostic testing as outlined below.
  • First level list item 1
    • Second level list item 1
Differential Diagnosis
  • A wide range of disorders may manifest with chest discomfort and may include both cardiovascular and noncardiovascular etiologies (Table 18).
  • A careful history focused on cardiac risk factors, physical exam, and initial laboratory evaluation usually narrows the differential diagnosis.
  • Despite these efforts, further diagnostic testing is often required to determine the likelihood of CAD (see stress testing).
Table 18 Differential Diagnosis of Chest Pain

Diagnosis

Comments

Cardiovascular

Aortic stenosis

Anginal episodes can occur with severe aortic stenosis.

HCM

Subendocardial ischemia may occur with exercise and/or exertion.

Prinzmetal's angina

Coronary vasospasm that may be elicited by exertion or emotional stress.

Syndrome X

Ischemic chest pain in the presence of normal coronary arteries that is thought to be related to microvascular disease.

Pericarditis

Pleuritic chest pain associated with pericardial inflammation from infectious or autoimmune disease.

Aortic dissection

May mimic anginal pain and/or involve the coronary arteries.

Cocaine use

Results in coronary vasospasm and/or thrombus formation.

Other

Anemia

Marked anemia can result in a myocardial O2 supply-demand mismatch.

Thyrotoxicosis

Increase in myocardial demand may result in an O2 supply-demand mismatch.

Esophageal disease

GERD and esophageal spasm can mimic angina (responsive to NTG).

Biliary colic

Gallstones can usually be visualized on abdominal sonography.

Pneumonia

Usually visualized on chest x-ray. The pain may be pleuritic.

Musculoskeletal

Costochondritis (Tsetse's syndrome).

HCM, hypertrophic cardiomyopathy; GERD, gastroesophageal reflux disease; NTG, nitroglycerin.

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Diagnostic Testing
  • Stress testing and indications
    • Patients without known CAD:
      • Not indicated in asymptomatic patients as a screening test.
      • Patients with anginal symptoms.
      • Asymptomatic intermediate-risk patients who plan on beginning a vigorous exercise program or those with high-risk occupations (e.g., airline pilot).
      • Asymptomatic high-risk patients with risk factors such as diabetes or peripheral vascular disease.
    • Patients with known CAD:
      • Post-MI risk stratification (see section on STEMI).
      • Preoperative risk assessment.
      • Recurrent anginal symptoms despite medical therapy or revascularization.
      • Routine screening in asymptomatic patients after revascularization is controversial.
  • Exercise stress testing (ETT)
    • The test of choice for evaluating most patients of intermediate risk for CAD (Table 17).
    • Bruce Protocol: Consists of 3-minute stages of increasing treadmill speed and incline. BP, heart rate, and ECG are monitored throughout the study and the recovery period.
    • Specificity and sensitivity of 70% to 80% if the patient has a normal resting ECG and reaches the target heart rate (85% of maximal predicted heart rate for age).
    • The study is considered positive if:
      • New ST-segment depressions of >1 mm in multiple leads
      • Hypotensive response to exercise
      • Sustained ventricular arrhythmias are precipitated by exercise
    • The Duke Treadmill Score provides prognostic information for patients presenting with chronic angina (Table 19).
  • Stress testing with imaging
    • Recommended for patients with the following baseline ECG abnormalities:
      • Preexcitation (Wolf-Parkinson-White syndrome)
      • Left ventricular hypertrophy (LVH)
      • Left bundle branch block (LBBB) or paced rhythm
      • Intraventricular conduction delay (IVCD)
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      • Digoxin effects
      • Resting ST-segment or T-wave changes
    • Myocardial perfusion imaging. Commonly utilizes tracers Thalium-201 or technetium-99m in conjunction with exercise or pharmacologic stress. Perfusion imaging allows the diagnosis and localization of areas of ischemia and allows determination of ejection fraction. Myocardial viability can also be assessed via this technique. Nuclear perfusion stress imaging has a sensitivity of 85% to 90% and specificity of 70%.
    • Echocardiographic imaging. Exercise or dobutamine stress testing can be performed with echocardiography to aid in the diagnosis of CAD. As with nuclear imaging, echocardiography adds to the sensitivity and specificity of the test by revealing areas with wall motion abnormalities. The technical quality of this study can be limited by imaging quality (i.e., obesity). Stress echocardiography has a sensitivity of 75% and specificity of 85% to 90%.
    • Magnetic resonance perfusion imaging with adenosine utilizing contrast enhancement is another tool to evaluate myocardial ischemia and viability.
  • Pharmacologic stress testing
    • In patients who are unable to exercise, pharmacologic stress testing may be preferable.
    • Dipyridamole, adenosine, and regadenoson are vasodilators that are commonly used in conjunction with myocardial perfusion scintigraphy. These agents are the agents of choice in patients with LBBB or paced rhythm on ECG due to the increased incidence of false-positive stress tests with either exercise or dobutamine infusion.
    • Dobutamine is a positive inotrope commonly used with echocardiographic stress tests.
  • Contraindications to stress testing
    • Acute MI within 2 days
    • UA not previously stabilized by medical therapy
    • Cardiac arrhythmias causing symptoms or hemodynamic compromise
    • Symptomatic severe aortic stenosis
    • Symptomatic heart failure
    • Acute pulmonary embolus, myocarditis, pericarditis, or aortic dissection
Table 19 Exercise Stress Testing: Duke Treadmill Score Score

Minutes exercised - [5 × maximum ST-segment deviation] - [4 × anginal score]

Score

Angina score: 0 = none, 1 = not test limiting, 2 = test limiting

>5

Annual mortality 0.25%

Medical therapy

-10 to 4

Annual mortality 1.25%

Further testing based on risk factors and imaging

<-10

Annual mortality >5%

Coronary angiography

In general β-blockers, other nodal blocking agents, and nitrates should be discontinued prior to stress testing.

From NEJM 1991;325:849, with permission.

Diagnostic Procedures
Coronary Angiography
  • The gold standard for evaluating coronary anatomy that quantifies the presence and severity of atherosclerotic lesions.
  • Should be performed in patients with known or suspected angina with a markedly positive stress test or who have survived sudden cardiac death.
  • Can be used to evaluate patients who are suspected of having a nonatherosclerotic cause of ischemia (e.g., coronary anomaly, coronary dissection, radiation vasculopathy).
  • Consider cardiac catheterization in patients who have recurrent chest pain despite aggressive medical therapy for angina.
  • Can assist in the diagnosis of vasospasm.
  • Intravascular ultrasound (IVUS): Can assess plaque burden, providing definitive assessment of the coronary vasculature at time of catheterization.
  • Coronary flow reserve as measured by Doppler or pressure techniques aids in the assessment of the functional significance of a stenotic lesion.
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  • Left ventricular catheterization: Allows measurement of LV filling pressure, aortic valve gradient, and an assessment of regional wall motion via contrast ventriculography.
  • Noninvasive alternatives to coronary angiography include coronary CT angiography and magnetic resonance angiography. These modalities are currently under intensive study. Compared to invasive coronary angiography, CT angiography has a sensitivity of 80% to 90% and specificity of 85% (Circulation 2006;114:2334). This modality is limited by radiation exposure, requirement for HR less than 70 bpm, and presence of coronary calcification or stents.
TREATMENT
  • The major goal of treatment in patients with stable angina is to prevent MI, cardiac death, and to reduce symptoms.
  • A combination of lifestyle modification, medical therapy, and coronary revascularization should be employed. A recommended strategy for the evaluation and management of the patient with stable angina can be found in Figure 1.
  • Medical treatment is aimed at improving myocardial oxygen supply, reducing myocardial oxygen demand, controlling exacerbating factors (anemia, valvular disease), and limiting the development of further atherosclerotic disease.
    • Aspirin (75 to 162 mg/d) reduces cardiovascular events including repeat revascularization, MI, and cardiac death by approximately 33% (BMJ 1994;308:81; Lancet 1992;114:1421).
      • Aspirin desensitization may be performed in selected patients with aspirin allergy.
      • Clopidogrel (75 mg/d) can be used in patients who are allergic or intolerant of aspirin.
      • Dual therapy with aspirin and clopidogrel may reduce the incidence of adverse cardiac outcomes in high-risk patients such as those with a prior MI (NEJM 2006;354:1706; JACC 2007;49:1982).
    • β-Adrenergic antagonists (Table 20) control anginal symptoms by decreasing heart rate and myocardial work leading to reduced myocardial oxygen demand.
      • The dosage can be adjusted to result in a resting heart rate of 50 to 60 bpm.
      • Use of β-blockers is contraindicated in patients with severe active bronchospasm, significant AV block, marked resting bradycardia, or poorly compensated HF.
      • β-Blockers may worsen coronary vasospasm and should be avoided in such patients.
    • Calcium channel blockers can be used either in conjunction with or in lieu of β-blockers in the presence of contraindications or adverse effects (Table 21).
      • Calcium antagonists are often used in conjunction with β-blockers if the latter are not fully effective at relieving anginal symptoms. Both long-acting dihydropyridines and nondihydropyridine agents can be used.
      • Calcium channel blockers are effective agents for the treatment of coronary vasospasm.
      • The use of short-acting dihydropyridines (nifedipine) should be avoided due to the potential to increase the risk of adverse cardiac events (Circulation 1995;92: 1326).
    • Nitrates, either long-acting formulations for chronic use or sublingual preparations for acute anginal symptoms, can be used as adjunctive antianginal agents (Table 22).
      • Sublingual preparations should be used at the first indication of angina or prophylactically before engaging in activities that are known to precipitate angina.
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        Patients should seek prompt medical attention if angina occurs at rest or fails to respond to the third sublingual dose.
      • Nitrate tolerance resulting in reduced therapeutic response may occur with all nitrate preparations. The institution of a nitrate-free period of 10 to 12 hours (usually at night) can enhance treatment efficacy.
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    • ACE inhibitors may have additive benefit in the treatment of stable angina.
      • A reduction of exercise-induced myocardial ischemia has been reported with the addition of an ACE inhibitor in patients with stable angina and normal LV function receiving optimal β-blocker therapy (NEJM 2004;351:2048; Lancet 2003;362:782).
      • ACEI therapy in high-risk patients with vascular disease or diabetes and at least one other cardiovascular risk factor reduced the rate of death, MI, or stroke (NEJM 2000;342:145).
    • Ranolazine is a novel antianginal agent that does not depend upon reductions in heart rate or BP. Its exact mechanism of action is unknown; however, it appears to have effect on cardiomyocyte metabolism and sodium ion channel function.
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      It has shown benefit in the symptomatic relief of refractory angina (Clin Ther 2006;28:1996).
    • Cholesterol-lowering agents including statins, fibrates, bile acid sequestrants, and niacin reduce recurrent events and improve overall outcome in patients with established CAD.
      • HMG-CoA reductase inhibitors (statins) are the best studied agents and have been shown to limit atherosclerotic burden and reduce cardiac outcomes in patients with CAD (Lancet 2002;360:7; 4S: Lancet 1994;344:1383; NEJM 1996; 355:1001).
      • Recent studies have demonstrated that more intensive statin therapy is superior in preventing cardiovascular outcomes (NEJM 2005;352:1425; NEJM 2004; 350:1495).
  • Coronary revascularization
    • In general, medical therapy with at least two, and preferably three, classes of antianginal agents should be attempted before this approach is considered a failure and coronary revascularization pursued.
    • In patients with stable angina and preserved LV function, medical therapy results in similar cardiovascular outcomes when compared to percutaneous coronary intervention (PCI). Of the patients who receive medical therapy only, there is a higher need for revascularization to control anginal symptoms (NEJM 2007;256:1503; RITA-2: Lancet 1997;350:461).
    • PCI and/or coronary artery bypass graft (CABG) surgery is indicated in patients who present with the following:
      • Angina refractory to medical therapy
      • Angina and reduced LV function
      • Severe activity limiting angina (CCS class III-IV)
      • Angina in the presence of left main or severe three-vessel CAD
    • The choice between PCI and CABG is dependent on the coronary anatomy, medical comorbidities, and patient preference. CABG is preferred in diabetics with multivessel disease and LV dysfunction (BARI: NEJM 1996;335:217).
      • The Syntax trial compared PCI versus CABG in patients with previously untreated three-vessel CAD or left main CAD. The study demonstrated an
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        increased risk of major adverse cardiac and vascular events in the PCI group attributable to repeat intervention (Syntax: N Engl J Med 2009 March 5;360: 961).
      • CABG carries a 1% to 3% mortality rate, 5% to 10% incidence of perioperative MI, and a small risk of perioperative stroke. The use of internal mammary artery grafts is associated with 90% graft patency at 10 years, compared with 40% to 50% for saphenous vein grafts. The long-term patency of a radial artery graft is 80% at 5 years. After 10 years of follow-up, 50% of patients develop recurrent angina or other adverse cardiac events related to late vein graft failure or progression of native CAD (NEJM 1996;334:216).
      • The risks of elective PCI include <1% mortality, a 2% to 5% rate of nonfatal MI, and <1% need for emergent CABG for an unsuccessful procedure. Patients undergoing PCI have shorter hospital stays and similar outcomes with respect to subsequent cardiac events and mortality compared to those undergoing CABG. PCI does have a higher rate of target lesion stenosis that can be minimized using drug-eluting stents (DES) (NEJM 2005;352:2174).
  • Alternative therapies are available for patients with chronic stable angina who are refractory to medical management and who are not candidates for further percutaneous or surgical revascularization.
    • Transmyocardial laser revascularization has been delivered by percutaneous and epicardial surgical techniques. Surgical transmyocardial laser revascularization has been shown to improve symptoms in patients with stable angina, although the mechanism that is responsible is controversial. No benefit has been demonstrated in terms of increasing myocardial perfusion or mortality.
    • Therapeutic angiogenesis is a novel approach that aims to facilitate the growth of collateral blood vessels by delivering proangiogenic growth factors (VEGF and FGF) to the myocardium. Small studies have suggested some benefit in exercise capacity and myocardial perfusion.
Figure 1. Approach to the evaluation and management of the patient of stable angina. Patients with clinical heart failure, severe limiting angina, and those with LV dysfunction should undergo coronary angiography to define underlying coronary artery disease. Patients without the above features may undergo further risk stratification with stress testing. Following stress testing, patients may undergo either coronary angiography or empiric medical therapy depending on their risk profile. Patients initially treated with medical therapy who have refractory systems should undergo angiography. 1PCI results in equivalent cardiovascular outcomes to CABG with the exception of increased target vessel revascularization. 2PCI should be reserved for patients who have high-grade lesions, severe ischemia, and those refractory to medical therapy. NYHA, New York Heart Association; CCS, Canadian Cardiovascular Society Classification (angina); LV, left ventricle; WMA, wall motion abnormality; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; NICM, nonischemic cardiomyopathy.
Table 20 β-Blockers Commonly Used for Ischemic Heart Disease

Drug

β-Receptor Selectivity

Dose

Propranolol

β1 and β2

20-80 mg bid

Metoprolol

β1

50-200 mg bid

Atenolol

β1

50-200 mg daily

Nebivolol

β1

5-40 mg daily

Nadolol

β1 and β2

40-80 mg daily

Timolol

β1 and β2

10-30 mg tid

Acebutolol

β1

200-600 mg bid

Bisoprolol

β1

10-20 mg daily

Esmolol (IV)

β1

50-300 mcg/kg/min

Labetalol Combined

α, β1, β2

200-600 mg bid

Pindolol

β1 and β2

2.5-7.5 mg tid

Carvedilol

Combined α, β1, β2

3.125-25 mg bid

Table 21 Calcium Channel Blockers Commonly Used for Ischemic Heart Disease

Drug

Duration of Action

Usual Dosage

Dihydropyridines

Nifedipine

Slow release

Long

30-180 mg/d

Amlodipine

Long

5-10 mg/d

Felodipine (SR)

Long

5-10 mg/d

Isradipine (SR)

Medium

2.5-10 mg/d

Nicardipine

Short

20-40 mg tid

Nondihydropyridines

Diltiazem

Immediate release

Short

30-80 mg qid

Slow release

Long

120-360 mg/d

Verapamil

Immediate release

Short

80-160 mg tid

Slow release

Long

120-480 mg/d

Table 22 Nitrate Preparations Commonly Used for Ischemic Heart Disease

Preparation

Dosage

Onset (min)

Duration

Sublingual nitroglycerin

0.3-0.6 mg prn

2-5

10-30 min

Aerosol nitroglycerin

0.4 mg prn

2-5

10-30 min

Oral isosorbide dinitrate

5-40 mg tid

30-60

4-6 hr

Oral isosorbide mononitrate

10-20 mg bid

30-60

6-8 hr

Oral isosorbide mononitrate SR

30-120 mg daily

30-60

12-18 hr

2% Nitroglycerin ointment

0.5-2.0 in. tid

20-60

3-8 hr

Transdermal nitroglycerin patches

5-15 mg daily

>60

12 hr

Intravenous nitroglycerin

10-200 mcg/min

<2

During infusion

PATIENT EDUCATION
  • Compliance with medications, diet, and exercise should be stressed to patients. All patients should be encouraged to participate in cardiac rehab as well as meet with a registered dietician.
  • Patients with known CAD should present for evaluation if any change in chest pain pattern, frequency, or intensity develops.
  • Patients should also be evaluated if they report the presence of any HF symptoms including dyspnea, orthopnea, or paroxysmal nocturnal dyspnea.
MONITORING/FOLLOW-UP
  • Close patient follow-up is a critical component of the treatment of CAD as lifestyle modification and secondary risk factor reduction require serial reassessment and interventions.
  • Relatively minor changes in anginal symptoms can be safely treated with titration and/or addition of antianginal medications.
  • Significant changes in anginal complaints (frequency, severity, or time to onset with activity) should be evaluated by either stress testing (usually in conjunction with an imaging modality) or cardiac catheterization as warranted.
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  • Patients with angina refractory to medical therapy should be considered for coronary revascularization if the anatomy is amenable to revascularization.
Acute Coronary Syndrome—Unstable Angina and Non-ST-segment Elevation MI
GENERAL PRINCIPLES
Definition
  • Acute coronary syndrome (ACS) refers to any constellation of clinical symptoms that are compatible with acute myocardial ischemia. For simplicity, ACS can be divided into STEMI, NSTEMI, and UA.
  • STEMI results from complete and prolonged occlusion of an epicardial coronary blood vessel and is defined based on ECG criteria (ST-segment elevation greater than 0.1 mV in at least two contiguous leads or a new LBBB).
  • NSTEMI and UA are considered to be closely related conditions whose pathogenesis and clinical presentations are similar but differ in severity. NSTEMI usually results from severe coronary artery narrowing, transient occlusion, or microembolization of thrombus and/or atheromatous material. If the stenosis is not severe enough or the occlusion does not persist long enough to cause myocardial necrosis (as indicated by positive biomarkers), the syndrome is labeled UA.
    • Approximately three-fourths of patients presenting with UA/NSTEMI will have an abnormal ECG, more often seen as labile ST-segment depression or T-wave inversions, or less frequently transient ST-segment elevations.
    • The diagnosis of UA confers a 10% to 20% risk of progression to acute MI in the untreated patient. Medical treatment reduces this risk to 5% to 7%.
  • NSTEMI is defined by an elevation of cardiac enzymes (creatine kinase MB [CK-MB] or troponin) and the absence of persistent ST-segment elevation. In the absence of elevated cardiac enzymes, the syndrome is termed UA.
  • The management of ACS should focus on rapid diagnosis, risk stratification, and institution of therapies that restore coronary blood flow and reduce myocardial ischemia.
Epidemiology
  • ACS accounts for almost 1.6 million hospitalizations each year (Circulation 2006;113:e85; JACC 2007;50:e1).
  • Among patients with ACS, approximately 60% have UA and 40% have MI, either NSTEMI or STEMI.
  • Of the patients with MI, two-thirds present with an NSTEMI and the remaining one-third present with an acute STEMI.
  • At 1 year, patients with UA/NSTEMI are at considerable risk for death (~6%), recurrent MI (~11%), and need for revascularization (~50% to 60%). It is important to note that although the short-term mortality of STEMI is greater than that of NSTEMI, the long-term mortality is the same (JACC 2007;50:e1; JAMA 1996;275: 1104).
Pathophysiology
  • Myocardial ischemia results from decreased myocardial oxygen supply and/or increased demand. In the majority of cases, NSTEMI is due to a sudden decrease
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    in blood supply via partial occlusion of the affected vessel. In some cases, marked increased myocardial oxygen demand may lead to NSTEMI, as seen in severe anemia or hypertensive crisis.
  • UA/NSTEMI most often represents acute atherosclerotic plaque rupture and superimposed thrombus formation. Alternatively, it may also be due to progressive mechanical obstruction from advancing atherosclerotic disease, in-stent restenosis (ISR), or bypass graft disease.
  • Atherosclerotic plaques that are prone to rupture are termed vulnerable plaques. Vulnerable plaques often do not cause critical stenosis and thus may be difficult to identify by angiography alone. Experimental imaging modalities that may identify vulnerable plaques prior to rupture are currently being evaluated.
  • Plaque rupture may be triggered by local and/or systemic inflammation as well as shear stress. Rupture leads to exposure of lipid-rich subendothelial components to circulating platelets and inflammatory cells serving as a potent substrate for thrombus formation.
  • Less common causes include dynamic obstruction of the coronary artery due to vasospasm (Prinzmetal angina), syndrome X, coronary vasculitis, dissection, embolus, and myocardial bridge.
Risk Factors
  • The approach to clinical testing, pharmacologic treatment, and timing of possible invasive therapy is guided by the probability of progression to MI and/or reinfarction and risk of subsequent mortality.
  • Patients at highest risk for progression to MI include those with:
    • Rest angina
    • Associated dynamic ischemic ECG changes (ST-segment deviations or T-wave inversions)
    • Continued symptoms despite initiation of medical therapy
  • Several clinical tools have been developed to estimate a patient's risk of MI and cardiac mortality, including the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) risk score.
  • The TIMI risk score can be used to determine the patient's short-term risk of death or nonfatal MI (JAMA 2000;284:835). Patients can be classified as low, intermediate, or high risk on the basis of their clinical profile (Fig. 2).
    • Low-risk patients (TIMI 0 or 1) may be observed with cardiac monitoring in a chest pain or observation unit.
      • If the patient remains chest pain free, has normal cardiac enzymes, and has no clinical signs of HF, a noninvasive stress test should be obtained for further risk stratification.
      • Patients should have negative cardiac enzymes for 24 hours prior to stress testing. If a patient presents with positive cardiac enzymes and noninvasive testing is selected, a submaximal or pharmacologic stress test 72 hours after the peak value may be performed.
      • Low-risk patients with a positive stress test should be managed with medication and invasive testing individualized based on clinical status and the severity of the ischemic burden.
    • Intermediate- and high-risk patients should be admitted to the hospital for observation and management.
      • Patients with ongoing symptoms should be admitted to the ICU for more aggressive monitoring with consideration for urgent cardiac catheterization.
      • Intermediate- and high-risk patients should undergo noninvasive stress testing or coronary angiography based on their clinical course and risk profile (see below).
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Figure 2. Top. 14-day rates of death, MI, or urgent revascularization from the TIMI 11B and ESSENCE trials based on increasing TIMI risk score. Coronary artery disease (CAD) risk factors include family history of CAD, diabetes, hypertension, hyperlipidemia, and tobacco use. TIMI, Thrombolysis in Myocardial Infarction; MI, myocardial infarction. (Adapted from JAMA 2000;284:835-842.) Bottom. Differing management strategies in patients with ACS based on TIMI risk score. UFH, unfractionated heparin; LWMH, low-molecular-weight heparin; ASA, aspirin; dual antiplatelet therapy includes either ASA and clopidogrel or ASA and a glycoprotein IIb/IIIa inhibitor; triple antiplatelet therapy denotes ASA, clopidogrel, and a glycoprotein IIb/IIIa inhibitor.
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DIAGNOSIS
Initial assessment of the patient with UA/NSTEMI includes the clinical presentation (history and physical examination), 12-lead ECG, and measurement of cardiac-specific biomarkers (troponin or CK-MB).
Clinical Presentation
History
  • The three principal presentations for UA are rest angina (angina occurring at rest and prolonged, usually >20 minutes), new-onset angina, and progressive angina (previously diagnosed angina that has become more frequent, lasts longer, or occurs with less exertion). New-onset and progressive angina should occur with at least mild to moderate activity (CCS class III severity).
Physical Examination
  • Evaluation and management should be individualized based on the patient's clinical presentation, risk factors, and ECG. A physical exam should be performed focusing on objective evidence of HF, including peripheral hypoperfusion, heart murmur, elevated jugular venous pulsation, pulmonary edema, and peripheral edema.
  • The presence of severe underlying coronary disease is suggested in patients with refractory chest discomfort, clinical evidence of LV dysfunction such as CHF, hypotension, and new ECG changes that are consistent with myocardial ischemia.
Laboratories
Biochemical makers
  • A CBC, fasting glucose, and lipid profile should be obtained in all patients with suspected CAD.
  • High-sensitivity CRP, lipoprotein A, and homocysteine are all associated with increased risk of CAD; however, these markers have not yet been embraced in standard of care guidelines.
Diagnostic Testing
Electrocardiography
  • A baseline ECG should be recorded in all patients with suspected CAD. A normal tracing does not exclude the presence of disease.
  • Possible indicators of CAD include significant Q waves, ST-segment changes, and T-wave inversions.
  • If the patient is experiencing anginal symptoms, serial ECGs should be obtained to assess for dynamic ischemic changes.
Imaging
  • Chest x-ray can be helpful by providing information on heart size and lung parenchyma.
  • Should be obtained in patients with evidence of CHF, valvular heart disease, or aortic disease.
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  • Echocardiogram permits measurement of global LV systolic, wall motion abnormalities, diastolic function, and valvular disease. LV function may guide appropriate medical or surgical therapy, rehabilitation, and work status.
  • May be helpful in establishing pathophysiologic mechanisms and guiding therapy in patients with heart failure in addition to angina.
  • Additional imaging modalities including coronary calcium screening (CAC) and carotid intima-media thickness may play an important role in the at-risk patient, but have limited role in the symptomatic patient.
Laboratories
Measurement of cardiac-specific markers
  • Cardiac biomarkers are essential in the diagnosis of UA/NSTEMI and should be obtained in all patients who present with chest discomfort suggestive of ACS. In patients with negative cardiac markers within 6 hours of the onset of pain, a second sample should be drawn within 6 to 12 hours. The most commonly measured markers are troponins, CK-MB, and myoglobin (Table 23).
  • Cardiac-specific troponin is the preferred marker and should be measured in all patients.
    • Troponin T and I assays are highly specific and sensitive markers of myocardial necrosis. Serum troponin levels are usually undetectable in normal individuals, and any elevation is considered abnormal.
    • MI size and risk of subsequent cardiac death is directly proportional to the absolute increase in cardiac-specific troponin (NEJM 1996;335:1333; Circulation 1998;98:1853).
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  • CK-MB is also an acceptable marker of myocardial necrosis, but lacks specificity, as it is present in both skeletal and cardiac muscle cells.
    • Specificity can be improved by using the CK-MB/total CK fraction. A CK-MB fraction greater than 2.5% is suggestive of myocardial injury.
    • CK-MB is a useful assay for detecting postinfarct ischemia, as a fall and subsequent rise in enzyme levels suggests reinfarction.
    • Similarly, CK-MB levels are often followed after percutaneous revascularization. Small rises in CK-MB often represent distal microembolization, while large rises suggest more significant complications, such as acute stent thrombosis.
  • Myoglobin is released more rapidly following myocardial damage than either CK-MB, troponin T, or troponin I, but lacks specificity.
  • Lactate dehydrogenase (LDH), alanine transaminase (ALT), and aspartame transaminase (AST) are nonspecific markers of myocardial necrosis and should not be used.
  • C-reactive protein levels may aid in initial risk assessment in ACS patients and predict mortality independent of troponin elevations (JACC 1998;31:1460).
Table 23 Cardiac Biomarkers

Detectable

Peak

Return to Baseline

Troponin I, T

3-6 hr

24-36 hr

5-14 d

CK-MB

2-6 hr

12-18 hr

24-48 hr

Myoglobin

1-2 hr

6-8 hr

12-24 hr

image

Electrocardiography
  • A 12-lead ECG should be obtained immediately in patients with ongoing chest discomfort and as rapidly as possible in patients whose chest discomfort subsided prior to evaluation.
  • Approximately 50% of patients with UA/NSTEMI have significant ECG abnormalities, including transient ST-segment elevations, ST depressions, and T-wave inversions (JACC 2007;50:e1).
    • ST-segment depression >0.05 mV (0.5 mm) in two contiguous leads is a sensitive indicator of myocardial ischemia, especially if dynamic and associated with symptoms.
    • Symmetrical T-wave inversions of >0.2 mV (2 mm) across the precordium (Wellens' waves) are strongly suggestive for myocardial ischemia and particularly worrisome for a critical lesion in the left anterior descending (LAD) artery distribution.
    • Nonspecific ST-segment changes or T-wave inversions (those that do not meet voltage criteria) are less helpful.
TREATMENT
  • Goals of therapy. In addition to prompt risk stratification, patients presenting with UA/NSTEMI should receive medications that reduce myocardial ischemia through reduction in myocardial oxygen demand, improvement in coronary perfusion, and prevention of further thrombus formation.
  • Early conservative versus invasive strategies. Two different strategies have evolved for patients with UA/NSTEMI (Fig. 3).
    • Early conservative strategy. The patient is treated with medical therapy at maximally tolerated doses and coronary angiography is reserved for patients with evidence of recurrent ischemia despite medical therapy or a positive stress test. Although the choice should always be individualized to a particular patient, in general, an early conservative approach can be used in low-risk patients and selected intermediate-risk patients without adverse effects on clinical outcomes.
    • Early invasive strategy. Patients are routinely referred for coronary angiography and subsequent revascularization, as warranted. High-risk patients, including those with recurrent ischemia on medical therapy, evidence of myocardial injury, CHF, LV dysfunction, sustained ventricular tachycardia (VT), or prior coronary revascularization (PCI within 6 months or CABG), are best assessed with an early invasive approach. Angiography in these individuals defines coronary anatomy and directs the choice of revascularization options, if appropriate.
      • An early invasive strategy is also warranted in low- or intermediate-risk patients with repeated ACS presentations despite appropriate therapy. Cardiac catheterization provides the means to distinguish between those with no significant coronary disease and those with anatomy that is amenable to revascularization.
      • Multiple clinical trials and meta-analysis have demonstrated the benefit of an early invasive strategy in high-risk (and possibly intermediate risk) patients, especially those with refractory angina, new or dynamic ST-segment changes, elevated cardiac enzymes, diabetes, and high TIMI risk scores (Lancet 1999;354:708; NEJM 2001;344:1879; JAMA 2003;290:1593; Lancet 2002;360:743; NEJM 2009;360:2165; JAMA 2005;293:2908).
      • Patients with mild to moderate renal insufficiency (creatinine clearance greater than 30) also benefit from an early invasive strategy. No benefit was seen in patients with a creatinine clearance less than 30 or those receiving dialysis (Circulation 2009;120:851).
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Figure 3. Diagnostic and therapeutic approach to patients presenting with ACS focusing on antiplatelet and antithrombotic therapy. *Bivalirudin and fondaparinux are appropriate alternatives to UFH and LMWH. Clopidogrel should be given when there is a reasonable certainty that the patient will not require CABG. GP IIb/IIIa inhibitors can be used as an alternative to clopidogrel when dual antiplatelet therapy is indicated and need for CABG is possible. In this setting, clopidogrel can be given after diagnostic angiography. ††GP IIb/IIIa inhibitors can be administered, in addition to ASA and clopidogrel, in high-risk patients. #Indicators of recurrent ischemia include worsening chest pain, increasing cardiac enzymes, and dynamic ECG changes. 1GP IIb/IIIa inhibitors should be continued per cath lab protocols. 2UFH, LWMH, or alternative agents should be continued for 48 to 72 hours. 3Clopidogrel should be given to patients with likely CAD who elected for a conservative approach and to patients who presented with myocardial injury. ACS, acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; Rx, treatment; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; GP IIb/IIIa, glycoprotein IIb/IIIa inhibitor; EF, ejection fraction; CAD, coronary artery disease; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; WMA, wall motion abnormality. (Adapted from the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction.)
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Medications
The goal of pharmacologic treatment is to provide relief from chest pain and limit thrombus formation through inhibition of platelet activation and aggregation.
  • This approach should include antiplatelet, anticoagulant, and antianginal medications (Table 24).
  • All patients presenting with UA/NSTEMI should be restricted to bedrest and provided supplemental oxygen as needed.
  • Antiplatelet therapy (Table 25)
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    • All patients should receive aspirin (ASA) unless a contraindication exists.
      • ASA effectively blocks platelet aggregation within minutes and should be administered immediately by EMS or on arrival to the ER.
      • The only contraindications to ASA therapy are a history of documented drug allergy and active bleeding. Patients with an ASA allergy should immediately receive clopidogrel (see below), and an allergy consultation should be obtained for possible desensitization.
    • Clopidogrel (Plavix), Ticlopidine (Ticlid), and Prasugrel (Effient) are ADP receptor antagonists that inhibit platelet activation and aggregation. Clopidogrel is preferred over ticlopidine because of a lower risk of gastrointestinal bleeding, neutropenia, and thrombotic thrombocytopenic purpura (TTP). Prasugrel was recently approved by the FDA for treatment of patients following ACS.
      • Clopidogrel can be used in patients who are intolerant or allergic to aspirin.
      • A minimum of 1 month of therapy should be given if medical or percutaneous treatment is planned and ideally continued for at least 1 year. The length of treatment will depend upon the type of stent placed (see section on STEMI).
      • The issue of CABG surgery is of particular concern with regards to clopidogrel administration and timing. It is currently recommended that clopidogrel be withheld from patients for at least 5 days prior to CABG, given the risk of bleeding and its long drug half-life.
        • - A recent multicentered study demonstrated that the increased risk of bleeding from clopidogrel therapy may be restricted to the first 2 to 3 days following drug cessation (JACC 2008;52(21):1693).
        • - Intermediate- to high-risk patients should receive dual antiplatelet therapy upon presentation regardless of their likelihood of requiring CABG. Glycoprotein IIb/IIIa antagonists (see below) are potent IV agents with a short plasma half-life and are thus attractive alternatives to clopidogrel in this setting.
      • Clopidogrel resistance is a newly recognized entity that confers increased risk of adverse outcomes in patients presenting with ACS. A polymorphism in the CYP2C19 gene has been associated with decreased platelet inhibition and increased risk of major adverse cardiovascular outcomes in patients receiving clopidogrel (NEJM 2009;360:354; NEJM 2009;360:363).
        • - Reduced CYP2C19 activity leads to impaired cytochrome P450-mediated conversion of clopidogrel to its active metabolite.
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        • - Clopidogrel resistance can be screened for using point-of-care platelet inhibition assays or genotyping.
        • - Proposed strategies to combat clopidogrel resistance include elevated clopidogrel dosing and first-line use of prasugrel, which does not require cytochrome P450-mediated conversion to an active metabolite.
    • Prasugrel has increased potency and results in greater and more uniform platelet inhibition compared to clopidogrel. While it decreased adverse outcomes in patients following ACS, prasugrel treatment increased bleeding rates and should be avoided in patients older than 75 years, less than 60 kg, and those with prior stroke or TIA.
      • Glycoprotein IIb/IIIa (GP IIb/IIIa) antagonists block the interaction between platelets (GP IIb/IIIa receptor) and fibrinogen, thus targeting the final common pathway for platelet aggregation. GP IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) should be considered in the treatment of all high-risk patients with refractory UA/NSTEMI, especially those with significant ST-T changes or elevated cardiac enzymes.
        • - GP IIb/IIIa antagonists should be used in conjunction with therapeutically dosed unfractionated heparin (UFH) or enoxaparin.
        • - The utility of GP IIb/IIIa antagonists in conjunction with ASA, clopidogrel, and heparin therapy appears to be restricted to patients with elevated
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          cardiac biomarkers and those with diabetes (JAMA 2006;295:1531; Circulation 2001;104:2767; NEJM 2009;360:2176).
        • - GP IIb/IIIa antagonists may be used as an alternative to clopidogrel in intermediate- to high-risk patients presenting with UA/NSTEMI that may require surgical revascularization.
        • - GP IIb/IIIa antagonists increase the risk of major bleeding, especially when used in combination with clopidogrel.
        • - Thrombocytopenia, which can be severe, is an uncommon complication of all these agents and should prompt discontinuation of the drug.
  • Anticoagulant therapy (Table 26)
    • Anticoagulation is a key component in the management of patients with ACS and should be routinely used in conjunction with ASA. Available therapeutic agents include intravenous UFH, enoxaparin (low-molecular-weight heparin [LMWH], fondaparinux, and bivalirudin (Angiomax).
    • UFH and LMWH minimize thrombus formation by inhibiting factors IIa and Xa, respectively. The use of both agents is limited by heparin-induced thrombocytopenia (HIT).
    • Fondaparinux is a synthetic polysaccharide that contains the same pentasaccharide sequence found in UFH and LMWH. It selectively inhibits factor Xa and does not bind PF4, making HIT unlikely with its use.
    • Bivalirudin (Angiomax) is a direct thrombin inhibitor. Bivalirudin can be given in conjunction with ASA and clopidogrel in patients presenting with UA/NSTEMI who will undergo an early invasive strategy.
      • Bivalirudin is particularly useful in the management of both cardiac and cardiac surgery patients with HIT.
    • Thrombolytic therapy is not indicated in UA/NSTEMI and has been shown to increase mortality.
  • Anti-ischemic therapy (Table 27)
    • Nitroglycerin reduces myocardial oxygen demand and enhances myocardial oxygen delivery. The choice of preparation depends on the severity of symptoms.
      • Treatment can be initiated at the time of presentation with sublingual nitroglycerin.
      • Less stable patients or those who require additional agents to control significant hypertension should be treated with intravenous nitroglycerin until pain relief, hypertension control, or both are achieved.
    • β-Adrenergic blockers limit cardiac ischemia by reducing myocardial oxygen demand and should be started early in the absence of contraindications. In high-risk patients, intravenous, followed by oral, preparations can be used. Treatment with an oral preparation alone is acceptable, especially if the patient is intermediate to low risk or is unable to tolerate intravenous agents.
      • The goals of therapy are to reduce the heart rate to 60 bpm and maintain an SBP greater than 90 to 100 mm Hg.
      • Contraindications to β-blocker therapy include advanced AV block, active bronchospasm, decompensated CHF, cardiogenic shock, hypotension, and bradycardia.
    • Calcium channel blockers can be used as third-line agent in patients continuing to have chest pain in the setting of adequate β-blocker and nitrate therapy.
      • Nifedipine, amlodipine, diltiazem, and verapamil appear to have similar coronary dilatory properties. Neither of these agents has demonstrated an effect on mortality or recurrent MI.
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      • Calcium channel blockers are useful in vasospastic angina, cocaine-induced vasospasm, and among patients in whom β-blockade is contraindicated.
    • Ranolazine is a novel antianginal agent that is useful in the treatment of chronic stable angina. Addition of ranolazine to standard medical therapy does not reduce recurrent ischemia, MI, or death in patients presenting with UA/NSTEMI (JAMA 2007;297:1775).
    • Blood transfusion improves oxygen-carrying capacity and myocardial oxygen supply. The potential benefit of routine blood transfusions in patients presenting with an NSTEMI is based on limited clinic data (NEJM 2001;345:1230).
      • The recommended target hemoglobin and hematocrit is 10 mg/dL and 30%, respectively.
      • Patients presenting with UA/NSTEMI who are actively bleeding and/or significantly anemic should be transfused routinely.
  • Other medical therapies
    • ACE inhibitors are effective antihypertensive agents and have been shown to reduce mortality in patients with CAD and LV systolic dysfunction.
      • ACE inhibitors should be used in patients with LV dysfunction (EF <40%), hypertension, or diabetes presenting with ACS. ARBs are appropriate in patients who cannot tolerate ACE inhibitors (NEJM 2003;349:1893).
    • HMG-CoA reductase inhibitors (statins) are potent lipid-lowering agents that reduce the incidence of ischemia, MI, and death in patients with CAD. Statins should be routinely administered within 24 hours of presentation in patients presenting with ACS.
      • Statin therapy reduces adverse outcomes through lipid lowering, anti-inflammatory, and atherosclerotic plaque-stabilizing effects.
      • Aggressive statin therapy reduces the risk of recurrent ischemia, MI, and death in patients presenting with ACS (JAMA 2001;285:1711).
      • The reduction in adverse outcomes following early initiation of aggressive lipid lowering to target LDL less than 70 therapy can be seen within 30 days following initial presentation (NEJM 2004;350:1495). Aggressive LDL lowering also reduces the incidence of peri-procedural MI following PCI (JACC 2007;49: 1272).
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    • NSAIDS are associated with an increased risk of death, MI, myocardial rupture, hypertension, and HF in large meta-analyses (Circulation 2006;113:2906). Adverse outcomes have been observed for both nonselective and COX-2 selective agents.
      • NSAIDS should be discontinued in patients presenting with UA/NSTEMI.
      • Acetaminophen is an acceptable alternative for the treatment of osteoarthritis and other musculoskeletal pain.
Table 24 Initial Medical Regimen for Unstable Angina/NSTEMI

Medications

Route

Dosage

Nitroglycerin

Sublingual

0.3-0.6 mg prn

Aerosol

0.4 mg prn

Intravenous

10-200 mcg/min

Oxygen

Nasal canula

2-4 L as needed

Morphine

Intravenous

2-4 mg prn

β-Blocker (metoprolol)

Intravenous

5 mg (3 doses)

Oral

25 mg qid

Aspirin

Oral

325 mg

Heparin

Intravenous

4,000 unit bolus, 12-14 units/kg/hr

Table 25 Antiplatelet Agents in Unstable Angina/NSTEMI

Medication

Dosage

Comments

Aspirin (ASA)

162-325 mg daily

Aspirin reduces subsequent MI and cardiac death in patients with unstable angina.

Clopidogrel (Plavix)

300-600 mg loading dose, 75 mg daily

In combination with ASA, clopidogrel (300 mg loading dose, then 75 mg/d) decreased the composite end point of cardiovascular death, MI, or stroke by 18% to 30% in patients with UA/NSTEMI (NEJM 2001;345:494; Lancet 2001;358:527; JAMA 2002;288:2411).

There may be further benefit in using a clopidogrel loading dose of 600 mg without an increased risk of bleeding in patients undergoing PCI (Circulation 2005;111:2099).

Ticlopidine (Ticlid)

250 mg bid

Prasugrel

60 mg loading dose, 10 mg daily

Prasugrel has increased antiplatelet potency compared to clopidogrel.

Prasugrel reduced the incidence of cardiovascular death, myocardial infarction, and stroke (9.9% vs. 12.1%) at the expense of increased major (2.4% vs. 1.1%) and fatal bleeding (0.4% vs. 0.1%), compared to clopidogrel (NEJM 2007; 357:2001).

Eptifibatide (Integrilin)a

180 mcg/kg IV bolus, 2 mcg/kg/mina,b

Eptifibatide reduces the risk of death or MI in patients with ACS undergoing either invasive or noninvasive therapy in combination with ASA and heparin (NEJM 1998;339:436; Circulation 2000;101:751).

Compared to abciximab and tirofiban, eptifibatide has the most consistent effects on platelet inhibition with shortest on-time and drug half-life (Circulation 2002;106:1470-1476).

Tirofiban (Aggrastat)

0.4 mcg/kg IV bolus, 0.1 mcg/kg/mina,b

Tirofiban reduces the risk of death or MI in patients with ACS undergoing either invasive or noninvasive therapy in combination with ASA and heparin (Circulation 1997; 96:1445; NEJM 1998;338: 1498; NEJM 1998;338:1488).

Abciximab (ReoPro)

0.25 mg/kg IV bolus, 10 mcg/mina,c

Abciximab reduces the risk of death or MI in patients with ACS undergoing coronary intervention (NEJM 1994;330:956; Lancet 1997;349:1429; NEJM 1997; 336:1689). It should not be used in patients in whom percutaneous intervention is not planned (Lancet 2001;357:1915).

Platelet inhibition may be reversed by platelet transfusion.

a The recommended duration of treatment is 72 to 96 hours following presentation or at least 12 hours after any percutaneous intervention.

b Infusion doses should be decreased by 50% in patients with a GFR less than 30 mL/min and avoided in patients on HD.

c Abciximab may be used in patients with ESRD, as it is not cleared by the kidney.

Table 26 Anticoagulant Medications

Medication

Dosage

Comments

Heparin (UFH)

60 units/kg IV bolus (maximum dose: 4,000 units), 12-14 units/kg/hr

Heparin therapy, when used in conjunction with ASA, has been shown to reduce the early rate of death or MI by up to 60% (JAMA 1996;276:811).

The activated partial thromboplastin time (aPTT) should be adjusted to maintain a value of 1.5-2.0 times control.

Enoxaparin (LMWH)

1 mg/kg SC bida

LMWH is at least as efficacious as UFH and may further reduce the rate of death, MI, or recurrent angina (NEJM 1997;337:447).

LMWH may increase the rate of bleeding (JAMA 2004;292:45) and cannot be reversed in the setting of refractory bleeding.

LMWH does not require monitoring for clinical effect. If cardiac catheterization is planned, then the dose should be withheld on the morning of procedure.

Fondaparinux

2.5 mg SC daily

Fondaparinux has efficacy similar to that of LMWH with possibly reduced bleeding rates (NEJM 2006;354:1464).

Bivalirudin (Angiomax)b

0.75 mg/kg IV bolus, 1.75 mg/kg/hr

When used in conjunction with ASA and clopidogrel, bivalirudin is at least as effective as the combination of ASA, UFH, clopidogrel, and GP IIb/IIIa antagonists with decreased bleeding rates (NEJM 2006;355:2203).

Monitoring is required with a goal aPTT of 1.5-2.5 times control.

a LMWH should be given at reduced dose (50%) in patients with a serum creatinine greater than 2 mg/dL or GFR less than 30 mL/min.

b Bivalirudin requires dosage adjustment in patients with a GFR less than 30 mL/min or those on hemodialysis.

Table 27 Antianginal Medications

Medication

Dosage

Comments

Nitroglycerin (NTG)

SL: 0.4 mg every 5 min
Topical: 0.5-2 in.
IV: 10-200 mcg/min

Significant antianginal effects are not seen above 200 mcg/min, but doses of up to 400 mcg/min can be used for BP control.

Nitroglycerin is contraindicated in patients who have used PDE5 inhibitors (e.g., within 24 hr of sildenafil or 48 hr of tadalafil) given the risk of severe hypotension. Appropriate timing for vardenafil dosing with nitrates is unknown and should be avoided.

Nitrates are relatively contraindicated in patients who are preload dependent, including those with severe aortic stenosis and hypertrophic obstructive cardiomyopathy.

Morphine

2-4 mg IV

IV narcotics are effective agents for relief of anginal symptoms and should be used if NTG does not provide complete relief or cannot be titrated further due to hypotension or headache.

β-Blockers

Metoprolol: 5 mg IV (3 doses)
25 mg PO qid
Bisoprolol: 10-20 mg PO daily
Carvedilol: 3.125-25 mg PO bid
Atenolol: 50-200 mg PO daily
Propranolol: 20-80 mg PO bid
Esmolol: 50-300 mcg/kg/min
Nebivolol: 5-40 mg PO daily

β-Adrenergic blockade reduces the risk of recurrent ischemia, myocardial infarction, and mortality in patients with UA/NSTEMI (J Interv Cardiol 2003;16:299).
The efficacy of β-blockade is limited by the development of cardiogenic shock. Those at risk include patients greater than 70 yr of age, SBP less than 120 mm Hg, and heart rate greater than 110 bpm or less than 60 bpm. In such cases, oral agents at reduced doses may be cautiously used (Lancet 2005;366:1622).

Calcium channel blockers

Nifedipine 30-180 mg daily
Amlodipine 5-10 mg daily
Diltiazem 30-80 mg qid
Verapamil 80-160 mg tid

Short-acting nifedipine preparations should be avoided in the absence of adequate concurrent β-blocker therapy because of increased risk of myocardial infarction and death.
Verapamil and diltiazem should be avoided in patients with evidence of severe LV dysfunction, pulmonary congestion, or AV block.

Other Nonoperative Therapies
  • Revascularization
    • The indications for PCI and CABG in patients with UA/NSTEMI are similar to those for individuals with stable angina.
      • Patients who are optimally managed with CABG include those with:
        • - Significant left main CAD
        • - Three-vessel disease and abnormal LV function (EF <50%)
        • - Two-vessel disease with a significant proximal LAD artery stenosis and abnormal LV function
        • - Diabetes and multivessel disease
      • Patients with multivessel coronary disease requiring revascularization can be treated with CABG or PCI. Patients who are treated with CABG tend to have a lower incidence of angina, less need for subsequent revascularization, but increased risk of stroke. There is no difference in the rates of cardiac death or MI between the two treatment strategies with either the use of bare metal stents (BMS) or DES. While the preferred treatment of unprotected left main disease remains CABG, however, recent data do suggest an important role for PCI (Circulation 2008;118:1146; NEJM 2009;360:961).
      • The decision between PCI and CABG should be based on the extent and complexity of coronary disease, medical comorbidities, and patient preference.
    • If there is uncertainty regarding the hemodynamic significance of a coronary lesion, fractional flow reserve (FFR) can be performed to quantify the functional severity of blood flow limitation. This modality has been shown to reduce death, recurrent MI, or revascularization compared to conventional PCI at 1 year in patients with multivessel CAD (NEJM 2009;360:213).
    • DES significantly reduce the rate of ISR and adverse cardiac outcomes compared to BMS (NEJM 2003;349:1315; Circulation 2003;108:788). However DES imparts an additional risk of late stent thrombosis, most notably following the discontinuation of clopidogrel therapy within 1 year following stent placement (JAMA 2007;297:159).
    • The management of patients following PCI is discussed in detail in the section on hypertension, dyslipidemia and stable angina.
Lifestyle/Risk Modification
Risk factor modification is addressed in detail in the section on STEMI and should include attention to smoking cessation, weight loss, exercise, control of hypertension, diabetes, and hyperlipidemia.
COMPLICATIONS
The highest rate of progression to MI or development of recurrent MI is in the first 2 months after presentation with the index episode. Beyond that time point, most patients have a clinical course similar to those with chronic stable angina.
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MONITORING/FOLLOW-UP
  • It is incumbent on the entire hospital staff (physicians, nurses, dietitians, pharmacists, and rehabilitation specialists) to prepare the patient for hospital discharge. The patient should be discharged on a medical regimen that takes advantage of proven methods of secondary prevention. The patient should also be provided a sublingual or spray formulation of nitroglycerin and instructed on its appropriate use.
  • Arrangements for follow-up care should also be established before hospital discharge.
ST-Segment Elevation Myocardial Infarction
GENERAL PRINCIPLES
  • STEMI is a medical emergency caused by acute occlusion of an epicardial coronary artery. Vessel occlusion is most often due to atherosclerotic plaque rupture and subsequent thrombus formation.
  • Compared to UA/NSTEMI, STEMI is associated with a higher in-hospital and long-term morbidity and mortality. Left untreated, the mortality rate of uncomplicated STEMI can exceed 30% and the presence of mechanical complications (papillary muscle rupture, ventricular septal defect [VSD], and free wall rupture) increases the mortality rate to 90%. Over the past few decades, there has been a dramatic improvement in short-term mortality to the current rate of 6% to 10%.
  • Ventricular fibrillation accounts for approximately 50% of mortality and occurs within the first hour from symptom onset.
  • Keys to treatment of STEMI include rapid recognition and diagnosis, coordinated mobilization of health care resources, and prompt reperfusion therapy.
  • Mortality is directly related to total ischemia time and restoration of coronary blood flow.
Prevention
Secondary prevention. The strategies outlined for primary prevention and the management of stable angina have also been shown to decrease the rates of repeat infarction, progression to CHF, and incidence of cardiovascular deaths in patients with known CAD (see stable angina).
DIAGNOSIS
Clinical Presentation
Clinical stratification on initial presentation
  • Multiple risk assessment tools have been developed to stratify patients presenting with acute STEMI into low-, intermediate-, and high-risk groups based on history, physical exam, and hemodynamic monitoring (Fig. 4).
  • The Killip classification system utilizes history and physical exam findings (S3 gallop, pulmonary congestion, and cardiogenic shock) to predict 30-day mortality in the absence of reperfusion therapy (Am J Cardiol 1967;20:457). In contrast, the TIMI risk score for STEMI incorporates a combination of history and physical to predict 30-day mortality in patients who receive thrombolytic therapy (Circulation 2000;102:2031). The Forrester classification system uses invasive
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    hemodynamic data including cardiac index and pulmonary capillary wedge pressure (NEJM 1976;295:1356).
Figure 4. Risk indices for ST-segment elevation MI. Killip classification in acute MI. Top. TIMI risk score for STEMI (Circulation 2000;102:2031). Bottom. Killip classification system (Am J Cardiol 1967;20:457). The TIMI risk score incorporates prognosis following coronary reperfusion with thrombolytic therapy. The Killip classification system was devised before reperfusion therapy was routinely used. HTN, hypertension; BP, blood pressure.
History
  • Chest pain from STEMI resembles angina, but lasts longer, is more intense, and is not relieved by rest or sublingual nitroglycerin. Chest discomfort may be accompanied by dyspnea, diaphoresis, palpitations, nausea, vomiting, fatigue, and/or syncope.
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  • It is imperative to determine the time of symptom onset, as this is critical in determining the appropriate means of reperfusion (Table 28).
  • STEMI may have atypical presentations particularly in women, elderly and postoperative patients as well as those with diabetes and chronic or end-stage kidney disease. Such patients may experience atypical or no chest pain and may instead present with confusion, dyspnea, unexplained hypotension, or CHF.
  • If the patient has a history of previous cardiac catheterization or revascularization, it is important to obtain these records, as these can provide valuable information with respect to PCI planning, particularly in the setting of previous coronary artery bypass grafting. However, this should not delay definitive therapy.
  • Review absolute and relative contraindications to thrombolytic therapy (see below) and potential issues complicating primary PCI (IV contrast allergy, PVD/peripheral revascularization, renal dysfunction, CNS disease, pregnancy, and bleeding diathesis).
  • Inquire about recent cocaine use. In this setting, aggressive medical therapy with nitroglycerin, coronary vasodilators, and benzodiazepines should be administered before reperfusion therapy is considered.
Table 28 Key Information in the Patient Presenting with STEMI

History and Physical Exam

Laboratory Values

Records

Inquire about the exact time of chest pain onset

Complete blood cell count

Prior ECGs

Consider other etiologies of chest pain with ST-segment elevation (i.e., aortic dissection, cocaine use)

Basic chemistry panel

Last cardiac catheterization

Identify absolute and relative contraindications to PCI and thrombolysis

PTT, PT and INR

CABG operative report

Evaluate for signs of heart failure, mechanical complications of MI, aortic dissection, and neurologic disease

Cardiac enzymes

Prior echocardiogram

Physical Examination
Physical examination should be directed at identifying hemodynamic instability, pulmonary congestion, mechanical complications of MI, and other causes of acute chest discomfort.
  • The identification of a new systolic murmur may suggest the presence of ischemic mitral regurgitation (MR) or a VSD.
  • A limited neurologic exam to detect baseline cognitive and motor deficits and a vascular examination (lower extremity pulses and bruits) will aid in determining candidacy for reperfusion treatment.
  • Cardiogenic shock due to right ventricular myocardial infarction (RVMI) may be clinically suspected by the presence of hypotension, elevated jugular venous pressure,
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    and absence of pulmonary congestion. While RVMI may be seen in isolation, it more commonly complicates inferior/posterior MI.
  • Bilateral arm BPs should be obtained to assess for the presence of aortic dissection.
Diagnostic Criteria
STEMI requires the presence of at least two of the following criteria:
  • History of prolonged chest discomfort or anginal equivalent (30 minutes)
  • Presence of ≥1 mm ST-segment elevation in two consecutive ECG leads or new LBBB
  • Presence of elevated cardiac biomarkers
Diagnostic Testing
Laboratories
Blood samples should be sent for cardiac enzymes (Troponin, CK-MB), complete blood cell count, coagulation studies (PTT, prothrombin time [PT], international normalized ratio [INR]), creatinine, electrolytes including magnesium, and type and screen. A fasting lipid profile should be obtained in all patients with STEMI for secondary prevention.
  • Initial cardiac enzymes (including high-sensitivity troponin assays) may be normal, depending upon the time in relation to symptom onset. In general, cardiac enzymes should have little role in the initial decision making process and awaiting these studies may lead to unnecessary delays in delivering therapy.
  • CK-MB can be used to confirm that myocardial injury occurred within the previous 48 hours, as troponin levels may remain elevated for several days after MI. CK-MB is also useful to detect periprocedural infarctions.
  • The risk of subsequent cardiac death is directly proportional to the increase in cardiac-specific troponins, even when CK-MB levels are not elevated. Cardiac enzymes should be measured daily until the peak level has been reached to determine the extent of myocardial damage.
  • Routine use of cardiac noninvasive imaging is not recommended for the initial diagnosis of STEMI. When the diagnosis is in question, a transthoracic echocardiogram (TTE) can be performed to document regional wall motion abnormalities. If not adequately evaluated by TTE, a transesophageal echocardiogram (TEE) can be obtained to assess for acute complications of MI and presence of aortic dissection.
  • A portable chest radiograph is useful to assess for pulmonary edema and evaluate for other causes of chest pain including aortic dissection. Importantly, a normal mediastinal width does not exclude aortic dissection, especially if clinically suspected.
Electrocardiography
The ECG is paramount to the diagnosis of STEMI and should be obtained within 5 minutes of presentation. If the diagnosis of STEMI is in doubt, serial ECGs may help elucidate the diagnosis. Classic findings include (Table 29):
  • T waves. Peaked upright T waves may be the first ECG manifestation of myocardial injury.
  • ST-segment changes
    • Convex ST-segment elevation ≥ 1 mm in two consecutive leads with peaked or inverted T waves is usually indicative of myocardial injury and correlates with the territory of injured myocardium (Fig. 8).
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    • Posterior wall MI is recognized by ST-segment depression in leads V1 to V3, ST-segment elevation in V7 to V9 and is treated as a STEMI.
    • RVMI is diagnosed with ST-segment elevation in lead V4R.
    • ECG criteria for ischemic changes in patients with preexisting LBBB or RV-pacing can be found in Table 30.
  • Qwaves. Development of new pathologic Q waves (>40 milliseconds) is considered diagnostic for MI, but may occur in patients with prolonged ischemia.
  • A new LBBB suggests anterior wall injury.
  • Infarction of the left circumflex territory may be electrocardiographically silent.
  • The presence of reciprocal ST-segment depression opposite of the infarct territory increases the specificity for acute MI.
  • ECG changes that mimic MI. ST-segment elevation and Q waves may result from numerous etiologies other than acute MI including prior MI with aneurysm formation, aortic dissection, LV hypertrophy, pericarditis, myocarditis, and pulmonary embolism (Table 31). It is critical to obtain prior ECGs to clarify the diagnosis.
Table 29 ECG-Based Anatomic Distribution

ST Elevation

Myocardial Territory

Coronary Artery

V1-V6 or LBBB

Anterior and septal walls

Proximal LAD or left main

V1-V2

Septum

Proximal LAD or septal branch

V2-V4

Anterior wall

LAD

V5-V6

Lateral wall

LCX

II, III, aVF

Inferior wall

RCA or LCX

I, aVL

High lateral wall

Diagonal or proximal LCX

LBBB, left bundle branch block; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

TREATMENT
  • Acute management. Prompt treatment should be initiated as soon as the diagnosis is suspected, as mortality and subsequent HF are directly related to ischemia time (Fig. 5). All medical centers should utilize an AHA/ACC guideline-based STEMI protocol. Centers that are not primary PCI capable should have protocols in place to
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    meet accepted time to therapy guidelines for either administration of thrombolytic therapy with subsequent transfer or rapid transfer to a primary PCI-capable facility.
  • Before presentation to the hospital. The general public should be informed of the signs and symptoms consistent with an acute MI that should lead them to seek urgent medical care. Availability of “911” access and emergency medical services facilitates delivery of patients to emergency medical care.
  • In the emergency department, an acute MI protocol should be activated that includes a targeted clinical examination and a 12-lead ECG completed within 10 minutes of arrival.
  • Immediate management. The goal of immediate management in patients with STEMI is to identify candidates for reperfusion therapy. The goal is a door-to-needle time of <30 minutes or door-to-balloon time of <90 minutes. Other key priorities include relief of ischemic pain as well as recognition and treatment of hypotension, pulmonary edema, and arrhythmia.
  • General measures include continuous BP, pulse oximetry, and telemetry monitoring.
    • Supplemental oxygen should be administered if saturations are <90%. If necessary, institution of mechanical ventilation decreases the work of breathing and reduces myocardial oxygen demand.
    • Two peripheral IV catheters should be inserted upon arrival.
    • Serial ECGs should be obtained for patients who do not have ST-segment elevation on the initial ECG, but experience ongoing chest discomfort as they may demonstrate evolving ST-segment elevation.
Table 30 Criteria for ST-segment Elevation for Prior LBBB or RV-paced Rhythm

ECG change

ST-segment elevation greater than 1 mm in the presence of a positive QRS complex (concordant with the QRS)

ST-segment elevation greater than 5 mm in the presence of a negative QRS complex (disconcordant with the QRS)

ST-segment depression greater than 1 mm in V1-V3.

Sgarbossa's (GUSTO) criteria: Am J Cardiol 1996;77:423; NEJM 1996;334:481; PACE 2001; 24:1289.

Table 31 Differential Diagnosis of ST-Segment Elevation

Cardiac Etiologies

Other Etiologies

Prior MI with aneurysm formation

Pulmonary embolism

Aortic dissection with coronary involvement

Hyperkalemia

Pericarditis

Myocarditis

LV hypertrophy or aortic stenosis (with straina)

Hypertrophic cardiomyopathy

Coronary vasospasm (cocaine, Prinzmetal angina)

Early repolarization (normal variant)

Brugada syndrome

a Strain may occur in numerous settings including systemic hypertension, hypotension, tachycardia, exercise, and sepsis.

Medications
Upstream medical therapy should include administration of antiplatelet and anticoagulant medications as well as agents that reduce myocardial ischemia (Table 32).
  • Aspirin (ASA) should be given immediately to all patients with suspected acute MI. ASA treatment resulted in relative reduction in cardiovascular mortality by 23% and the incidence of nonfatal MI by 49% (Lancet 1988;2:349).
  • Clopidogrel reduces mortality, reinfarction, and acute stent thrombosis without an increase in serious bleeding or intracranial hemorrhage when given in conjunction
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    with thrombolytic therapy or PCI (Lancet 2005;366:1607; NEJM 2005;352:1179; JAMA 2005;294:1224). Clopidogrel can be given as an alternative to aspirin in the setting of true aspirin allergy (anaphylaxis). Subsequent allergy consultation for aspirin desensitization should be obtained as ASA and clopidogrel treatment is superior to either agent alone.
  • Prasugrel may be used as an alternative to clopidogrel. In patients who presented with STEMI, prasugrel decreased adverse cardiac outcomes without an increase in major bleeding events compared to clopidogrel (300 mg loading dose, 75 mg maintenance dose) (NEJM 2007;357:2002; Lancet 2009;373:723).
  • Glycoprotein (GP) IIb/IIIa inhibitors have shown limited efficacy and increased bleeding rates when used in conjunction with ASA and clopidogrel prior to primary
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    PCI (see facilitated PCI). However, it may be reasonable to use GP IIb/IIIa inhibitors as an alternative to clopidogrel, particularly in patients who present with acute complications of MI requiring surgery (ischemic MR, ruptured papillary muscle, or VSD).
  • Anticoagulant therapy (UFH, LMWH, or bivalirudin) should be initiated in all patients with acute MI regardless of the choice of PCI, thrombolytic, or medical therapy.
    • LMWH (enoxaparin) is an alternative to UFH with more predictable kinetics and easier route of administration that has shown efficacy in conjunction with thrombolysis and PCI (Lancet 2001;358:605; NEJM 2006;354:1477; JACC 2007;49:2238). UFH is preferred during PCI as real-time therapeutic monitoring of LWMH in the catheterization laboratory is often not possible.
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    • Bivalirudin should be given to patients with HIT and has equivalent efficacy to UFH with respect to overall mortality when given in combination with ASA and clopidogrel in patients undergoing primary PCI. Bivalirudin reduced bleeding rates at the expense of an increased frequency of acute stent thrombosis (NEJM 2008;358:2218; Lancet 2009;374:1149).
    • UFH or LMWH should be administered to patients receiving selective fibrinolytic agents (alteplase, reteplase, or tenecteplase). UFH has been shown to increase bleeding without improving mortality in patients who receive streptokinase.
  • Nitroglycerin should be administered to patients with ischemic chest pain. Nitroglycerin should either be avoided or used with caution in patients with:
    • Hypotension (SBP < 90 mm Hg)
    • RVMI
    • HR greater than 100 or less than 50 bpm
    • Documented use of phosphodiesterase inhibitors
  • Morphine (2 to 4 mg IV) can be used for refractory chest pain that is not responsive to nitroglycerin. Adequate analgesia decreases levels of circulating catecholamines and reduces myocardial oxygen consumption.
  • β-Adrenergic blockade improves myocardial ischemia, limits infarct size, and reduces major adverse cardiac events including mortality, recurrent ischemia, and malignant arrhythmias. IV β-blockers can increase mortality in patients with HF, cardiogenic shock (Killip II or greater), age older than 70 years, SBP less than 120 mm Hg, HR greater than 110 or less than 60 bpm (Lancet 2005;366:1622). Oral β-blockers may be used with caution in select patients.
  • Acute coronary reperfusion
    • The majority of patients who suffer an acute STEMI have thrombotic occlusion of the infarct-related coronary artery. Early restoration of coronary perfusion limits infarct size, preserves LV function, and reduces mortality.
      • All patients who present with a STEMI within 12 to 24 hours of symptom onset should be considered for immediate reperfusion therapy.
      • Unless spontaneous resolution of ischemia occurs (as determined by resolution of chest discomfort and normalization of ST elevation), the choice of reperfusion strategy includes thrombolysis, primary PCI, or emergent CABG (Fig. 6).
      • The choice of reperfusion therapy should almost be considered of secondary importance to the overall goal of achieving reperfusion in a timely fashion as the morbidity and mortality associated with an acute MI are linearly related to the time to treatment.
      • In general, primary PCI is the preferred reperfusion strategy when available within 90 minutes of medical contact (including transfer to a PCI-capable facility). If cardiac catheterization is not readily available, thrombolytic therapy should be administered within 30 minutes of medical contact.
      • PCI is preferred over thrombolysis in patients who:
        • - Are <75 years of age and present with cardiogenic shock within 36 hours of MI and PCI can be performed within 18 hours of shock
        • - Have a contraindication to fibrinolytic therapy
        • - Are at high risk of death or development of CHF
        • - Underwent recent PCI or prior CABG
      • Thrombolysis may be preferred if patients are presenting to the hospital within the first 2 hours of symptom onset.
    • Primary PCI is the preferred reperfusion strategy when performed in a timely fashion at an appropriate facility. Compared to thrombolytic therapy, PCI offers
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      superior vessel patency and improved survival regardless of lesion location or patient age (NEJM 1997;336:1621; Lancet 2003;361:13).
      • Primary PCI should be considered if an available catheterization facility can provide a door-to-balloon time of less than 90 minutes. Optimally, operators should perform greater than 75 PCIs per year at experienced centers with a volume that exceeds 200 PCIs per year.
      • Patients who present to a facility where cardiac catheterization is not available should be immediately transferred to a PCI-capable center with an estimated total door-to-balloon time of less than 90 minutes. In this setting, primary
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        PCI significantly lowered the incidence of death, MI, or stroke compared to on-site thrombolysis (NEJM 2003;249:733; JACC 2002;39:1713; Eur Heart J 2000;21:823). If the estimated transfer time will exceed a total door-to-balloon time of 90 minutes, on-site thrombolysis should be performed (see below).
      • PCI is also indicated in patients who present with cardiogenic shock, refractory arrhythmias, have contraindications to thrombolytic therapy, or if the diagnosis is uncertain.
      • Treatment is optimal when the angioplasty is performed within 12 hours of symptom onset and may be effective beyond that point if symptoms persist.
      • Additional advantages of primary PCI include immediate assessment of coronary anatomy, atherosclerotic disease burden, and LV function.
      • If the patient has multivessel coronary disease, the appropriateness and timing of complete revascularization should be determined after the infarct-related artery is opened and the patient stabilized.
        • - If the functional significance of coronary lesions is not readily apparent, an invasive (FFR) or noninvasive (stress testing) assessment should be undertaken.
        • - Complete revascularization is best performed in a staged manner to minimize contrast-mediated renal toxicity.
      • Coronary stenting is superior to balloon angioplasty alone and reduces the rates of target vessel revascularization (NEJM 1999;341:1949; NEJM 2002;346:957). DES further reduce the need for target vessel revascularization without increasing the incidence of stent thrombosis (Circulation 2009;120:964; JACC 2008;51:618; JAMA 2008;299:1788).
      • Abciximab infusion at the time of PCI should be routinely used as it reduces the rate of death, MI, and urgent revascularization by approximately 50% (Circulation 1998;98:734; NEJM 2001;344:1895; JACC2003;42:1879). Recommended anticoagulation strategies for PCI are shown in Figure 7.
        • - Eptifibatide and tirofiban may have similar efficacy to abciximab (Am J Cardiol 2004;94:35; JAMA 2008;299:1788; JACC 2008;51:529).
        • - Bivalirudin is an acceptable alternative to the use of combined heparin and GP IIb/IIIa inhibitor during PCI with lower bleeding rates (NEJM 2008;358:2218 JAMA 2003;19:853).
      • Facilitated PCI, a strategy of reduced dose of GP IIb/IIIa inhibitors and/or thrombolytic agent prior to PCI, should not be routinely employed as it does not improve efficacy and significantly increases bleeding rates (Lancet 2006;367:569; NEJM 2008;358:2205; Lancet 2006;367:579).
    • Thrombolytic therapy offers the advantages of availability and rapid administration. The primary disadvantage of thrombolytic therapy is the risk of intracranial hemorrhage, uncertainty of whether normal coronary flow has been restored, and reocclusion of the infarct-related artery.
      • Thrombolytic therapy is most effective if given within 12 hours of the symptom onset with a pooled relative mortality reduction of 18% (Lancet 1994;343:311; Lancet 1987;2:871). Beyond 12 hours, thrombolysis yields little benefit.
      • Thrombolytic therapy is not indicated for patients with resolved chest pain or those with ST-segment depression.
      • Absolute and relative contraindications to thrombolytic therapy are listed in Table 33.
      • Multiple thrombolytic agents are available and are classified into two groups based on their selectivity for fibrin substrates. Fibrin-selective agents include recombinant tissue plasminogen activator (rt-PA), reteplase (r-PA), and
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        tenecteplase (TNK-tPA). Streptokinase is the only nonselective agent in use. Further details and dosing information can be found in Table 34.
        • - The choice of thrombolytic agent is guided by considerations of efficacy, bleeding risk, availability, ease of administration, and cost. Compared with streptokinase, rt-PA is associated with a slightly greater risk of intracranial hemorrhage but offers the net clinical benefit of additional 10 lives saved per 1,000 patients treated (NEJM 1993;329:673).
        • - Fibrin-selective agents should be used in combination with anticoagulant therapy (UFH, LMWH, fondaparinux, or bivalirudin). Recent studies have demonstrated that LMWH and fondaparinux may be superior to UFH (Lancet 2001;358:605; Circulation 2002;105:1642; NEJM 2006;354:1477; JAMA 2006;295:1519). Addition of UFH to streptokinase does not improve outcomes (NEJM 1993;329:673).
      • The therapeutic efficacy of thrombolytic treatment can be monitored by clinical response (resolution of chest pain), improvement in ST-segment elevation, or by the presence of accelerated idioventricular rhythm.
        • - Thrombolytic therapy does not achieve coronary artery patency in 30% of patients. In contrast, primary PCI results in restoration of normal coronary flow (TIMI 3) in greater than 95% of cases.
      • Individuals with persistent angina or persistent ischemic changes on the ECG (<50% reduction in ST-segment elevation) 60 to 90 minutes after the initiation of thrombolytic therapy should be considered for urgent coronary angiography and PCI (rescue PCI).
        • - Rescue PCI reduces the incidence of death, reinfarction, and HF by nearly 50% (Circulation 1994;90:2280; NEJM 2005;353:2758).
        • - Routine coronary angiography within 24 hours of thrombolysis has reduced adverse cardiac events compared to rescue PCI (Lancet 2004;264:1045). Routine PCI has also proved beneficial for patients who receive thrombolysis as an initial therapy and are subsequently transferred to a PCI-capable facility (Lancet 2008;371:559). This strategy should be differentiated from facilitated PCI where thrombolytic agents are administered immediately before primary PCI.
      • The most common complication of thrombolytic therapy is bleeding. Intracranial hemorrhage occurs in 0.7% to 0.9% of cases and may result in death or permanent neurologic defects.
        • - The risk of intracranial hemorrhage is increased twofold in patients older than 75 years, less than 70 kg, on anticoagulation therapy (Coumadin), or with severe hypertension (BP > 170/90).
        • - Any patient who experiences a sudden change in neurologic status should undergo urgent head CT and all anticoagulant and thrombolytic therapies discontinued. Fresh frozen plasma should be given to patients with intracerebral hemorrhage. Cryoprecipitate may also be used to replenish fibrinogen and factor VIII levels. Platelet transfusions can be useful in patients with markedly prolonged bleeding times. Neurologic and neurosurgical consultation should be obtained immediately.
        • - Major bleeding complications that require blood transfusion occur in approximately 10% of patients.
        • - Venipuncture should be limited and arterial puncture avoided in patients treated with thrombolytic therapy for 24 hours after the initiation of treatment.
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  • Emergency CABG is a high-risk procedure that should be considered only if the patient has severe left main disease or refractory ischemia in the setting of failed PCI or coronary anatomy that is not amenable to PCI. Emergency surgery should also be considered for patients with acute mechanical complications of MI including papillary muscle rupture, severe ischemic MR, VSD, ventricular aneurysm formation in the setting of intractable ventricular arrhythmias, or ventricular free wall rupture.
Figure 5. The benefit of coronary reperfusion is inversely related to ischemia time. Top. Graphic representation of mortality benefit of coronary reperfusion as a function of ischemia time. (Adapted from JAMA 2005;293:979.) Bottom. Recommended timeline of events following chest pain onset as a according to ACC/AHA guidelines (Circulation 2008;117:296).
Table 32 Upstream Medical Therapy

Medication

Dosage

Comments

Aspirin (ASA)

162-325 mg

Nonenteric coated formulations (chewed or crushed) given orally or rectally facilitate rapid drug absorption and platelet inhibition.

Clopidogrel

300-600 mg loading dose, 75-150 mg daily

600 mg loading dose followed by 7 d of 150 mg maintenance dose may reduce the incidence of stent thrombosis and MI compared to the standard 300 mg loading dose and 75 mg maintenance dose.

Caution should be used in the elderly as clinical trials validating clopidogrel use in STEMI either did not include elderly patients or did not use a loading dose.

Prasugrel

60 mg loading dose 10 mg daily

Compared to clopidogrel, prasugrel is a quicker acting and more potent antiplatelet agent with improved efficacy, but did significantly increase CABG bleeding rates.

Prasugrel should not be used in patients greater than 75 yr old, less than 60 kg, or with a history of stroke/TIA.

Unfractionated heparin (UFH)

60 units/kg IV bolus, 12 units/kg/hr

UFH should be given to all patients undergoing PCI and those receiving thrombolytics with the exception of streptokinase.

The maximum IV bolus is 4,000 units.

Enoxaparin (LMWH)

30 mg IV bolus, 1 mg/kg SC bid

Patients greater than 75 yr of age should not be given a loading dose and receive 0.75 mg SC bid.

An additional loading dose of 0.3 mg/kg should be given if the last dose of LMWH was more than 8 hr prior to PCI. The use of LMWH is only validated in thrombolysis and rescue PCI.

Bivalirudin

0.75 mg/kg IV bolus, 1.75 mg/kg/hr

Bivalirudin has been validated in patients undergoing PCI and has not been studies in conjunction with thrombolysis.

Patients who received a heparin bolus prior to bivalirudin had a lower incidence of stent thrombosis than those who only received bivalirudin.

Fondaparinux

2.5 mg IV bolus, 2.5 mg SC daily

Shown to be superior to UFH when used during thrombolysis with decreased bleeding rates.

Fondaparinux increases the risk of catheter thrombosis when used during PCI (JAMA 2006;295:1519).

Nitroglycerin

0.4 mg SL or aerosol infusion: 10-200 mcg/min

Sublingual or aerosol nitroglycerin can be given every 5 min for a total of three doses in the absence of hypotension. IV nitroglycerin can be used for uncontrolled chest discomfort.

Metoprolol

5 mg IV (3 doses), 25 mg PO qid

β-Blockers should also be avoided in patients with evidence of heart failure, hemodynamic instability, marked first-degree AV block, advanced heart block, and bronchospasm.

Figure 6. Strategies for coronary reperfusion and risk assessment. 1Prasugrel may be used in place of clopidogrel in patients undergoing PCI. 2UFH may be used with either PCI or thrombolytic therapy, while bivalirudin has only been studied with PCI and LMWH has only been validated for thrombolytic therapy and rescue PCI. 3Patients who do not experience chest pain relief or ST-segment normalization 60 to 90 minutes following thrombolysis should undergo rescue PCI. 4Signs of successful reperfusion include chest pain relief, 50% reduction in ST-segment elevation and idioventricular rhythm. ASA, aspirin; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; NTG, nitroglycerin; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.
Figure 7. Recommended strategies for upstream therapy prior to PCI. 1Prasugrel may be used in place of clopidogrel in patients undergoing PCI. GP IIb/IIIa inhibitors may be used instead of clopidogrel in patients who present with mechanical complications of MI and require urgent cardiac surgery. 2In comparison to UFH + GP IIb/IIIa inhibitor, bivalirudin improves mortality and decreases bleeding in patients presenting with STEMI. A heparin bolus should be given prior to bivalirudin to decrease the rate of stent thrombosis (NEJM2008;358:2218). 3LMWH has only been studied in rescue PCI and has not been validated for primary PCI (NEJM 2006;354:1477). ASA, aspirin; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; NTG, nitroglycerin; PCI, percutaneous coronary intervention.
Table 33 Contraindications to Thrombolytic Therapy

Absolute Contraindications

Relative Contraindications

History of intracranial hemorrhage or hemorrhagic stroke

Prior ischemic stroke more than 3 mo ago

Ischemic stroke within 3 mo

Allergy or previous use of streptokinase (greater than 5 d ago)a

Known structural cerebrovascular lesion (AVMs, aneurysms, tumor)

Closed head injury within 3 mo

Recent internal bleeding (2-4 wk)

Aortic dissection

Prolonged/traumatic CPR more than 10 min

Severe uncontrolled hypertension (SBP > 180 mm Hg, DBP > 110 mm Hg)

Major surgery within 3 wk

Active peptic ulcer disease

Active bleeding or bleeding diathesis

Noncompressible vascular punctures

Acute pericarditis

Severe menstrual bleeding

History of intraocular bleeding

Pregnancy

AVM, arteriovenous malformation; CPR, cardiopulmonary resuscitation; DBP, diastolic blood pressure; SBP, systolic blood pressure.

a Thrombolytics other than streptokinase may be used.

Table 34 Thrombolytic Agents

Medication

Dosage

Comments

Streptokinase (SK)

1.5 million units IV over 60 min

Produces a generalized fibrinolytic state (not clot specific).

SK reduces mortality following STEMI: 18% relative risk reduction and 2% absolute risk reduction (Lancet 1987;2:871).

Allergic reactions including skin rashes, fever, and anaphylaxis may be seen in 1-2% of patients. Isolated hypotension occurs in 10% of patients and usually responds to volume expansion.

Because of the development of antibodies, patients who were previously treated with streptokinase should be given an alternate thrombolytic agent.

Recombinant tissue plasminogen activator (rt-PA)

15 mg IV bolus
0.75 mg/kg over 30 min (maximum 50 mg)
0.50 mg/kg over 60 min (maximum 35 mg)

Fibrin selective agent with improved clot specificity compared to SK.
Does not cause allergic reactions or hypotension.
Mortality benefit compared to SK at the expense of an increased risk of intracranial hemorrhage (NEJM 1993;329:673)

Reteplase (r-PA)

Two 10-unit IV boluses administered 30 min apart

Fibrin selective agent with a longer half-life but reduced clot specificity compared to rt-PA.
Mortality benefit equivalent to that of rt-PA (NEJM 1997;337:1118).

Tenecteplase (TNK-tPA)

0.50 mg/kg IV bolus (total dose 30-50 mg)

Genetically engineered variant of rt-PA with slower plasma clearance, improved fibrin specificity, and higher resistance to plasminogen activator inhibitor-1 (PAI-1).

Mortality benefit equivalent to that of rt-PA with reduced bleeding rates (Lancet 1999;354:716).

Monitoring is required with a goal aPTT of 1.5-2.5 times control.

Peri-infarct Management
  • The coronary care unit (CCU) was the first major advance in the modern era of treatment of acute MI. The majority of patients benefit from the specialized training of the nursing and support staff in the CCU. Most patients with acute MI should be observed for 24 to 48 hours in the CCU.
  • Bedrest is appropriate intermediate care for the first 24 hours after presentation with an acute MI. After 24 hours, clinically stable patients can progressively advance their activity as tolerated.
  • Patients should have continuous telemetry monitoring to detect for recurrent ischemia and arrhythmias. Daily evaluation should include assessment for recurrent chest discomfort and HF symptoms, physical exam focusing on new murmurs and evidence of HF, and routine ECGs.
  • A baseline echocardiogram should be obtained to document ejection fraction, wall motion abnormalities, valvular lesions, and presence of ventricular thrombus.
  • Hemodynamic monitoring may be useful to optimize medical therapy in unstable patients (see below).
  • Cardiac pacing may be required in the setting of an acute MI. Rhythm disturbance may be transient in nature, in which case temporary pacing is sufficient until a stable rhythm returns (see below).
Post-MI Medical Therapy
  • Aspirin is the preferred antiplatelet agent after MI and should be used indefinitely. Doses of 75 to 325 mg/d have been shown to reduce the risk of recurrent MI, stroke, and cardiac death.
  • Clopidogrel (75 mg/d) or Prasugrel (10 mg/d) should be given for a minimum of 1 month in patients who receive a BMS and for at least 1 year in patients who receive a DES.
  • β-Blockers confer a mortality benefit following acute MI. Treatment should begin as soon as possible (preferably within the first 24 hours) and continued indefinitely.
  • ACE inhibitors provide a reduction in short-term mortality and incidence of CHF and recurrent MI when initiated within the first 24 hours of an acute MI (Lancet 1994;343:1115; Lancet 1995;345:669).
    • Patients with ejection fraction less than 40%, large anterior MI, and prior MI derive the most benefit from ACE-inhibitor therapy.
    • Therapy may be initiated with captopril and titrated as BP permits. Conversion to a more long-acting agent is appropriate prior to discharge.
    • Contraindications include hypotension, acute renal failure, bilateral renal artery stenosis, and hyperkalemia. Care must be taken to avoid hypotension.
    • Angiotensin II receptor blockers can be used in patients who are intolerant of ACE inhibitors with equivalent efficacy.
  • HMG-CoA reductase inhibitors should be started in all patients in the absence of contraindications. Several trials have shown the benefit of early and aggressive use of
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    statins following AMI. The goal is at least 50% reduction in LDL or LDL less than 70 mg/dL.
  • Aldosterone receptor antagonists (Aldactone and eplerenone) have shown benefit in post-MI patients with LV ejection fraction of less than 40% (NEJM1999;341:709; NEJM 2003;348:1309). Caution should be used in patients with hyperkalemia and renal insufficiency.
SPECIAL CONSIDERATIONS
Risk assessment
  • Patients who present greater than 24 hours after symptom onset and those who receive thrombolysis or medical therapy alone should undergo further risk assessment. Patients may be evaluated using either a noninvasive (stress testing) or invasive (coronary angiography) strategy.
  • Stress testing can be used to determine prognosis, residual ischemia, and functional capacity.
    • A submaximal exercise stress test can be performed as early as 4 to 6 days following MI. Pharmacologic stress testing (preferably nuclear perfusion imaging) may also be used and is optimal for evaluating ischemic burden.
    • Alternatively, stress testing can be performed after hospital discharge (2 to 6 weeks) for low-risk patients.
    • Coronary angiography should be performed in patients with limiting angina, significant ischemic burden, and those with poor functional capacity.
  • Cardiac catheterization without prior noninvasive assessment is an alternative approach for high-risk individuals who presented greater than 24 hours after symptom onset or those managed medically. At the time of catheterization, decisions on revascularization should be made based on the patient's anatomy, ventricular function, and clinical status.
    • Recent studies have failed to show any benefit of opening totally occluded arteries greater than 3 days following acute MI in clinically stable patients (NEJM 2006;355:2395-2407). In this population, assessment of myocardial viability should be performed prior to PCI.
    • Angioplasty of a totally occluded infarct-related artery may be considered in clinically unstable patients, those with rest angina, NYHA class III-IV HF, or those with multivessel disease.
  • Patients treated medically who experience complications of MI, including recurrent angina/ischemia, HF, significant ventricular arrhythmia, or a mechanical complication of the MI, should proceed directly to coronary angiography to define their anatomy and offer an appropriate revascularization strategy.
  • Special clinical situations
    • RVMI is seen in approximately 50% of patients with an acute inferior MI. Roughly half of these patients have hemodynamic compromise as a result of right ventricular involvement.
      • Clinical signs may include hypotension, cardiogenic shock, elevated jugular venous pulsation, Kussmaul sign (an increase in jugular venous pressures with inspiration), and right-sided third or fourth heart sounds. The lung fields are often clear in the absence of a large inferior infarct or MR.
      • Right precordial ECG leads should be obtained and analyzed for ST elevation (V4R is the most sensitive and specific lead and is transient).
      • P.145

      • LV filling pressures are typically normal or decreased, the right atrial pressures are elevated (>10 mm Hg), and the cardiac index is depressed. In some patients, elevated right atrial pressures may not be evident until IV fluids are administered.
      • Initial therapy is intravenous fluids. If hypotension persists, inotropic support with dobutamine and/or an intra-aortic balloon pump (IABP) may be necessary. Invasive hemodynamic monitoring is critical in the hypotensive patient as it guides volume status and the need for inotropic and mechanical support.
      • In patients with heart block and AV dyssynchrony, sequential AV pacing may have a marked beneficial effect.
    • ISR and stent thrombosis are disease entities unique to patients who have previously undergone coronary angioplasty. Risk factors for ISR and stent thrombosis can be found in Table 35.
      • ISR is a result of intimal hyperplasia and occurs within 6 to 9 months following balloon angioplasty and stent deployment. Progressive exertional angina is the typical presenting symptom. Prior to BMS, the incidence of target lesion restenosis 1 year following balloon angioplasty was 35% to 40%. BMS placement reduced the rate of angiographic restenosis to 20% to 30% and DES have further reduced the 1-year restenosis rate to 3% to 5%.
        • - DES placement is the treatment of choice for ISR. Several DES systems are available including paclitaxel (TAXUS), sirolimus (CYPHER), and everolimus (Xience) eluting stents. The TAXUS and CYPHER stents are the best studied and significantly reduce ISR rates (NEJM 2002;346:1773; NEJM 2003;349:1315; JAMA 2005;294:1215), with the CYPHER stent producing the lowest rates of lumen loss (JAMA 2006;295:895; Circulation 2006;114:2148). Early studies with the Xience stent have demonstrated improved results compared to the TAXUS stent (JAMA 2008;299:1903; Circulation 2009;119:680).
        • - Other proposed treatments for ISR including rotational atherectomy and brachytherapy produce inferior results compared to DES placement, and in the case of brachytherapy increase the risk of stent thrombosis (JAMA 2006;295: 1264; JAMA 2006;295:1253).
      • P.146

      • Stent thrombosis occurs with BMS or DES, and is due to poor endothelial repair. Stent thrombosis commonly presents either as an ACS or as sudden cardiac death. The etiology of stent thrombosis is based on the time from prior coronary intervention (JAMA 2005;293:2126; JACC 2009;53:1399).
        • - Acute stent thrombosis occurs within 24 hours and is due to mechanical procedural complications as well as inadequate anticoagulation and antiplatelet therapies.
        • - Subacute stent thrombosis (24 hours to 30 days) is a consequence of inadequate platelet inhibition and mechanical stent complications. Cessation of clopidogrel therapy during this time yields a 30- to 100-fold risk of stent thrombosis.
        • - Late (30 days to 1 year) and very late (greater than 1 year) stent thrombosis occur principally with DES and are associated with clopidogrel cessation (fourto sixfold increased risk) and resistance.
        • - Given the high mortality rate, the best treatment for stent thrombosis is prevention. In general, PCI with thrombus aspiration and repeat stent deployment is recommended. Screening for clopidogrel resistance and initiation of more potent antiplatelet regimens such as prasugrel or clopidogrel 150 mg in combination with cilostazol is warranted (JACC 2005;46:1833; Circulation 2009;119:3207).
    • Ischemic MR is a poor prognostic indicator following MI that most often presents with HF. It is associated with posterior infarcts and resultant posterior papillary muscle involvement. The presence of MR following MI significantly increases mortality (Ann Intern Med 1992;117:10; Am J Med 2006;119:103).
      • The mechanism of acute MR includes papillary muscle dysfunction or leaflet tethering due to posterior wall akinesis.
      • Progressive MR following MI may develop as a result of LV chamber dilation, apical remodeling, or posterior wall dyskinesis. These changes lead to leaflet tethering or mitral annular dilation.
      • Echocardiography is the diagnostic modality of choice. Ischemic MR is not always readily identified on physical exam and may have unusual characteristics due to the posteriorly directed regurgitant jet. TEE may be required to access the severity and mechanism of MR.
      • Initial treatment involves aggressive afterload reduction and revascularization. Stable patients should receive a trial of medical therapy and undergo surgery only if they fail to improve. Early surgical intervention is warranted for patients with severe ischemic MR and HF as well as those who are unlikely to benefit from revascularization.
    • STEMI in the setting of recent cocaine use presents a unique and challenging management situation (Circulation 2008;117:1897-1907). ST elevation can result from myocardial ischemia due to coronary vasospasm, in situ thrombus formation, and/or increased myocardial oxygen demand. The common pathophysiology is excessive stimulation of α- and β-adrenergic receptors. Chest pain due to cocaine use usually occurs within 3 hours, but may be seen several days following use.
      • Oxygen, aspirin, and heparin (UFH or LMWH) should be administered to all patients with cocaine-associated STEMI.
      • Nitrates should be used preferentially to treat vasospasm. Additionally, benzodiazepines may confer additional relief by decreasing sympathetic tone.
      • Selective β1-adrenergic blockers are contraindicated due to the potential for unopposed α-adrenergic activity.
      • P.147

      • Phentolamine (α-adrenergic antagonist) and calcium channel blockers may reverse coronary vasospasm and are recommended as second-line agents.
      • The use of reperfusion therapy is controversial and should be reserved for those patients whose symptoms persist despite initial medical therapy.
        • - Primary PCI is the preferred approach for the patient with persistent symptoms and ECG changes despite aggressive medical therapy. It is important to note that coronary angiography and intervention carry a significant risk of worsening vasospasm.
        • - Fibrinolytic therapy should be reserved for patients who are clearly having a STEMI who cannot undergo PCI.
Table 35 Risk Factors for ISR and Stent Thrombosis

ISR

Stent Thrombosis

Diabetes

Clopidogrel discontinuation

Chronic kidney disease

Clopidogrel resistance

Prior restenosis

Diabetes

Prior stent placed in the setting of ACS

Chronic kidney disease

Small luminal diameter (<2.5 mm)

Malignancy

Long lesion length

Prior brachytherapy

Proximal LAD lesion

Small luminal diameter (<3 mm)

Saphenous vein graft lesion

Long lesion length

Residual stenosis following prior intervention

Bifurcation lesion

Margin dissection

Incomplete wall apposition

Overlapping stents

ISR, in-stent restenosis; ACS, acute coronary syndrome; LAD, left anterior descending artery.

COMPLICATIONS
Complications following acute MI
Myocardial damage predisposes the patient to several potential adverse consequences and complications that should be considered if the patient experiences new clinical signs and/or symptoms. These include recurrent chest pain, cardiac arrhythmias, cardiogenic shock, and mechanical complications of MI.
  • Recurrent chest pain may be due to ischemia in the territory of the original infarction, pericarditis, myocardial rupture, or pulmonary embolism.
    • Recurrent angina is experienced by 20% to 30% of patients after MI who receive fibrinolytic therapy and up to 10% of patients in the early time period following percutaneous revascularization. These symptoms may represent recurrence of ischemia or infarct extension.
      • Assessment of the patient may include evaluation for new murmurs or friction rubs, ECG to assess for new ischemic changes, cardiac enzymes (troponin and CK-MB), echocardiography, and repeat coronary angiography if indicated.
      • Patients with recurrent chest pain should continue to receive ASA, clopidogrel, heparin, nitroglycerin, and β-adrenergic antagonist therapy.
      • If recurrent angina is refractory to medical treatment, repeat coronary angiography and intervention should be considered along with possible placement of an IABP.
    • Acute pericarditis occurs 24 to 96 hours after MI in approximately 10% to 15% of patients. The associated chest pain is often pleuritic and may be relieved in the upright position. A friction rub may be noted on clinical examination and the ECG may show diffuse ST-segment elevation. Treatment is directed at pain management.
      • Aspirin is generally considered a first-line agent. NSAIDs such as indomethacin (25 to 50 mg qid) may be used if aspirin is not effective.
      • Glucocorticoids (prednisone, 1 mg/kg daily) may be useful if symptoms are severe and refractory to initial therapy. Steroid use should be deferred until at least 4 weeks after acute MI due to their adverse impact on infarct healing and risk of ventricular rupture (Am Heart J 1981;101:750). Colchicine may be beneficial for recurrent symptoms.
      • Heparin should be avoided in the setting of pericarditis with or without effusion as it may lead to pericardial hemorrhage.
    • Dressler syndrome is thought to be an autoimmune process characterized by malaise, fever, pericardial pain, leukocytosis, elevated sedimentation rate, and often
      P.148

      a pericardial effusion. In contrast to acute pericarditis, Dressler syndrome occurs 1 to 8 weeks after MI. Treatment is identical to acute pericarditis.
  • Arrhythmias. Cardiac rhythm abnormalities are common following MI and may include conduction block, atrial arrhythmias, and ventricular arrhythmias. Arrhythmias that result in hemodynamic compromise require prompt, aggressive intervention. If the arrhythmia precipitates refractory angina or HF, urgent therapy is warranted. For all rhythm disturbances exacerbating conditions should be addressed, including electrolyte imbalances, hypoxia, acidosis, and adverse drug effects. (Details on specific arrhythmias can be found in Table 36.)
    • Transcutaneous and transvenous pacing. Conduction system disease that progresses to complete heart block or results in symptomatic bradycardia can be effectively treated with cardiac pacing. A transcutaneous pacing device can be used under emergent circumstances, and a temporary transvenous system can be used for longer-duration therapy.
      • Absolute indications for temporary transvenous pacing include asystole, symptomatic bradycardia, recurrent sinus pauses, complete heart block, and incessant VT.
      • Temporary transvenous pacing may also be warranted for new trifascicular block, new Mobitz II block, and for patients with LBBB who require a pulmonary artery catheter, given the risk of developing complete heart block.
    • Implantable cardioverter-defibrillators (ICDs) should not routinely be implanted in patients with reduced LV function following MI or those with ventricular tachycardia/fibrillation (VT/VF) in the setting of ischemia or immediately following reperfusion.
      • Routine insertion of ICDs into patients with reduced LV function immediately following MI does not improve outcomes (NEJM 2004;351:2481).
      • In contrast, patients who continue to have depressed LV function (EF <35%) greater than 1 month following MI benefit from ICD therapy (NEJM 2005;352: 225).
      • ICD therapy is also indicated for patients with recurrent episodes of sustained VT or VF despite coronary reperfusion.
  • Cardiogenic shock is an infrequent but serious complication of MI and is defined as hypotension in the setting of inadequate ventricular function to meet the metabolic needs of the peripheral tissue. Risk factors include prior MI, older age, diabetes, and anterior infarction. Organ hypoperfusion may manifest as progressive renal failure, dyspnea, diaphoresis, or mental status changes. Hemodynamic monitoring reveals elevated filling pressures (wedge pressure >20 mm Hg) and depressed cardiac index (<2.5 L/kg/min).
    • Patients with cardiogenic shock in the setting of MI have a mortality in excess of 50%. Such patients may require invasive hemodynamic monitoring and advanced therapeutic modalities including inotropic and mechanical support (Fig. 8).
    • Dobutamine is the inotrope of choice for patients with relatively preserved SBP (>90 mm Hg) as it both increases myocardial contractility and decreases ventricular afterload.
    • Dopamine is the preferred therapeutic agent in patients with an SBP less than 80 mm Hg. Addition of norepinephrine or phenylephrine may be required in markedly hypotensive patients (SBP <70 mm Hg).
    • Milrinone should be added in patients who are either not responding to dobutamine or who are experiencing excessive tachycardia in response to dobutamine. It should not be routinely used in patients with renal insufficiency.
    • P.149

      P.150

      P.151

    • Patients in whom contraindications do not exist should be considered for insertion of an IABP, as inotropes increase myocardial oxygen consumption and may worsen ischemia (Table 37).
    • All patients with cardiogenic shock should undergo echocardiography to evaluate for mechanical complications of MI (see below).
    • For patients who present with cardiogenic shock, an early revascularization strategy is superior to initial medical stabilization. This benefit did not extend to patients older than 75 years (NEJM 1999;341:625).
    • Select patients with refractory HF who fail to respond to inotropes and require prolonged mechanical support may be considered for either cardiac transplant or placement of a LV assist device (LVAD).
  • Patients with large anterior infarcts, documented LV thrombus, or chronic atrial fibrillation should receive continued anticoagulant therapy. Heparin (UFH or LMWH) can be used until a therapeutic INR of 2 to 3 is achieved.
    • Patients with anterior apical akinesis or documented LV thrombus as assessed by echocardiography at the time of discharge should receive Coumadin for 3 to 6 months unless other indications warrant its continued use. The dose of aspirin should be reduced to 81 mg to decrease bleeding risk.
    • If HIT develops, heparin should be discontinued immediately and anticoagulation performed with a direct thrombin inhibitor (bivalirudin or argatroban).
  • P.152

    P.153

  • Mechanical complications
    • Aneurysm. After MI, the affected area of the myocardium may undergo infarct expansion and thinning, forming an aneurysm. The wall motion may become dyskinetic, and the endocardial surface is at risk for mural thrombus formation.
      • LV aneurysm is suggested by persistent ST elevation on the ECG and may be diagnosed by imaging studies including ventriculography, echocardiography, and MRI.
      • Anticoagulation is warranted to lower the risk of embolic events, especially if a mural thrombus is present (see above).
      • Surgical intervention may be appropriate if the aneurysm results in HF or ventricular arrhythmias that are not satisfactorily managed with medical therapy.
    • Ventricular pseudoaneurysm. Incomplete rupture of the myocardial free wall can result in formation of a ventricular pseudoaneurysm. In this case, blood escapes through the myocardial wall and is contained within the visceral pericardium. In the post-CABG patient, hemorrhage from frank ventricular rupture may be contained within the fibrotic pericardial space producing a pseudoaneurysm.
      • Echocardiography (TTE with contrast or TEE) is the preferred diagnostic test to assess for a pseudoaneurysm, often allowing differentiation from a true aneurysm.
      • Prompt surgical intervention for pseudoaneurysms is advised because of the high incidence of myocardial rupture.
    • Free wall rupture represents a catastrophic complication of acute MI accounting for 10% of early deaths. Rupture typically occurs within the first week after MI and presents with sudden hemodynamic collapse. This complication can occur after anterior or inferior MI but is more commonly seen in hypertensive women with a first-large transmural MI, treated late with fibrinolytic therapy, and given NSAIDs or glucocorticoids.
      • Echocardiography may identify patients with particularly thinned ventricular walls at risk for rupture.
      • Pericardiocentesis and intra-aortic balloon pump support may be necessary for patients awaiting emergent surgical correction.
      • Despite optimal intervention, mortality of free wall rupture remains greater than 90%.
    • P.154

    • Papillary muscle rupture is a rare complication after MI and is associated with abrupt clinical deterioration. The posterior medial papillary muscle is most commonly affected due to its isolated vascular supply, but anterolateral and right ventricular papillary rupture have been reported. Of note, papillary muscle rupture may be seen in the setting of a relatively small MI.
      • The diagnostic test of choice is echocardiography with Doppler imaging as physical exam reveals a murmur in only ~50% of cases.
      • Initial medical therapy should include aggressive afterload reduction. Patients with refractory HF and those with hemodynamic instability may require inotropic support with dobutamine and/or intra-aortic balloon counterpulsation. Surgical repair is indicated in the majority of patients.
    • Ventricular septal rupture (or defect) formation is most commonly associated with anterior MI. The perforation may follow a direct course between the ventricles or a serpiginous route through the septal wall.
      • Diagnosis can be made by echocardiography with Doppler imaging and often requires TEE.
      • Diagnosis should be suspected in the postinfarct patient who develops HF symptoms and a new holosystolic murmur.
      • Stabilization with afterload reduction, inotropic support, and/or intra-aortic balloon pump may be necessary for hemodynamically unstable patients until definitive therapy with surgical repair can be performed.
      • In hemodynamically stable patients, surgery is best deferred for at least a week to improve patient outcome. Left untreated, mortality approaches 90%.
      • Percutaneous device closure in the cardiac catheterization laboratory can be performed on a compassionate basis in select patients with an unacceptable surgical risk.
Table 36 Arrhythmias Complicating MI

Arrhythmia

Treatment

Comments

Intraventricular conduction delays

None

The left anterior fascicle is most commonly affected because of isolated coronary blood supply.

Bifascicular and trifascicular block may progress to complete heart block and other rhythm disturbances.

Sinus bradycardia

None

Sinus bradycardia is common in patients with RCA infarcts.

Atropine 0.5 mg

Temporary pacinga

In the absence of hypotension or significant ventricular ectopy, observation is indicated.

AV block

Temporary pacinga

First-degree AV block usually does not require specific treatment.

Mobitz I second-degree block occurs more often with inferior MI. The block is usually within the His bundle and does not require treatment unless symptomatic bradycardia is present.

Mobitz II second-degree AV block originates below the His bundle and is more commonly associated with anterior MI. Because of the significant risk of progression to complete heart block, patients should be observed in the CCU and treated with temporary pacing if symptomatic.

Third-degree AV block complicates large anterior and RV infarcts. In patients with anterior MI, third-degree heart block often occurs 12-24 hr after initial presentation and may appear suddenly. Temporary pacing is recommended because of the risk of progression to ventricular asystole.

Sinus tachycardia

Noneb

Sinus tachycardia is common in patients with acute MI and is often due to enhanced sympathetic activity resulting from pain, anxiety, hypovolemia, anxiety, heart failure, or fever.

Persistent sinus tachycardia suggests poor underlying ventricular function and is associated with excess mortality.

Atrial fibrillation and flutter

β-Blockers

Atrial fibrillation and flutter are observed in up to 20% of patients with acute MI.

Anticoagulation

Cardioversion

Because atrial fibrillation and atrial flutter are usually transient in the acute MI period, long-term anticoagulation is often not necessary after documentation of stable sinus rhythm.

Accelerated junctional rhythm

None

Accelerated junctional rhythm occurs in conjunction with inferior MI. The rhythm is usually benign and warrants treatment only if hypotension is present. Digitalis intoxication should be considered in patients with accelerated junctional rhythm.

Ventricular premature depolarizations (VPDs)

β-Blockers if symptomaticc

VPDs are common in the course of an acute MI.

Prophylactic treatment with lidocaine or other antiarrhythmics has been associated with increased overall mortality and is not recommended (NEJM 1989; 321:406).

Accelerated idioventricular rhythm (AIVR)

None

Commonly seen within 48 hr of successful reperfusion and is not associated with an increased incidence of adverse outcomes.

If hemodynamically unstable, sinus activity may be restored with atropine or temporary atrial pacing.

Ventricular tachycardia (VT)

Cardioversion for sustained VT

Nonsustained ventricular tachycardia (NSVT, <30 sec) is common in the first 24 hr after MI and is only associated with increased mortality when occurring late in the post-MI course.

Lidocaine or amiodarone for 24-48 hrd

Sustained VT (>30 sec) during the first 48 hr after acute MI is associated with increased in-hospital mortality.

Ventricular fibrillation (VF)

Unsynchronized cardioversion

VF occurs in up to 5% of patients in the early post-MI period and is life threatening.

Lidocaine or amiodarone for 24-48 hrd

a Atropine and temporary pacing should only be used for symptomatic or hemodynamically unstable patients.

b The use of β-blockers in the setting of sinus tachycardia and poor LV function may result in decompensated heart failure.

c β-Blockers should be used with caution in the setting of bradycardia and frequent VPDs as they may increase the risk of polymorphic VT.

d Lidocaine should be used as a 1 mg/kg bolus followed by a 1 to 2 mg/kg/hr infusion. Amiodarone should be given as a 150 to 300 mg bolus followed by an infusion of 1 mg/kg/hr for 6 hours and then 0.5 mg/kg/hr for 18 hours.

Figure 8. Recommended diagnostic and therapeutic strategy for patients presenting with STEMI and cardiogenic shock. 1PCI may be preferable if CABG cannot be readily performed or if surgery imposes unacceptable risk. 2Advanced heart therapy modalities including percutaneous LV assist devices (TandemHeart, Impella), external ventricular assist devices, and extracorporeal membrane oxygenation (ECMO) may be required prior to placement of a permanent LVAD or cardiac transplant. PCI, percutaneous coronary intervention; WMA, wall motion abnormality; TEE, transesophageal echocardiography; IABP, intra-aortic balloon counterpulsation; LVAD, left ventricular assist device; CABG, coronary artery bypass graft.
Table 37 Intra-Aortic Balloon Counterpulsation

Indications

Contraindications

Monitoring

Cardiogenic shock, pump failure
Papillary muscle rupture
Severe ischemic mitral regurgitation
VSD
Facilitation of unprotected left main and LAD angioplasty or CABG
Complex PCI with severe underlying CAD

Aortic insufficiency
Severe peripheral vascular disease
Systemic infection, sepsis

Daily chest x-ray, platelet count, and creatinine
Regular evaluation of lower extremity pulses
Heparin infusion (PTT)

VSD, ventricular septal defect; LAD, left anterior descending artery; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.

MONITORING/FOLLOW-UP
Routine office visits 1 month after discharge and every 3 to 12 months thereafter are suggested for the patient presenting with an acute MI.
  • Patients should be instructed to seek more frequent or urgent follow-up evaluation if they experience any noticeable change in their clinical status.
  • Specific plans for long-term follow-up care should be individualized based upon clinical status, anatomy, prior interventions, and change in symptoms.
  • A stress imaging study is appropriate for patients who have a significant change in clinical status (either HF or angina). Routine testing is not warranted in patients without change in clinical status or in those with an estimated annual mortality (by prior risk assessment) of <1%.
  • Coronary angiography should be considered for patients with significant ischemic burden on stress testing that is potentially amenable to revascularization or those with marked limitations of ordinary activity despite maximal medical therapy.



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