syndrome; CAD, coronary artery disease; CABG, coronary artery bypass graft; CK, creatinine; ECG,
electrocardiogram; PCI, percutaneous intervention; NSTE-ACS, non-ST segment acute coronary syndrome;
in acute coronary syndromes. In: Richardson M et al, eds. Pharmacotherapy Self-Assessment Program.
Cardiology. 7th ed. Lenexa, KS: American College of Clinical Pharmacy; 2010:62.)
lateral ECG leads and are opposite the inferior leads.
the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50(7):e1–e157.)
The examination of a patient presenting with ACS begins with stratification for the
risk of death and reinfarction, taking into account the presenting signs and symptoms,
past medical history, ECG and cardiac biomarker changes. Patients can be stratified
into low, medium, or high risk for mortality, and the need for urgent coronary
angiography and PCI (Fig. 13-2). In 1967, Killip and Kimball introduced a useful,
convenient tool for early risk stratification for patients with STEMI. Higher Killip
class was found to be associated with increased in-hospital and 1-year mortality
14 The Thrombolysis in Myocardial Infarction (TIMI) risk score was
introduced in 2000 and can be used with either STEMI or NSTE-ACS (Table 13-
15,16 For STEMI, a higher risk score indicates a greater 30-day mortality rate.
Patients with STEMI are at the highest risk of death and reinfarction, and initial
treatment should proceed with immediate revascularization regardless of their risk
stratification score. “Time is tissue,” means the sooner the thrombosed artery is
opened, the lower the morality and greater amount of myocardium preserved.
Reperfusion therapy should be initiated in all eligible patients with STEMI with
symptom onset within the prior 12 hours. Primary PCI is the recommended method of
reperfusion. The ACC/AHA guidelines define a target time to initiate reperfusion for
STEMI within 30 minutes of hospital presentation for fibrinolytic therapy and within
90 minutes from presentation for PCI.
In the case of NSTE-ACS, a TIMI risk score of 5 to 7, 3 to 4, and 0 to 2 reflect a
high, moderate, and low risk for death, MI, or need for urgent coronary artery
revascularization, respectively (Table 13-1). A low-risk patient with negative
cardiac biomarkers may undergo a stress test or be discharged from the ED with a
diagnostic test scheduled within 72 hours. Moderate and high-risk patients are often
admitted to the hospital for pharmacologic treatment, further diagnostic tests, and
angiography with possible intervention. Additional risk stratification tools such as
the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using
Integrilin Therapy (PURSUIT) risk score and Global Registry of Acute Cardiac
Events (GRACE) risk score exist for in-hospital and 1-year morality.
scores are available to predict bleeding in patients with ACS.
The primary complications of ACS can be divided into three major groups: pump
failure, arrhythmias, and recurrent ischemia and reinfarction. Depression of cardiac
function after AMI is related directly to the extent of LV damage. As a result of
decreased cardiac output and decreased perfusion, a number of compensatory
mechanisms become activated. The levels of circulating catecholamines increase in
an attempt to increase contractility and restore normal perfusion. In addition, the
renin-angiotensin-aldosterone system is enhanced, leading to an increase in systemic
vascular resistance and sodium and water retention. These compensatory mechanisms
can eventually worsen the imbalance between myocardial oxygen supply and
consumption by increasing the myocardial oxygen demand.
Risk Stratification Tools for Acute Coronary Syndrome
Risk Factor No. of Points Risk Factor No. of Points
Age 65–74 years 2 Age ≥ 65 years 1
Age ≥ 75 years 3 ≥3 risk factors for CAD
SBP < 100 mm Hg 3 Prior history of CAD
2 Aspirin use in past 7 days 1
Killip class II–IV 2 ≥2 anginal events in past 24 hours 1
Weight < 67 kg 1 ST segment deviation ≥ 0.5 mm 1
1 Elevation of cardiac markers
Class Symptoms In-Hospital and 1-Year Mortality (%)
II Mild heart failure, rales, S3
2, 3 to 4, and 5 to 7 represent low, moderate, and high risk for death or repeat MI at 14 days.
imaging or echocardiographic changes required if female).
dEither troponin I or T or creatine kinase-MB.
year experience with 250 patients. Am J Cardiol. 1967;20:457.
CAD, coronary artery disease; HTN, hypertension; NSTE-ACS, non–ST segment elevation acute coronary
Signs and symptoms of HF are common in patients who have abnormal wall
motion affecting 20% to 25% of the LV. If 40% or more of the LV is damaged,
cardiogenic shock and death may occur. Ischemia and scar formation after an AMI
may lead to a decrease in ventricular compliance, resulting in abnormally high LV
filling pressures during diastole. (See Chapter 14, Heart Failure, for further
discussion on HF with reduced ejection fraction and preserved ejection fraction.)
Decreased contractility and a compensatory increase in LV end-diastolic volume
and pressure lead to increased wall stress within the left ventricle. LV enlargement is
an important determinant of mortality after AMI. During a period of days to months
after an AMI, the infarcted area may expand as a result of dilatation and thinning of
the LV wall. These changes are known as ventricular remodeling. In addition,
hypertrophy of the noninfarcted myocardium occurs. Administration of oral
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers
(ARBs), or aldosterone antagonists may limit remodeling and will attenuate the
During the peri-infarction period, the heart is irritable and subject to ventricular
arrhythmias. The continuous monitoring of patients in a coronary care unit has
reduced the in-hospital mortality rate related to ventricular arrhythmias. However,
patients who have had an AMI have an increased risk of sudden cardiac death for 1
to 2 years after hospital discharge. The most important predictor for sudden cardiac
death is an abnormal LV ejection fraction (LVEF). Other factors associated with an
increased risk for sudden cardiac death are complex ventricular ectopy, frequent
(>10/hour) premature ventricular complexes, and the identification of late potentials
OVERVIEW OF DRUG AND NONDRUG THERAPY
Overlap exists regarding the pharmacotherapy for both STEMI and NSTE-ACS.
According to the ACC/AHA guidelines, early therapies should consist of oxygen (if
oxygen saturation is <90%), sublingual
(SL) and/or intravenous (IV) nitroglycerin (NTG), IV morphine, ACE inhibitor or
ARB, aldosterone antagonist, antiplatelet agents, stool softener, β-blocker, statin, and
anticoagulant. Adjunctive therapies such as analgesics and vasodilators can also be
considered in selected patients. Table 13-2 summarizes the evidence-based
pharmacotherapies for both STEMI and NSTE-ACS. Figure 13-5 provides an initial
treatment algorithm for patients with STEMI, and Figure 13-6, for patients with
NSTE-ACS. Administration of these pharmacotherapies serves as a performance
measure for health systems to ensure effective, timely, safe, and efficient patientcentered care.
Because the majority of STEMI cases result from the sudden occlusion of a coronary
artery, the priority is to open the occluded artery as quickly as possible. This is
accomplished by administering a fibrinolytic agent that enhances the body’s own
fibrinolytic system or by mechanically reducing the obstruction with PCI.
Large clinical trials have proven that administration of a fibrinolytic agent reduces
mortality. Early mortality from STEMI was reduced by approximately one-third
(from 10%–15% to 6%–10%) with fibrinolytic therapy.
The fibrinolytic drugs currently used for STEMI patients in the United States are
alteplase (t-PA), reteplase (r-PA), and tenecteplase (TNK). Alteplase is a naturally
occurring enzyme produced by recombinant DNA technology. It cleaves the same
plasminogen peptide bond that urokinase cleaves. However, t-PA has a binding site
for fibrin, which allows it to bind to and preferentially lyse thrombin-bound instead
of circulating plasminogen. Reteplase is a genetically modified plasminogen
activator that is similar to t-PA. Reteplase has a longer half-life, allowing it to be
administered as two bolus injections 30 minutes apart, rather than as a bolus plus
infusion. TNK is a genetically modified form of t-PA. Compared with t-PA, TNK has
a longer plasma half-life, better fibrin specificity, and higher resistance to inhibition
by plasminogen-activator inhibitor.
21,22 The pharmacologic properties and dosing
regimens are compared in Table 13-3.
Unfortunately, an ideal fibrinolytic agent does not exist. Three problems common
to all fibrinolytic drugs are the inability to open 100% of coronary artery occlusions,
inconsistent ability to maintain good blood flow in the infarcted artery after it is
opened, and bleeding complications. When assessing coronary artery flow after
reperfusion therapy, the TIMI flow grade is used. Flow in coronary arteries is
classified as grade 0 (no flow), grade 1 (penetration without perfusion), grade 2
(partial perfusion), or grade 3 (complete perfusion).
23 When assessing an episode of
bleeding, the TIMI bleeding criteria are used. TIMI major bleeding consists of overt
clinical bleeding or documented intracranial or retroperitoneal hemorrhage that is
associated with a drop in hemoglobin of at least 5 g/dL or hematocrit of at least 15%
(absolute). TIMI minor bleeding is defined as overt clinical bleeding associated with
a fall in hemoglobin of 3 to 5 g/dL or in hematocrit of 9% to 15% (absolute).
To minimize the risk of bleeding complications, contraindications to the use of
fibrinolytic drugs must be evaluated before administration (Table 13-4). There are
relatively few absolute contraindications to fibrinolytic therapy, but each patient
should be assessed carefully to ascertain whether the potential benefit outweighs the
potential risk. Because of the serious nature of intracerebral hemorrhage, patients
should be selected carefully before receiving these agents. Generally, the diagnosis
of STEMI must be ensured, with a history consistent with ischemia, and presence of
ST segment elevation in two contiguous leads, or a new left bundle branch block on
the ECG. Once the diagnosis is made, the fibrinolytic agent should be administered
immediately if there are no contraindications.
Fibrinolytic therapy is indicated in patients with STEMI who present to the
hospital within 12 hours of symptom onset and are unable to undergo primary PCI
within 120 minutes from first medical contact.
5 The benefit derived from fibrinolytic
therapy is directly related to the time from the onset of chest pain to the time of
administration. Although the guidelines recommend initiation within 12 hours from
the onset of chest pain, data from clinical trials suggest that mortality reduction is
greater when fibrinolytic therapy is initiated within 0 to 2 hours of symptom onset
compared with treatment initiated more than 2 hours after symptoms have begun. The
guidelines recommend a “door-to-needle time” of 30 minutes, meaning the diagnosis
of STEMI and initiation of fibrinolytic therapy should ideally take place within 30
minutes from the time the patient arrives at the hospital door. Once stabilized, the
patient should be transferred to a facility capable of PCI in case reperfusion fails or
In patients with NSTE-ACS, fibrinolytic agents are not recommended. Thrombi in
this population are primarily platelet-rich rather than fibrin-rich, and less responsive
25 Additionally, data from the TIMI IIIB trials suggest that
compared with placebo, alteplase was not associated with any improvement in death,
MI, or failure of initial therapy and was associated with an increased incidence in
Antiplatelet and Anticoagulant Drugs
When thrombolysis occurs, whether because of the administration of a fibrinolytic
agent or through activation of the body’s own fibrinolytic system, the fibrin clot
begins to disintegrate. As the clot dissolves, there is a paradoxical increase in local
thrombin generation and enhanced platelet aggregability, which may lead to
rethrombosis. Antiplatelet agents (aspirin, P2Y12
receptor antagonists: clopidogrel,
prasugrel, or ticagrelor, and the glycoprotein [GP] IIb/IIIa inhibitors), as well as
parenteral anticoagulants (unfractionated heparin [UFH], low-molecular-weight
heparins [LMWH] such as enoxaparin, and direct thrombin inhibitors [DTIs] such as
bivalirudin), have been used to minimize rethrombosis. UFH has several limitations,
including a highly variable anticoagulant effect necessitating frequent monitoring and
development of heparin-induced thrombocytopenia (<0.2%). LMWH may offer
advantages compared with heparin owing to its ease of administration, improved
bioavailability, and need for less monitoring. Unlike UFH, the DTIs offer better
protection against thrombin reactivation after therapy discontinuation.
The GP IIb/IIIa receptor inhibitors, which are tirofiban, eptifibatide, and
abciximab are also used. Glycoprotein IIb/IIIa receptors are abundant on the platelet
surface. Platelets become activated when patients are having an acute ischemic event
or are undergoing PCI. With platelet activation, the GP IIb/IIIa receptor undergoes a
conformational change that increases its affinity for binding fibrinogen. The binding
of fibrinogen to receptors on platelets results in platelet aggregation, leading to
thrombus formation. The GP IIb/IIIa receptor inhibitors prevent platelet aggregation
by preventing fibrinogen from binding to GP IIb/IIIa receptor sites on activated
Acute thrombocytopenia is a rare but recognized side effect of all three agents, but
seen more often with abciximab.
27 The GP IIb/IIIa inhibitors are used in conjunction
with other antiplatelet drugs and anticoagulants in patients with NSTE-ACS and in
patients undergoing PCI. Although effective when used in conjunction with
fibrinolytic agents for patients with STEMI, the benefit is offset by high rates of
bleeding. Therefore, routine use of GP IIb/IIIa inhibitors is not recommended with
Evidenced-based Pharmacotherapies for Acute Coronary Syndromes
Drug Indication Dose and Duration
End Points Precautions Comments
administer an IV βblocker at the time of
contraindications to βblockade (PR interval >
Usual doses of calciumchannel blockers are
invasive or ischemiaguided strategy: 300–600
invasive or ischemiaguided strategies: 1 mg/kg
invasive or ischemiaguided strategies:
intermediate/highrisk features.
See Table 13-6. Avoid with active
invasive or ischemiaguided strategies:
or adequate antiischemic therapy.
invasive or ischemiaguided strategy: 180 mg
invasive or ischemiaguided strategies for at
1 tablet (2.08 mg) daily. Contraindicated
intravenous; LMWH, low-molecular-weight heparin; MI, myocardial infarction; NSAIDs, nonsteroidal
Indicates specific drug therapies that are known to reduce morbidity or mortality.
, oxygen; PCI, percutaneous coronary intervention; SL, sublingual; STEMI, ST segment elevation
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