Understanding ACS

Table of Contents

• Etiology of Acute Coronary Syndromes
• Initial Evaluation
• Risk Stratification
• Cardiac Biomarkers
• Therapeutics
  • Anti-Thrombotic Treatment
  • Other Treatments
• Exercise Testing in Acute Coronary Syndrome
• Special Circumstance: Cocaine Induced
  

ETIOLOGY OF ACUTE CORONARY SYNDROMES

By Ashish Aneja, MD
Acute coronary syndromes: unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI).

UA/NSTEMI

UA and NSTEMI are caused by a similar pathophysiologic mechanism in the setting of underlying coronary artery disease (CAD). The salient feature distinguishing the 2 conditions is evidence of cardiac bionecrosis, usually measured by elevation in cardiac troponin levels in NSTEMI patients. Once identified, these conditions categorize patients at a markedly elevated risk of future adverse cardiovascular events. Electrocardiographic (ECG) changes such as ST-segment depressions or T-wave inversions are frequently seen in patients with both UA and NSTEMI, and their presence is usually associated with a worse prognosis. Some patients presenting with symptoms typical of ACS do not present with ECG changes and are identified only by elevated markers of myocyte necrosis. All acute coronary syndromes including UA and NSTEMI result from rupture of a vulnerable atherosclerotic plaque. This leads to an intense local prothrombotic state because of release tissue factor and other platelet aggregatory factors, bringing about variable degrees of platelet aggregation that eventually results in impaired or coronary vascular flow.1 The reduction in coronary flow and the resulting ACS type depends on the degree of coronary occlusion. A completely occlusive thrombus usually results in transmural ischemia and often causes ST elevation to appear on the ECG. If sustained long enough, it often results in ST-elevation myocardial infarction. If spontaneous recanalization or incomplete occlusion results, either UA or NSTEMI occurs. Most patients with ST-segment elevation ultimately develop a Q-wave MI (QwMI), although a few develop a non-Q-wave MI (NQwMI). Transient ST elevation without evidence of myocardial necrosis usually indicates coronary vasospasm induced by CAD, usually in the vicinity of an atherosclerotic plaque, and is termed Prinzmetal’s angina. Cocaine use infrequently results in ST elevation because of severe coronary vasospasm. In rare instances, persistent ST-segment elevation results from dyssynchronous myocardial motion in a previously infarcted myocardial segment or from the presence of a ventricular aneurysm. On the other hand, most patients presenting with NSTEMI ultimately develop a non-Q-wave MI that appears on the ECG. Coronary thrombus eventually undergoes resorption or is followed by smooth muscle cell growth and collagen deposition.²

Unstable angina and NSTEMI usually result from reduction of myocardial oxygen supply. Platelet aggregate microembolization and disrupted plaque components result in the release of myocardial markers in many of these patients. Some patients with a completely occluded epicardial coronary vessel do not develop ST elevation because of an alternative supply from collateral vessels. Arterial inflammation and endothelial dysfunction resulting from the insult of common risk factors such as hyperlipidemia and cigarette smoking attracts lipid-laden macrophages under the arterial intima, leading to the development of atherosclerotic plaque. The plaque enlarges in size because of the growth of vasa vasorum and the further accumulation of lipids. The vasa vasorum walls occasionally get eroded because of the high local concentration of matrix metalloproteinases releasing blood and blood products into the soft plaque, leading to plaque expansion and an aggravated inflammatory response because of the blood products. Activated macrophages and T lymphocytes at the edge of a plaque increase the expression of enzymes such as metalloproteinases that cause thinning and disruption of the plaque, which in turn can lead to UA/NSTEMI.

Less commonly, the restriction to coronary flow is dynamic. Prinzmetal’s angina, discussed above, is among the more common causes of dynamic flow obstruction resulting from coronary vascular smooth muscle contraction and spasm. Small vessel dysfunction is occasionally responsible for symptoms of unstable angina and is the result of endothelial dysfunction in vessels coursing through the myocardial wall.

A fixed or worsening narrowing of an epicardial coronary vessel can occasionally result in symptoms of unstable angina. The most common causes include progression of native atherosclerosis or narrowing or stenosis following a percutaneous coronary intervention with or without stent deployment.

The term secondary unstable angina is used when patients with or without significant coronary stenoses develop conditions that either increase myocardial oxygen demand or redyce oxygen supply to the myocardium. Common examples include hyperdynamic states such as fever, tachyarrhythmias, hyperthyroidism, and significant reduction in coronary perfusion pressure from hypotension or reduced oxygen delivery from hypoxemia or severe anemia. The causes of UA/NSTEMI are not mutually exclusive, and NSTEMI can be considered a more severe manifestation of UA.

Risk factors for CHD: The major risk factors for developing CHD are smoking, family history, adverse lipid profiles, diabetes mellitus, and elevated blood pressure. These factors have been validated and well established from large, long-term epidemiological studies and can explain the development of coronary atherosclerosis and acute coronary syndromes in most cases.^3,4

Finally, pregnant and peripartal women occasionally develop coronary dissection that leads to UA or NSTEMI. A more common cause of coronary dissection is percutaneous balloon angioplasty. The treatment of coronary dissection in the setting of percutaneous coronary intervention usually consists of stent deployment.

STEMI

Patients presenting with persistent ST-segment elevation are candidates for prompt reperfusion therapy (either pharmacological or catheter based) to restore flow promptly in the occluded epicardial infarct-related artery because delays in revascularization therapy are associated with lesser degrees of myocardial salvage. A key feature following STEMI is ventricular remodeling, a term that refers to changes in size, shape, and thickness of the left ventricle involving both the infarcted and noninfarcted segments of the ventricle. The degree of ventricular remodeling depends on the degree of myocardial involvement, which in turn depends on the type of vessel occluded and the duration of the occlusion.^5,6 Acute dilatation and thinning of the area of infarction that is not a result of additional myocardial necrosis is referred to as infarct expansion.7 If a significant portion of the myocardium becomes necrotic, the residual functioning myocardium responds to this extra stress by undergoing compensatory hypertrophy. The rennin–angiotensin–aldosterone system, which likely plays a key role in development of this remodeling, is an important therapeutic target following STEMI, especially those with significant myocardial involvement.⁸ Additional important pathophysiological concepts in patients with STEMI include cardiac arrhythmia, pump failure/excessive sympathetic stimulation, and conduction disturbance. Mechanical problems that result from dysfunction or disruption of critical myocardial structures (eg, mitral regurgitation [MR], rupture of the interventricular septum, ventricular aneurysm formation, and free-wall rupture) often require a combination of pharmacological, catheter-based, and surgical treatments.

References

1. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69-e171.
2. National Heart Attack Alert Program. Emergency department: rapid identification and treatment of patients with acute myocardial infarction. U.S. Department of Health and Human Services. U.S. Public Health Service. National Institutes of Health. National Heart, Lung and Blood Institute; September 1993; NIH Publication No. 93-3278.
3. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
4. Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age Circulation. 2006;113:791-798.
5. Braunwald E, Pfeffer MA. Ventricular enlargement and remodeling following acute myocardial infarction: mechanisms and management. Am J Cardiol. 1991;68:1D-6D.
6. Pfeffer MA. Left ventricular remodeling after acute myocardial infarction. Annu Rev Med. 1995;46:455-466.
7. Weisman HF, Healy B. Myocardial infarct expansion, infarct extension, and reinfarction: pathophysiologic concepts. Prog Cardiovasc Dis. 1987;30:73-110.
8. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001;345:1689-1697.

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Initial Evaluation of Patients with Suspected ACS

Evaluation of the UA and NSTEMI Patient

Over the years few diagnostic challenges exist in the Emergency Room with a frequency and associated morbidity/mortality remotely comparable to the chest pain patient. Prudent ER physicians have become extremely mindful of patients with an unstable or potentially unstable cardiac presentation. Ultimately, endeavors which optimize the healthcare dollar while reducing the patient’s risk to a minimum forms the basis for establishing sensible, cost-effective algorithms and hospital order sets.

Patients presenting to the emergency room with an ST-elevation MI have certainly been addressed with appropriate treatment policies in most hospital emergency rooms across the country. However, far fewer decision-making models and algorithms exist for risk-stratifying patients presenting with an unspecified chest pain, unstable angina or Non-STEMI. Establishing a protocol which acknowledges important prognostic indicators will likely result in less hospital and/or managed care expense and a greater likelihood of a successful conclusion for these patients.

With more than 5.6 million emergency room visits each year in the United States for chest pain, second only to abdominal pain as the most common reason for an ER visit. Approximately 1.7 million are hospitalized for an acute coronary syndrome and 600,000 die due to an acute myocardial infarction. Approximately 1- 4% of patients with an acute MI are mistakenly discharged from the ER. Patients with atypical symptoms and chest pain free are the most likely discharged, with about 25% of these patients discharged home because of an ECG misinterpretation. ^1-3

There are basic categories and gradations of chest pain or anginal equivalents as follow:

• Classic or typical angina is a deep, poorly localized chest or arm discomfort exacerbated by physical exertion or emotional stress and relieved promptly with rest or nitroglycerin. The chest pain typically lasts less than five minutes and may radiate to the neck, jaw, shoulder or arms. Dyspnea with classical angina suggests an accompanying left ventricular or valvular dysfunction.
• Atypical chest pain is a chest discomfort not precipitated by exercise, relieved by rest or responsive to nitroglycerin and may be fleeting or last for many minutes.
• Silent Ischemia occurs when the patient is asymptomatic but has evidence on electrocardiogram or imaging of ischemia.
• Anginal equivalents such as jaw, neck, ear, arm, shoulder, back or epigastric pain may occur in the absence of a chest pain complaint. New or worsened exertional dyspnea is another anginal equivalent, along with nausea and vomiting, diaphoresis or unexplained fatigue, is more commonly seen in the elderly population as obscure indicators of a cardiac event.
• Unstable angina may present as prolonged angina at rest, new-onset angina that is severe, prolonged or frequent or as an established angina that has become distinctly more frequent, longer in duration or more easily provoked. There are certain features in the unstable anginal patient that increases their risk for acute MI or death. These indicators include prolonged angina at rest greater than twenty minutes, patient’s age greater than 65 years, pulmonary edema and hypotension.
• Unspecified chest pain patients often presents themselves as an enigma. These patients are usually considered at low cardiac risk based on a paucity of established risk factors and have complaints uncharacteristic for myocardial ischemia. Such complaints might include pleuritic-type chest pain that is accentuated by inspiration and cough, pain reproduced by movement and palpation of the chest wall and chest pain episodes that are very brief, lasting only a few seconds or less. These patients are typically “ruled out” with an ER or short hospitalization stay, with a prudent hospitalist or cardiologist often providing or arranging a treadmill or other stressing prior to discharge or in early follow-up, especially in those patients without a prior/recent cardiac work-up.

The ECG is instrumental in the patient's initial evaluation. Positive biomarkers are diagnostic of acute myocardial infarction in more than 90% of patients with a ST-segment elevation of greater than or equal to 1mm in at least two contiguous leads. Also of importance are transient ST-segment changes of 0.5 mm or more that occur during symptoms and resolve when the patient becomes asymptomatic. Such findings strongly suggest acute ischemia and a higher likelihood of underlying severe-grade coronary artery disease. Patients with a ST-segment depression are initially considered to have NSTEMI or UA, based on the presence or absence of positive cardiac biomarkers respectively. ⁴ There are other causes of ST-segment changes. For example, LV aneurysm, pericarditis, myocarditis, Prinzmetal's angina, early repolarization, Takotsubo cardiomyopathy and WPW syndrome might also cause a ST-segment elevation.

Inverted T-waves can also indicate UA or NSTEMI. Of particular importance, T-waves inverted 2 mm or more in the precordial leads strongly suggest acute ischemia involving the left anterior descending coronary artery. ⁵ Patients with a lesion in the distribution of the left anterior descending artery often demonstrate hypokinesis of the anterior wall on echocardiogram and are at high risk if given medical treatment alone. ⁶ Revascularization often reverses T-wave inversion in the anterior precordial leads and observed hypokinesis. ⁷ Other causes of deep T-wave inversion include drug therapy with phenothiazines and tricyclic antidepressants.

There are other portions of the heart when infarcted or in jeopardy which might not be reflected in a standard 12 lead ECG. For example, an acute MI due to occlusion of the left circumflex coronary artery is notorious in presenting with a non-diagnostic 12 lead ECG. Right ventricular infarcts may manifest ST-segment changes in the V4R through V6R leads, whereas the posterior infarct might be revealed by the "posterior leads" V7 through V9. A clue to a posterior MI might be seen by a ST-segment depression on leads V1 and V2. When present, identifying a posterior ST-segment elevation myocardial infarction on leads V7-V9 allows an opportunity to consider acute reperfusion therapy when it’s appropriate to do so and the opportunity not overlooked. ⁸

One of the earliest decisions often confronted by the hospitalist with the unstable angina and non-ST elevation MI (UA/NSTEMI) patient is determining whether a course of conservative or invasive management is to be followed. This is a particularly key step since the cardiologist should be consulted early in the patient’s hospital course if angiography is being contemplated. Advocates of early conservative measures argue angiography and its associated risks can be avoided in low risk patients and economic resources can be reserved for those who would most likely benefit by such procedures. Alternatively, proponents of an early invasive strategy point out that critical left main coronary artery disease and triple-vessel coronary disease can be identified with an early invasive procedure while other patients with low-risk coronary artery anatomy can be provided shorter hospital stays, of particular interest in the managed care environment.

Angina is most frequently caused by atherosclerosis of the coronary arteries. Less common causes for angina include coronary artery spasm, embolism, dissection, arteritis and anomalies. The right coronary artery might be involved in cases of aortic dissection. Angina may also occur in the presence of angiographically normal arteries and is referred to as Cardiac Syndrome X, an underlying pathophysiology thought to be related to microvascular dysfunction. The prognosis is generally considered good despite recurrent chest pain episodes.

It is essential a thorough history and a full description of the chest pain, including its character, onset, severity and duration is elicited. Jaw pain, neck pain, epigastric pain and arm pain may occur as an isolated event or jointly with the chest pain complaint. Other pertinent physical examination findings should also be noted and may point to other less frequent, but certainly serious, underlying causes of chest pain. For example, asymmetrical peripheral pulses, an early diastolic murmur and a “tearing” substernal chest pain with radiation to the back or interscapular region might indicate an aortic dissection. A systolic murmur to the base of the neck suggests aortic stenosis, whereas a systolic murmur that increases with a strain effort by a valsalva maneuver might suggest a hypertrophic cardiomyopathy, either of which could certainly cause an inordinate oxygen demand due to myocardial hypertrophy. Pleuritic-type chest pain may be due to a pulmonary embolus, pneumothorax or pneumonia.

As a result of concerted efforts and numerous studies, higher risk indicators have been identified which increase the likelihood of death or MI. This enables a much more effective utilization of the health care dollar while lessening adverse outcomes through greater physician awareness. The TIMI risk score (2000), “high risk indicators” described in the American College of Physicians 2007 textbook “ACP Medicine,” the recently released August 2007 ACC/AHA guidelines describing high-risk features, the PURSUIT (2000) and GRACE (2004) risk prediction models have paved the way to further characterize which patients may warrant an invasive management strategy.

In 2000 Dr Antman and colleagues described the TIMI risk score (Table 1) for the UA/NSTEMI patient, which initially divided the patients into mild, intermediate and high risk categories based on seven equally-weighted prognostic indicators ⁹.

The rate of death, myocardial infarction or urgent revascularization significantly increased based on TIMI risk scores from a low 5% for a risk score of 0 - 1 and 20% for a TIMI risk score of 4 to more than 40% with a score of 6 – 7. Patients with a TIMI high-risk score of 5-7 are highly recommended for early coronary angiography.

In addition to the TIMI risk score, there are high-risk indicators based upon randomized clinical trials, nonrandomized studies and observational registries (Table 2). UA/NSTEMI patients with any of these risk indicators are recommended for consultation by a cardiologist early in the triage period and considered for coronary angiography. Maintaining a careful vigilance for these high risk indicators as listed in Table 2 is prudent, particularly when a cardiologist hasn’t been consulted as yet and no cardiac catheterization is being contemplated. These recommendations are carefully outlined in the American College of Physician’s publication “ACP Medicine” 2007 Edition and described as having a Class I recommendation and a Level A evidence of support.

It is interesting to note, the occurrence of non-sustained ventricular tachycardia (lasting less than 30 seconds) during the first 48 hours of an acute myocardial infarction does not have long-term prognostic significance. Alternatively, asymptomatic non-sustained ventricular tachycardia more than 48 hours out, particularly in patients with an ejection fraction of 35% or less, has a potentially higher risk for sudden cardiac death and generally prompts consideration for an implantable cardiac-defibrillator.

The recently published 2007 ACC/AHA guidelines note patients with the following high risk features: age greater than 70 years, prior revascularization or MI, ST-segment deviation, heart failure, LV function 40% or less and diabetes could benefit by an invasive strategy. In those patients with unstable angina, a history of a prior PCI within the past six months suggests restenosis and the ACC guidelines note a repeat PCI can often effectively treat such patients. UA/NSTEMI patients with a prior CABG were also mentioned as another subgroup where early coronary angiography was usually indicated.

There are two recognized sources (PURSUIT and GRACE risk models) which predict the risk outcome of a patient with UA or NSEMI. The PURSUIT risk model predicts the probability of death or infarction/reinfarction in the first thirty days following an ACS event. The GRACE model predicted all-cause mortality in the ensuing six months following a diagnosis of ACS.

The PURSUIT risk model is based on the PURSUIT trial, and provides a guide in the clinical decision-making process. Specific parameters were identified which increase the probability of death or infarction/reinfarction. Increasing age played a prominent role in estimating the probability of death or infarction in the fist thirty days following an event. The specific risk indicators described in the PURSUIT risk model were advanced age, male gender, a worsening anginal class in the six weeks preceding the event, higher heart rate, lower systolic blood pressure, signs of heart failure and ST-depression. All the factors contributed to a higher morbidity or mortality probability in the next thirty days following an acute coronary syndrome. ¹⁰

Another revealing predictive model was published in JAMA 2004 “The GRACE risk model,” which acknowledged the importance of the patient’s serum creatinine in determining the overall risk of the patient. Interestingly, the GRACE model also included the added risk in having the patient admitted to a hospital which had no in-hospital percutaneous coronary intervention capability. The potential points scoring ranged from a low of only 1 point to a highest possible score of 263. A score of only one point would be for a patient less than 40 years of age with a resting heart rate less than 50, systolic blood pressure over 200, no ST-segment depression, initial serum creatinine less than 0.4, no cardiac biomarker elevation, the admitting hospital having PCI capability and the patient with neither a history of CHF nor MI. Alternatively, the highest score possible of 263 points, was given to a patient over 90 years of age with a resting heart rate over 200, a systolic blood pressure less than 80 mm Hg, ST-segment depression on ECG, an initial serum creatinine of 4 or more, there being no PCI capability in the admitting hospital and the patient having a history of CHF and MI. A prediction for all-cause mortality was provided by the GRACE model with a score of 180 points, for example, indicating there was a 25% probability of death in the first six months after discharge. A nomogram predicted the individual mortality risk for each patient ranging from 0-50% mortality risk with successive scores from 70-210 points, respectively.¹¹

The UA/NSTEMI patient falls in between the unspecified chest pain patient and the STEMI patient. Disregard for the TIMI risk score (Table 1), high-risk indicators (Table 2) described by the American College of Physicians and 2007 ACC/AHA guidelines and recognized prognostic indicators in the PURSUIT and GRACE models increases the likelihood of an indiscriminate use of coronary angiography from where it is clearly most fruitful in the UA/NSTEMI patient. Such practices risk an unnecessary use of a valuable healthcare resource for patients who don’t warrant an invasive procedure and an unnecessary risk to those that do.

Patients who present to the ER room with unimpressive ECG findings, negative cardiac biomarkers and various symptoms such as atypical chest pain, anginal equivalents or chest pains uncharacteristic for cardiac disease are frequently “ruled-out” for an MI in the next twelve-eighteen or perhaps twenty four hours. The next question often presents itself as an enigma. Did this patient have a cardiac-related event successfully stabilized during the ER/hospital stay with effective cardio-protective measures or were the symptoms non-cardiac from the outset? Limited resources and cost-containment is driving the healthcare community toward establishing guidelines with prudent, evidence-based medicine. Wisely consulting a cardiologist early in a patient’s hospital course when it’s warranted, transferring a patient to a hospital with PCI capability when it’s appropriate and recognizing anginal equivalent are but a few of the challenges facing the hospitalist from day to day.

References

1. McCarthy BD, Beshansky JR, D'Agostino RB, Selker HP. Missed diagnoses of acute myocardial infarction in the emergency department: results from a multicenter study Ann Emerg Med. 1993;22:579-82.
2. Pope JH, Aufderheide TP, Ruthazer R, Woolard RH, Feldman JA, Beshansky JR, et al. Missed diagnoses of acute cardiac ischemia in the emergency department N Engl J Med. 2000;342:1163-70.
3. Lee TH, Rouan GW, Weisberg MC, Brand DA, Acampora D, Stasiulewicz C, et al. Clinical characteristics and natural history of patients with acute myocardial infarction sent home from the emergency room Am J Cardiol. 1987;60:219-24.
4. Theroux P, Fuster V. Acute coronary syndromes: unstable angina and non-Q-wave myocardial infarction. Circulation 1998; 97:1195-1206.
5. de Zwaan C, Bar FW, Janssen JH, et al. Angiographic and clinical characteristics of patients with unstable angina showing an ECG pattern indicating critical narrowing of the proximal LAD coronary artery. Am Heart J 1989;117:657-65.
6. Haines DE, Raabe DS, Gundel WD, Wackers FJ. Anatomic and prognostic significance of new T-wave inversion in unstable angina. Am J Cardiol 1983;52:14-8.
7. Renkin J, Wijns W, Ladha Z, Col J. Reversal of segmental hypokinesis by coronary angioplasty in patients with unstable angina, persistent T wave inversion, and left anterior descending coronary artery stenosis. Additional evidence for myocardial stunning in humans. Circulation 1990;82:913-21.
8. Zalenski RJ, Rydman RJ, Sloan EP, et al. ST segment elevation and the prediction of hospital life-threatening complications: the role of right ventricular and posterior leads. J Electrocardiol 1998;3 Suppl:164-71.
9. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000;284:835-42. the TIMI risk score
10. Boersma E, Pieper KS, Stayerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 2000;101:2557-67.
11. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA 2004;291:2727-33. the GRACE Risk Model

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RISK STRATIFICATION

By H. B. Karunaratne, MD
Cardiologist, Florida Heart Group; director of coronary care unit and director of cardiovascular research, Florida Hospital

Risk stratification in UA/NSTEMI

The term acute coronary syndrome (ACS) is currently used to describe a group of clinical symptoms resulting from acute myocardial ischemia and consists of ST-segment-elevation MI (STEMI), non-ST-segment-elevation MI (NSTEMI), and unstable angina (UA).

The clinical syndrome of UA/NSTEMI is a subset of ACS usually caused by atherosclerotic coronary artery disease (CAD) that is associated with an increased risk of cardiac death and myocardial infarction (MI) and the presence of ECG changes of ST segment depression or prominent T-wave inversion in the absence of ST segment elevation. It is usually seen in patients presenting with chest pain or the angina equivalent (as defined in the ACC/AHA Guidelines UA/NSTEMI 2007). Pathologically, these patients most commonly have disruption or erosion of an atherosclerotic plaque that is usually nonocclusive. They frequently have multiple plaques and arterial inflammation and at times thrombosis and coronary vasospasm. These patients therefore remain at risk for long-term ischemic events.

More than 5.3 million patients present to emergency departments every year with chest pain, of whom approximately 1.5 million are hospitalized with suspected ACS. Of this number, approximately 25% have STEMI, usually caused by total occlusion of a coronary artery. Patients with this condition need to be promptly identified, which usually can be accomplished by an ECG performed within 5-10 minutes of arrival in the ED. Urgent reperfusion by thrombolytic therapy or PTCA can then be carried out and is the mainstay of therapy.

The rest of ACS patients are an undifferentiated group, and patients with life-threatening ACS may present with symptoms that may mimic many benign and noncardiac conditions. Therefore, careful evaluation of the history, physical findings, ECG, and cardiac biomarkers should be undertaken so that appropriate risk stratification is carried out to guide therapeutic decision making, prognostication, and management of these patients. Physical findings are often unremarkable. The ECG is nondiagnostic, and the cardiac biomarkers may be negative initially, compounding the difficulty of assessing these patients.

The initial risk stratification of these patients is often carried out in the ED and involves determining the likelihood that the presenting signs and symptoms represent acute coronary syndrome because of obstructive CAD (Table 1).

If it is determined that a patient’s likelihood of ACS is high, the patient should be admitted to an ICU or a monitored progressive care unit and should not be sent to an observation unit. If it is believed that the likelihood of ACS is low, the patient may either be discharged home to be followed up by his or her local MD in the next few days or, more likely, be admitted to an observation unit. Intermediate likelihood patients often end up in observation units, but some may require hospitalization in a PCU.

Along with this risk stratification of the likelihood that the symptoms represent ACS, it is equally important to address the likelihood of an adverse clinical outcome, that is, what is the likelihood that this patient may have myocardial infarction, stroke, heart failure, recurrent ischemia, serious arrhythmia, or death (Table 2). Although it is likely that most patients at high risk of an adverse outcome will be recognized early and admitted appropriately, patients sent to an observation unit and initially assigned to a low or intermediate risk may develop additional features during the observation unit stay, placing them in a higher risk category. Hence, observation unit physicians should be familiar with such risk assessments as well.

In developing the following plan for risk assessment and management, we closely followed the recommendations of the ACC/AHA 2007 Guidelines. Other risk assessment tools have been utilized and are discussed later.
Table 3 presents a brief description of the initial evaluation and highlights the important symptomatic features, physical findings, ECG changes, and biomarkers.
Table 4 provides a template for an observation unit record that encompasses the items necessary for managing a patient with ACS and doing a risk assessment.
Table 1, again closely following the AHA/ACC Guidelines, provides a risk assessment tool of the likelihood that a patient’s presentation is a result of ACS.
Table 2 provides a scheme for assigning risk of an adverse cardiac outcome to a patient who has been determined to have ACS on the basis of the evaluation described in Table 3.
Table 5 is a flow diagram outlining different management strategies that can be used after a risk assessment along the lines outlined above.

Table 1. Likelihood That ACS Symptoms Result from CAD

Table 2. Short-Term Risk of Death or Nonfatal MI in Patients with UA/STEMI

TABLE 3. Initial Evaluation Process

Note: The elderly, diabetics, women, and patients with chronic renal failure have atypical symptoms

Note: The elderly, diabetics, women, and patients with chronic renal failure have atypical symptoms

3. Risk factors

TABLE 4. Template for Observation Unit Record

Other risk assessment strategies

Goldman et al. made one of the earliest contributions to risk assessment of patients presenting with chest pain. They initially described a computer-derived protocol to aid in the management of acute chest pain in the emergency room (1982, 1988). They also described a risk assessment algorithm derived from an assessment of the risk of developing a major cardiac event within 72 hours and using older age, male sex, description of pain similar to prior MI or worse than prior angina, systolic BP less than 110 mm Hg, rales above the bases on initial physical exam, and initial ECG changes suggestive of MI or ischemia as the variables. Patients were then assigned to 1 of 4 groups according to the risk of an event within 24 hours, from very low to high risk. All these risk assessments also included patients who had STEMI but were useful in determining the disposition of a patient from the ER to the ICU, step-down unit, or observation unit and the appropriate intensity of subsequent medical care.

For a risk assessment tool to be effective it should have a high degree of prognostic discriminatory capacity, and the variables used in constructing the tool should have independent prognostic information. The variables should also be part of a routine medical evaluation and be assessable at the bedside early after presentation.

The TIMI risk score is a simple tool composed of 7 indicators obtained at initial presentation.

Table 6. TIMI Score for NSTEMI/UA

The score was validated in several clinical trials of ACS patients and has performed adequately when tested in an unselected ED population. The risk score assesses the risk of major adverse cardiac events, from a low of 4.7% for a risk score of 0-1 to a very high risk of 40.9% for a score of 6-7.

The GRACE risk model, described by Eagle, uses 8 variables: older age, Killip class, systolic BP, ST segment deviation, cardiac arrest during presentation; serum creatine level, positive initial cardiac biomarkers, and heart rate. It has been used to predict hospitals death as well as to assess all-cause mortality from hospital discharge to 6 months.

It must be stressed that ultimately regardless of the risk assessment tool used, risk stratification is a dynamic ongoing process and should be reassessed periodically from initial presentation to discharge.

References

1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. J Am Coll Cardiol. 2007;50:e1-e157.
2. Gibler WB, Cannon C, Blomkalns AL, et al. Practical implementation of the guidelines for unstable angina/non-ST segment elevation myocardial infarction in the emergency department: a scientific statement from the American Heart Association Council on Clinical Cardiology (Subcommittee on Acute Cardiac Care), Council on Cardiovascular Nursing, and Quality of Care and Outcomes Research Interdisciplinary Working Group in collaboration with the Society of Chest Pain Centers. Circulation. 2005;111:2669-2710.
3. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 Guideline update for the management of patients with unstable angina and non-ST segment elevation myocardial infarction — summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guideline (Committee on the Management of Patients with Unstable Angina) J Am Coll Cardiol. 2002;40:1366-1374.
4. Morrow DA, Antman EM, Giugliano RP, et al. A simple risk index for rapid initial triage of patients with ST elevation myocardial infarction: an InTIME II substudy. Lancet. 2001;358:1571-1575.
5. Wiviott SD, Morrow DA, Frederick PD, et al. Application of the thrombolysis in myocardial infarction risk index in non-ST elevation myocardial infarction, evaluation of patients in the National Registry of Myocardial Infarction. J Am Coll Cardiol. 2006;47:1553-1558.
   
6. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low molecular weight heparin with unfractionated heparin for unstable coronary artery disease. N Eng J Med. 1997;337:447-452.
7. Pollock CV, Sites FD, Shofer ES, et al. Application of the TIMI risk score for unstable angina and non-ST elevation acute coronary syndrome to an unselected emergency department chest pain population. Acad Emerg Med. 2006;13:13-18.
8. Granger CB, Goldberg RJ, Dabbous O, et al. Predications of hospital mortality in the global registry on acute coronary events. Arch Intern Med. 2003;163:2345-2353.
9. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month post discharge death in an international registry. JAMA. 2004;291:2727-2733.
10. Betrand ME, Simoons ML, Fox KA, et al. Management of acute coronary syndrome in patients presenting without, persistent ST- segment elevation. Eur Heart J. 2002;23:1809-1840
11. Lee T.H., Juarez G, et al. Ruling out acute myocardial infarction. A prospective multicenter validation of a 12 hour strategy for patients at low risk. N Engl J Med. 1991;324:1239-1246.
12. Goldman L, Weinberg M, Weisberg M, et al. A computer derived protocol to aid in the diagnosis of emergency room patients with acute chest pain. N Engl J Med. 1982;307:588-596.
13. Goldman L, Cook EF, Johnson PA, et al. Prediction of the need for intensive care in patients who come to emergency department with acute chest pain. N Engl J Med. 1996;334:1498-1504.
14. Lee TH, Goldman L. Evaluation of the patient with acute chest pain. N Engl J Med. 2000;342:1187-1195.
15. Gaspoz JM, Lee TH, Cook EF, et al. Outcome of patients who were admitted to a new short stay unit to “rule out” myocardial infarction. Am J Cardiol. 1991;68:145-149.

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CARDIAC BIOMARKERS

By Larry D. Appel, MD
Associate Professor of Medicine, Mercer University School of Medicine, Savannah, Georgia

By Naveen Bandarupalli, MBBS
Echocardiography Fellow, University of Alabama Birmingham

By Vivian Nguyen, MD
Internal Medicine Resident, Memorial Health University Medical Center, Savannah GA

By Deborah Haywood, RN, BSN
Memorial Health University Medical Center, Savannah, Georgia

Cardiac enzymes and ACS

The most important thing to understand about cardiac enzymes is that they are just markers. They are just lab values, not final determinants!! Multiple clinical factors other than the results of biomarkers should be included in the decision about referral for revascularization.12 What happened to me last week illustrates this point:

A 63-year-old man with a history of hypertension came to our ER reporting 4 hours of intermittent chest pain and was pain free when I examined him. He didn’t have other risk factors for coronary artery disease (CAD). He was normotensive (BP 130/68), had a heart rate of 70, and had a very nonspecific ECG. His initial creatine kinase (CK) was 210 U/L, and his troponin was less than 0.1 µg/L. We observed him for 24 hours with an appropriate rule-out protocol, and surprisingly, his second troponin was 18. He was in the cath lab at 2 am, and fortunately, he did well. But he could have lost muscle. Why? The cardiologist and I relied too much on the cardiac enzymes.

Issues with CKs

At this time, most hospitalists, emergency room physicians, and cardiologists typically review 2 types of lab values of our patients with chest pain: CKs and troponins.

There are several issues with CKs.

CK stands for creatine kinase, which is an enzyme released in essentially 3 parts of the body: brain, skeletal muscle, and heart. In the setting of acute myocardial infarction, the physician should see a rise in the amount of CK attributed to the heart and an overall elevation of plasma CK. Until about 9 years ago, CKs were the best marker we had. In retrospect, they were really not so good. It is estimated that about one-third of patients presenting without ST elevation who would have previously been diagnosed as experiencing unstable angina (UA) on the basis of normal CK levels are now diagnosed as having a non-ST-segment-elevation MI (NSTEMI) because of detectable troponin levels.13
Fundamentally, there are really 2 limitations in the usage of CK-MB as a solo marker.

They are:

1. Troponin The CK-MB fraction is often measured as a weight, done on a gas chromatograph, and the values are reported in nanograms per milliliter. An issue arises whenever this is listed as an MB “fraction.” In fact, the CK-MB measurement is a ratio, as total CK is measured as an assay in units per liter. Thus, the CK-MB ratio compares a weight to an assay. This ratio only has correlational value, which significantly limits it strength. In some centers, CK-MB is now determined by immunoassay. Even when CK-MB mass is determined by immunoassay, its sensitivity is still limited by volume requirements.
2. The second limitation of the CK-MB ratio is its overall sensitivity and specificity. Overall CK does not increase with small levels of myocardial injury as troponin does. Furthermore, especially at lower levels, specificity is an issue. Overall, the sensitivity of a single CK-MB is 47%, and the specificity is 96%.12-14 Serial testing does improve sensitivity but only to about 87%-90%. The amount of CK-MB normally varies between individuals from 2% to 6% of total CK in the blood.14 Thus, in the setting of normal or slightly elevated CK values, the CK-MB value can be quite confounding. Many institutions do not run MBs when the total CK is normal.

CK-MB remains the primary marker for reinfarction in somebody who has already experienced infarction or angina. This is a result of the rapid fall that allows for a retreat to close to baseline during initial infarction, thus allowing detection of reinfarction or angina in a way that troponin cannot, as it doesn’t fall as rapidly.
CK-MB is also helpful after thrombolysis in confirming successful reperfusion, as it peaks early in this setting.

Troponin is basically a very helpful and accurate marker of ACS; the only significant problem is its oversensitivity. It seems like it can be “positive,” or at least not negative, depending on how loudly one articulates the word troponin. This high sensitivity can be very helpful, though, as it allows for pretty good data to support the idea that negative troponins, appropriately timed, are strong indicators that a patient is not suffering from ACS. For a table of common noncardiac conditions that elevate troponin, see “Elevated cardiac troponins: their significance in acute coronary syndrome and noncardiac conditions,” by M. Clark and J. Payne (J Okla State Med Assoc. 2006;99:363-367).

There are actually 2 types of troponins, each with a unique amino acid sequence in the heart, thus conferring high specificity. They’re in almost every cardiac myocyte, and with cell injury comes cell damage and troponin “leak,” conferring high specificity.

Troponin T binds to tropomyosin, is less specific than troponin I, and remains elevated for 8-21 days.1 Troponin I binds to actin, is more specific in renal failure, and remains elevated for 5-10 days.1 Most institutions now use troponin I.
Several issues are posed with troponin.

When is a troponin “positive”?
Essentially, a troponin is “positive” anytime it is not completely negative. A positive troponin indicates myocardial necrosis almost by definition. A positive troponin can and often does indicate ACS, but it can also reflect insignificant levels of myocardial necrosis. Oversensitivity as an issue is a problem, and there are several causes of troponin elevation other than CAD. That being said, though, beware of a positive troponin, regardless of the number. Even very small elevations of troponin correlate with worse clinical outcomes in ACS,2 and troponin elevation does correlate strongly with intracoronary thrombus that is being looked at angioscopically.3 See Table 1, Elevated Cardiac Troponins without Acute Coronary Syndrome, in R. Giugliano and E. Braunwald, “The year in non-ST-segment elevation acute coronary syndromes (J Am Coll Cardiol. 2005;46:906-919).

Note that since 2000, a positive troponin has been the key differentiator in determining unstable angina versus non-ST-elevation MI. ACS can be broken down into ST-elevation MI (STEMI), non-ST-elevation MI (NSTEMI), or unstable angina (UA).
Essentially, a positive troponin defines an event as a NSTEMI and a negative troponin defines an event as unstable angina.1

This is not to say that a positive troponin is pathognomonic for NSTE-ACS, but it is to say that myocyte injury has occurred most of the time, except if the troponin measurement is a false positive.

The functional issue that also arises is demand-related ischemia, in which troponin elevation technically does represent myocyte injury but not necessarily ACS, and management should be directed at relieving the acute process creating the excessive demand (ie, volume overload)

What about trends in troponins, even at customarily very low values?
A common scenario that hospitalists encounter is a patient who comes in with equivocal chest pain that has fully resolved, a nonspecific ECG, a first troponin that is positive but low, and a second troponin that is slightly higher than the first.
Take care with these patients as this can actually be significant. Even a small elevation of troponin indicates an increased risk of adverse events,1 and an increased risk of NSTEMI is related quantitatively to serum troponin level, especially as levels increase.1,4

What is the significance of 1 negative troponin and also of 2 negative troponins?
The significance of a negative troponin is really a timing issue rather than, strictly speaking, a number issue. In other words, there are good studies that show that negative troponin values 6 and 8 hours after someone arrives in the ER, coupled with a normal or nearly normal ECG, place patients at very low risk of major cardiac events over the next 30 days.4-6

Troponin T usually begins to increase 3 hours after injury and troponin I to increase 4 hours after injury, although there is certainly variability.¹

So, traditionally, what happens is that patients have their blood drawn soon after arriving in the ER, and this is the “first” troponin. If that is negative, then it really becomes a matter of how long the interval needs to be before a second troponin will be of enough value that the hospitalists or ER physician will have a sufficient comfort level in knowing the patient does not have ACS. At this point, it depends on the reliability and timing of the patient’s history. If all are very comfortable that the pain occurred 8 hours or more before the patient arrived, then wait 4 or 6 hours for the second troponin. If it is negative, that can put the patient into the low-risk category.5

The problem is that patients do not always remember exactly when their symptoms started, and they cannot always differentiate changes in or degrees of pain. This in fact was what happened to the patient we mentioned at the beginning of this discussion. In retrospect, this patient’s symptoms really became significant only 2 hours before admission, so that our first troponin, which was drawn on admission, was not timely at all and in fact was misleading. Having a second troponin drawn 4 hours after admission, instead of waiting the customary 8 hours that our hospital protocol currently uses, could have been useful for this patient.

What about the situation in which CK is “positive” and troponin is negative?
The good news here is that if the timing of these lab values takes into account when these markers should be positive, then the troponin will usually trump the CK-MB. Often, you’ll find a CK-MB as “positive” when the total CK value is either normal or just above normal and the MB ratio is just above normal. In this setting, if the troponin is drawn simultaneously and in an appropriately timed manner, then follow the troponin.

Again, keep in mind, the reverse is also true. A positive troponin, even slightly, in the setting of a negative CK, means you should still follow the troponin.7

What makes troponin false positive?
There are many conditions in which elevation of cardiac troponin is seen, but the patients do not necessarily have acute coronary syndrome. In fact, there are some conditions that show an elevated troponin where patients do not necessarily have any evidence of coronary artery disease. This is where it can be very confusing for the physician.

Table 1 Elevated cardiac troponins: their significance in acute coronary syndrome and non cardiac conditions" by Clark, M and Payne J. Journal Oklahoma State Med Assoc 2006 jun 99 (6): 363-7. Illustrates the wide variety of medical conditions in which an elevated cardiac troponin has been reported without acute coronary syndrome.

A few of these conditions are worth mentioning, as there are still some implications of a positive troponin.

Pulmonary embolism: Troponin can be frequently elevated in patients with pulmonary emboli (PEs),⁸ and troponin can indicate a worse prognosis.⁸ In fact, troponin can be a better marker of significance and mortality in relation to a PE than right ventricular dysfunction.1

Sepsis: Elevated troponin is frequently seen in patients with sepsis and certainly in septic shock. This elevation can indicate worsening left ventricular function and can be irreversible. This is not always the case, however. Some who survive septic shock do have normal LV function return as well.⁹

Renal failure: The biggest thing to note is that in patients with chronic renal failure, troponin T is usually positive, whereas troponin I is not.

A positive troponin T is associated with a worse prognosis and higher 2-year mortality.¹⁰

Note that with troponin I, asymptomatic chronic renal failure patients are not noted to have troponin levels greater than 0.8. So although a troponin I may not be less than 0.1, if it is greater than 0.8, suspect myocardial injury.¹¹

New markers

There are several new markers that may offer significant assistance in the diagnosis of ACS. In fact, a multimarker approach to risk stratification may be the future standard of care. Inflammatory markers such as hs-CRP, and CD40L, atherosclerosis accelerators such as Hgba1c or glucose, vascular damage markers such as crcl, cystatin C, and microalbumin, and stress markers such as BNP and NT-pro BNP may all be on the horizon.⁵

Two of the most hopeful are detailed below. Neither is commonly used yet, but be on the lookout.

Myoglobin

For example, if a patient experiences chest pain 24-48 hours after a procedure such as angioplasty, the myoglobin level will rapidly reassess and fall if the symptoms are cardiac related.⁴ It is possible to observe an acute rise within 1 hour and an acute fall in plasma myoglobin over 3-4 hours, indicating new myocyte injury.

CK-MB subforms

Conclusion

The state of cardiac biomarkers has evolved in the last 10 years to the point where they play a very integral role in the diagnosis and treatment of ACS. The challenge for physicians is to understand their strengths and limitations and to continue to use these powerful tools appropriately.

References

1. Clark M, Payne J. Elevated cardiac troponins: their significance in acute coronary syndrome and noncardiac conditions. J Okla State Med Assoc. 2006;99:363-367.
2. Henrikson CA, Howell EE, Bush DE, et al. Prognostic usefulness of marginal troponin T elevation. Am J Cardiol. 2004;93:275-279.
3. Giugliano R, Braunwald E. The year in non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol. 2005;46:906-919.
4. Achar S, Kundu S, Norcross W. Diagnosis of acute coronary syndrome. Am Fam Physician. 2005;72:119-126.
5. Hamm CW, Goldmann BU, Heeschen C, et al. Emergency room triage of patients with acute chest pain by means or rapid testing for cardiac troponin T or troponin I. N Engl J Med. 1997;337:1648-1653.
6. Lloyd-James DM, Camargo CA, Giugliano RP, et al. Electrocardiographic and clinical predictors of acute myocardial infarction in patients with unstable angina pectoris. Am J Cardiol. 1998;81:1182-1186.
7. Antmann EM. Troponin measurements in ischemic heart disease: more than just a black and white picture. J Am Coll Cardiol. 2001;38:987-990.
8. Yalamachi K, Sukhij R, Aronow WS, et al. Prevalence of increased cardiac troponin I levels in patients with and without acute pulmonary embolism and relationship of increased cardiac troponin levels with in hospital mortality in patients with acute pulmonary embolism. Am J Cardiol. 2004;93:263-264.
9. Turner A, Tsamitros M, Bellomo R. Myocardial cell injury in septic shock. Crit Care Med. 1999;27:1775-1780.
10. Wood GN, Keevil B, Gupta J. Serum troponin T measurement in patients w chronic renal impairment predicts survival and vascular disease: a 2 year prospective study. Nephrol Dial Transplant. 2003;8:1610-1615.
11. Donnino MW, Karriem-Norwood V, Rivers EP, et al. Prevalence of elevated troponin I in end stage renal disease patients receiving hemodialysis. Acad Emerg Med. 2004;11:979-981.
12. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable agina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284:835-842.
13. Braumwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for management of Patients with unstable angina on non-ST-segment elevation MI, a report for the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2000;36:970-1062.
14. Zipes DP. ST elevation myocardial infarction; pathology, pathophysiology, and clinical features — cardiac specific troponins. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia: Saunders; 2005.

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Therapeutics: ANTITHROMBOTIC TREATMENT IN ACS

By Yousaf Ali, MD, MS
Antithrombotic treatment in ACS is discussed in the context of STEMI and UA/NSTEMI with oral antiplatelets, heparins, platelet-GPIIb/IIIa inhibitors, direct thrombin inhibitors, and warfarin.

STEMI and antithrombotic treatment

Decision for percutaneous coronary intervention (PCI) versus medical management should be made by the receiving physician in consultation with the cardiologist and in consideration of the type of facilities available at the treating hospital for STEMI patients.

ASA

• Chewable aspirin as soon as possible after the event, then once daily.
• Dose of 162 up to 325 mg.

Clopidogrel (Plavix) and ticlopidine (Ticlid)

• Alternative to ASA in case of hypersensitivity or major GI side effect from ASA.
• Clopidrogrel (Plavix), 75 mg daily preferable.
• Ticlopidine (Ticlid), 250 mg twice daily, is also available but not preferred because of delayed onset of action.
• Both can cause TTP.

Unfractionated heparin as ancillary therapy to reperfusion therapy

• Patients undergoing percutaneous or surgical revascularization should receive unfractionated heparin (UFH).
• UFH should be given intravenously to patients undergoing reperfusion therapy with alteplase, reteplase, or tenecteplase with dosing as follows: bolus of 60 U/kg (maximum 4000 U), followed by an infusion of 12 U/kg per hour (maximum 1000 U) initially adjusted to maintain activated partial thromboplastin time (aPTT) at 1.5 to 2.0 times the control (approximately 50-70 seconds).
• Unfractionated heparin should be given intravenously to patients treated with nonselective fibrinolytic agents (streptokinase, anistreplase, urokinase) who are at high risk for systemic emboli (large or anterior MI, atrial fibrillation, previous embolus, or known LV thrombus).
• Platelet counts should be monitored daily in patients taking UFH.
• It may also be reasonable to administer UFH intravenously to patients undergoing reperfusion therapy with streptokinase who are not at high risk for emboli.

LMWH versus UFH

• In thrombolytic- and aspirin-treated patients with STEMI, low-molecular-weight heparin (LMWH) is more effective than UFH and placebo in preventing reinfarction.
• LMWH is also better than placebo in reducing mortality.

Platelet-GPIIb/IIIa inhibitors

• The role of these agents in STEMI will be discussed in further detail at the end of this section.

Direct thrombin inhibitors (bivalirudin, hirudin, and others)

• In patients with known heparin-induced thrombocytopenia, it is reasonable to consider bivalirudin as a useful alternative to heparin when used in conjunction with streptokinase. A number of these inhibitors are now available for use in HIT and DVT but are not yet approved for the treatment of acute coronary syndrome.1-11
• Dose according to the HERO-2 regimen (a bolus of 0.25 mg/kg followed by an intravenous infusion of 0.5 mg/kg per hour for the first 12 hours and 0.25 mg/kg per hour for the next 36 hours) is recommended, but with a reduction in the infusion rate if the partial thromboplastin time is above 75 seconds within the first 12 hours.13
• Bivalirudin has been approved for use in patients with unstable angina undergoing PCI.\
• But efficacy was less evident for univalent thrombin inhibitors (argatroban, efegatran, and inogatran).
• Bivalirudin causes less major bleeding than do heparin and hirudin and no difference in major bleeding than do univalent thrombin inhibitors.1
• On the basis of the data in the HERO-2 trial, the writing committee believes that bivalirudin could be considered an acceptable alternative to UFH in those patients with STEMI who receive fibrinolysis with streptokinase, who have heparin-induced thrombocytopenia, and who, in the opinion of the treating physician, would benefit from anticoagulation.13

Selective factor Xa inhibitors

• A phase 2 angiographic trial pentasaccharide as an adjunct in ST-segment myocardial infarction (PENTALYSE) evaluated fondaparinux, a synthetic pentasaccharide that is a highly selective inhibitor of factor Xa. Fondaparinux selectively binds antithrombin III, inducing a conformational change that increases the anti-Xa activity of antithrombin III more than 300 times, which results in dose-dependent inhibition of factor Xa.12
• A total of 333 patients with evolving STEMI were treated with aspirin and alteplase and randomized to UFH given intravenously for 48 to 72 hours or to a low, medium, or high dose of fondaparinux. The percentage of patients achieving TIMI grade 3 flows at 90 minutes was 68% in the UFH control group and ranged between 60% and 69% with fondaparinux. Thus, selective factor Xa inhibition appears to be an attractive therapeutic conception in patients presenting with STEMI; however, further study is required before it can be recommended for routine administration.

Warfarin

• In conventional studies warfarin has demonstrated a reduction in risk of death of 13% and a reduction in relative risk of both stroke and reinfarction of 41%. ASA was not used in control groups in these studies, so the results are difficult to assess. But cost-effectiveness analysis suggests ASA is the better one to use.
• Warfarin is also indicated for atrial fibrillation and LV thrombus post-MI. 

UA/NSTEMI and antithrombotic treatment

ASA

• There is good evidence that platelet inhibition-irreversible inhibition of thromboxane (after plaque disruption/thrombus formation) is the likely reason for clinical benefit from ASA. Another mechanism such as anti-inflammatory effects is unlikely to be the reason.
• Dose 75-325 mg/day. The ISIS-2 trial used 160 mg/day as the first dose, which showed significant benefit.
• All trials ASA versus placebo (P value .005).

Clopidogrel (Plavix)/ticlopidine (Ticlid)

• These drugs are indicated in patients with UA/NSTEMI who are unable to tolerate ASA because of hypersensitivity or major GI contraindications.
• Clopidogrel is preferred to ticlopidine because of more rapid platelet inhibition and lower incidence of adverse effects.
• Ticlopidine is not recommended (by ACC/AHA) during the acute phase because it takes several days to achieve its maximal antiplatelet effect.
• The addition of clopidogrel to ASA gives the added benefit of reduction in the rate of MI at a cost of an increase in bleeding (CURE trial). Early use of clopidogrel is recommended in addition to ASA in centers using a nonaggressive approach with medical therapy (CURE trial).

UFH

• Early administration of UFH is associated with a reduction in the incidence of AMI and ischemia in UA/NSTEMI
• The risk of death or MI is reduced between 33% and 56% when ASA and UFH has been used, but most of the benefits are short term and are not maintained on a long-term basis.
• Problems with UFH are poor bioavailability and marked variability in anticoagulant response among patients. Hence, with APTT monitoring is required. Also APTT has variable response because of age (higher APTT value) and diabetes mellitus (causes lower APTT value).

LMWH

• LMWH is associated with a significantly reduced event rate compared with ASA alone and with UFH.
• The FRSC trial showed a 63% reduction in risk of death or MI during first 6 days and also a significant decrease after 40 days.
• The FRIC study did not show this result.
• In the ESSENCE trial, the composite outcome of death, MI, or recurrent angina was reduced by 16% on day 14 and by 19% on day 30.
• TIMI 11B showed reduced death, MI, and need for revascularization on day 8 from 14.5% to 12.4% and on day 43 from 19.6% to 17.3%. The rate of death or MI was reduced from 6.9% to 5.7% on day 14 and from 8.9% to 7.9% on day 43.
• The FRAXIS study showed trends toward more frequent death and more frequent death or MI in nadroparin-treated patients.
• Long-term benefit — FRISC, FRIC, TIMI 11B did not show a benefit of treatment beyond the acute phase.
• The FRISC 11 trial, which had a different study design, showed some benefit of LMWH after 3 months in a selected patient population in whom angiography was delayed.
• So ease of administration, reduced need for monitoring, and comparable or better results make LMWH a good choice for the general population. However, there is a lower incidence of minor bleeding with UFH.

Platelet-GPIIb/IIIa inhibitors

• The role of these agents in UA/NSTEMI will be discussed in further detail at the end of this section. 

UA/NSTEMI and direct thrombin inhibitors

Hirudin

• Binds directly to thrombin.
• Hirudin provides modest short-term reduction in the composite end point of death or nonfatal MI with modest increase in risk of bleeding.

Bivalurudin (Hirulog)

• A synthetic analogue of hirudin binds reversibly to thrombin.
• Some trials have shown evidence of reduction in death or MI and less bleeding than with UFH. 

Warfarin

• The use of warfarin for long-term treatment in patients with UA/NSTEMI is not recommended because of lack of evidence of any benefit, as shown by CHAMP and CARs trials.
• The OASIS pilot study showed some benefit from the moderate-intensity warfarin regimen in its addition to ASA for 7 months over ASA alone, but these results were not reproduced in the OASIS 2 study.

References

1. Direct Thrombin Inhibitor Trialists' Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet. 2002;359:294-302.
2. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation. 1994;90:1631-1637.
3. Neuhaus KL, von Essen R, Tebbe U, et al. Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study: a study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK). Circulation. 1994;90:1638-42.
4. Antman EM. Hirudin in acute myocardial infarction: thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9B trial. Circulation. 1996;94:911-921.
5. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med. 1996;335:775-782.
6. Antman EM. Hirudin in acute myocardial infarction: a safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial. Circulation. 1994;90:1624-1630.
7. Cannon CP, McCabe CH, Henry TD, et al. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial. J Am Coll Cardiol. 1994;23:993-1003.
8. Lidón RM, Théroux P, Lespérance J, et al. A pilot, early angiographic patency study using a direct thrombin inhibitor as adjunctive therapy to streptokinase in acute myocardial infarction. Circulation. 1994;89:1567-1572.
9. Théroux P, Pérez-Villa F, Waters D, Lespérance J, Shabani F, Bonan R. Randomized double-blind comparison of two doses of Hirulog with heparin as adjunctive therapy to streptokinase to promote early patency of the infarct-related artery in acute myocardial infarction. Circulation. 1995;91:2132-2139.
10. Neuhaus KL, Molhoek GP, Zeymer U, et al. Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial. J Am Coll Cardiol. 1999;34:966-973.
11. Fung AY, Lorch G, Cambier PA, et al, for the ESCALAT Investigators. Efegatran sulfate as an adjunct to streptokinase versus heparin as an adjunct to tissue plasminogen activator in patients with acute myocardial infarction. Am Heart J. 1999;138:696-704.
12. Coussement PK, Bassand JP, Convens C, et al, for the PENTALYSE investigators. A synthetic factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. The PENTALYSE study. Eur Heart. 2001;22:1716-1724.
13. White H, for the Hirulog and Early Reperfusion or Occlusion (HERO)-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised vascutrial. Lancet. 2001;358:1855-1863.

Glycoprotein IIb/IIIa inhibitors

By Raja Shekhar R. Sappati Biyyani, MD

• Platelet surface is abundant with glycoprotein IIb/IIIa (GPIIb/IIIa) receptors.
• Activation of platelets leads to conformational change and thereby increases affinity to fibrinogen.¹
• GPIIb/IIIa inhibitors competitively bind to the receptors and inhibit platelet aggregation.
• The various GPIIb/IIIa inhibitors currently available are:
• Abciximab, a Fab fragment of a humanized murine antibody.
• Eptifibatide is a synthetic GPIIb/IIIa antagonist with cyclic heptapeptide containing the KGD (Lys-Gly-Asp) sequence.
• Tirofiban is another synthetic GPIIb/IIIa antagonist and a nonpeptide mimetic of the RGD (Arg-Gly-Asp) sequence of fibrinogen.
• Multiple clinical trials have proven the efficacy of GPIIb/IIIa use in reducing the risk of death, revascularization, or myocardial infarction (MI) after 30 days and 6 months.²
• Risk stratification is critically important. Elevated troponin level is a major factor in decision making for the use of GPIIb/IIIa inhibitors in UA/NSTEMI.
• Use of GPIIb/IIIa inhibitors is of substantial benefit in patients with unstable angina (UA)/non-ST-elevation MI (NSTEMI) undergoing PCI.²
• GPIIb/IIIa inhibitors along with clopidogrel should be given before angiography for high-risk, troponin-positive patients (class I recommendations from the ACC/AHA joint guidelines for the management of UA/NSTEMI).³
• Intravenous GPIIb/IIIa inhibitor or clopidogrel should be added to ASA and anticoagulant therapy before diagnostic angiography (upstream) for lower-risk, troponin-negative patients (class I recommendations from the ACC/AHA joint guidelines for the management of UA/NSTEMI).³
• Abciximab is approved for the treatment of UA/NSTEMI as an adjunct to PCI or when PCI is planned within 24 hours.⁴
• The GUSTO IV-ACS trial failed to show the benefits of abciximab in patients with UA/NSTEMI in whom early (after less than 48 hours) revascularization was not planned.⁵
• Tirofiban in combination with heparin has been approved for the treatment of patients with ACS, including patients who are managed medically and those who are undergoing PCI.^6,7
• Eptifibatide is approved for the treatment of patients with ACS (UA/NSTEMI) who are treated medically or with PCI.⁸
• For UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, there less evidence of benefit. The addition of eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy may be reasonable for high-risk UA/NSTEMI patients.
• The timing of the above treatment should be made in consultation with cardiology. If cardiac catheterization is immediate, any of the above 3 GPIIb/IIIa antagonists could be used. However, if catheterization is delayed, there is evidence only supporting the use of eptifibatide.
• In patients with STEMI who have received primary medical reperfusion therapy, abciximab can be used to prevent complications of infarction in well-defined patients (anterior infarct, age > 75, and no increased risk of bleeding)³
• In patients with STEMI undergoing PCI, GPIIb/IIIa receptor blockers can be started prior to PCI. Abciximab has the greatest evidence supporting its use, but it is reasonable to use either eptifibatide or tirofiban based on class effect.³
• Aspirin is used with intravenous GPIIb/IIIa receptor blockers in all the trials.
• Use of heparin with GPIIb/IIIa inhibitors is currently strongly recommended. GPIIb/IIIa inhibitors can increase the ACT when combined with heparin. Lower heparin doses diminish the bleeding risk associated with GPIIb/IIIa blockade in the setting of PCI.
• Several trials have demonstrated that GPIIb/IIIa inhibitors can be used with LMWH among patients with unstable ischemic syndromes. There is no increase in the incidence of major and minor bleeding.⁹
• Treatment with GPIIb/IIIa inhibitors increases the risk of mucocutaneous and access site bleeding. No trials have shown an excess of intracranial bleeding with a GPIIb/IIIa inhibitor.
• Hemoglobin and platelet counts should be monitored, and patient surveillance for bleeding should be performed daily during the administration of GPIIb/IIIa receptor blockers.
• Thrombocytopenia is an unusual complication of this class of agents.

The ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction provides an outstanding comprehensive clinical care guideline that provides a more detailed discussion of these agents.

References

1. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995; 332:1553-1559.
2. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomized clinical trials. Lancet 2002; 359:189-198.
3. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2007;50:e1-157.
4. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet1997; 349:1429–1435.
5. Simoons ML. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularization: the GUSTO IV-ACS randomized trial. Lancet 2001; 357:1915-1924.
6. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. N Engl J Med 1998; 338:1498–1505.
7. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998; 338:1488–1497.
8. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998; 339(7):436-43.
9. Cohen M, Theroux P, Borzak S, et al. ACUTE II Investigators Randomized double-blind safety study of enoxaparin versus unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes treated with tirofiban and aspirin: the ACUTE II studyThe Antithrombotic Combination Using Tirofiban and Enoxaparin. Am Heart J 2002; 144:470-477.

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Therapeutics: OTHER TREATMENTS

By Chad Whelan, MD

Pharmacologic Therapeutics

Patients with ACS require many medications during their acute hospitalization, several of which will continue beyond the hospitalization.  Some of these medications have highly specific indications depending on risk stratification, the type of ACS, and the likelihood of PCI.  These considerations are of most concern in the area of anti-thrombotics.  Therefore, a more detailed discussion of these agents is provided.  Most of the other medications though are indicated for all types of ACS and their mechanisms of action should be clear to physicians leading improvement efforts in the area of ACS.  For these agents, a briefer discussion follows immediately.

Beta blockers should be given to all patients with suspected ACS without contraindications.  In the setting of ongoing evidence of ischemia, the initial dose should be given intravenously.  In patients with known CAD, beta blockers should be continued at discharge.  Relative contraindications include: heart block, symptomatic bradycardia, hypotension, reactive airway disease, and decompensated systolic dysfunction.  In those patients with cardiovascular contraindications, consultation with a cardiologist may be used to best determine the risk benefit profile.

In patients who present with symptoms of ongoing ischemia, particularly chest discomfort, NTG, usually SL, should be given.  If effective, the initial dosing can be followed by a longer acting route of administration, such as intravenous.  Nitrate induced hypotension is usually fluid responsive. Use of nitrates in the outpatient setting should be considered but is not required for all patients being discharged after an admission for ACS.  Patients given prescriptions for SL NTG need to be educated on the proper use of NTG and the role of EMS.  Caution should be used in patients with hypotension.  Nitrates must be avoided within 24 hours of PDE Inhibitors.

Morphine

Morphine can be a useful adjuvant therapy in patients with ongoing chest pain, agitation or symptomatic pulmonary venous congestion.  Generally, morphine should be used after NTG for these symptoms.  Opioid induced hypotension is usually fluid responsive.

ACE Inhibitors

All patients with ACS complicated by systolic dysfunction and/or diabetes should be prescribed an ACEI if their blood pressure tolerates it.  In addition, ACEI should be considered for all patients with ACS.  If initiated, ACEI should be continued after the patient is discharged.

Calcium Channel Blockers

The role of CCBs is more limited in ACS than for the above medications. They can be used as an anti-anginal therapy (or to control blood pressure) when beta blockers are contraindicated or when beta blocker and nitrate therapy is not adequately controlling anginal symptoms.  Generally, long acting CCBs are preferred.  Short acting dihydorpyridine CCBs should not be used without the concurrent use of a beta blocker to prevent tachycardia.

HMG Co A Reductase Inhibitors (Statins)

A lipid lowering regimen is indicated for all patients with LDL >100.  Usually, a statin based regimen is initiated.  These should be continued after discharge.  Dose titration can occur in the outpatient setting as needed.

References

Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2007;50:e1–157.

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EXERCISE TESTING IN ACUTE CORONARY SYNDROME

By Joshua Liberman, MD

The appropriate identification and management of the patient presenting with possible ACS remain problematic even in the current era of medical diagnostics and therapeutics. Among the large number of patients who present with possible ACS nationwide, the actual incidence of true or definite ACS is quite low. Additionally, patients with true ACS are at risk of a poor outcome, and effective therapies are time sensitive. Therefore, large numbers of such patients are admitted to hospitals for prolonged observation to find the few patients with definite ACS. Most of these patients ultimately are found not to have had an acute ischemic syndrome, resulting in significant overutilization of resources.

Stress and/or functional cardiac testing play an important role in the diagnosis, risk stratification, and initial management of the patient with possible ACS. These patients generally report typical or atypical angina but have negative biomarkers and a nonischemic ECG during the initial observation period. At the end of this observation period, the patient can be reevaluated with functional cardiac imaging (resting nuclear scan or echocardiography) and/or stress testing (treadmill, stress echocardiography, or stress nuclear testing).

Functional imaging

Echocardiography can be useful in the diagnosis of patients with ACS in certain settings. When the ECG is nondiagnostic because of baseline abnormalities (chronic left bundle branch block, paced rhythms, or chronic repolarization changes), reversible wall motion abnormalities during pain can document the presence of ischemia as well as the coronary territory involved and the amount of jeopardized myocardium.

Nuclear cardiac imaging can also be useful in the initial evaluation of patients with possible ACS. Acute rest myocardial perfusion imaging (MPI) performed during or within 2 hours of chest pain has a high negative predictive value, ranging from 99% to 100%, for excluding myocardial infarction as well as for predicting the absence of future cardiac events. In fact, current guidelines recommend that patients with possible ACS and normal acute rest MPI results do not need to be hospitalized. Multiple studies, including prospective randomized trials, have shown that these patients may be safely discharged from the ED and scheduled for an outpatient stress test and follow-up within 1 week. These studies have also shown significant cost savings, as well as shorter lengths of hospital stay. Alternatively, patients with abnormal acute rest MPI results have a high probability of ACS and require hospital admission for observation and treatment.

Stress Testing

Stress testing plays a role in the risk stratification of patients with ACS and an intermediate probability of having CAD. Patients sent for testing need to be carefully selected, as those at high risk for adverse outcomes (patients with recurrent rest angina, hemodynamic instability, or severe LV dysfunction despite medical therapy) would not benefit from further risk stratification. These patients should be referred for coronary angiography. Likewise, patients with a low likelihood of CAD after the initial evaluation also should not receive noninvasive testing, as even an abnormal test finding is unlikely to prompt additional therapy to reduce risk further.

Most patients presenting with ACS, however, do not fall into these clearly high- or low-risk categories and are therefore appropriate candidates for risk stratification with noninvasive testing. The patients who are candidates are those who are pain free, have either a normal or nonischemic ECG, and have normal cardiac biomarker measurements on admission and after 6 to 12 hours of observation. These patients may be considered for an early symptom-limited stress test in an attempt to elicit ischemia. This can be performed as an alternative to inpatient admission from the ED or as an outpatient within 72 hours. Importantly, low-risk patients who are referred for outpatient stress testing should be given precautionary pharmacotherapy (eg, ASA, sublingual NTG, and/or beta-blockers) while awaiting results of the stress test.

Type of stress test

The choice of test depends on the patient’s ability to exercise and the availability of different testing modalities at the individual institution. Patients who are capable of exercise and who have a normal or near-normal ECG can be evaluated with routine symptom-limited exercise stress testing. Patients who are incapable of exercise or who have an ECG pattern that would interfere with interpretation of the ST segment (LV hypertrophy, resting ST-segment changes or paced rhythms) should have an exercise test with either nuclear perfusion or echocardiography imaging. Those who cannot exercise and those with a chronic left bundle branch block should receive pharmacological stress testing. It is important to note that an imaging-enhanced test also may be more predictive in women than conventional ECG exercise stress testing and therefore may be considered a first-line choice.

Stress test interpretation

Provocation of ischemia or ischemic ECG changes at a low workload is usually the result of significant disease and is associated with an increased risk for adverse outcomes. These patients generally should be referred for coronary angiography. Alternatively, the ability to achieve a higher workload (>6.5 METS) without evidence of ischemia is associated with a better prognosis, and these patients can often be safely managed conservatively.

The imaging modalities can also be used to identify those patients at high risk for adverse outcomes. Findings of severe resting LV dysfunction (LVEF < 0.35), large perfusion defects (particularly if anterior), or multiple perfusion defects of moderate size induced by stress are just a few examples of these high-risk features. Alternatively, normal or small myocardial perfusion defects at rest or with stress or normal stress echocardiographic wall motion or minimal changes in small resting defects identify patients who can be safely managed as outpatients.

References

1. ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50:1-157.
2. Gibbons RJ, Balady GJ, Bricker JT, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Committee to Update the 1997 Exercise Testing Guidelines. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40:1531-1540.
3. Wackers FJ, Brown KA, Heller GV, et al. American Society of Nuclear Cardiology position statement on radionuclide imaging in patients with suspected acute ischemic syndromes in the emergency department or chest pain center. J Nucl Cardiol. 2002;9:246-250.

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SPECIAL CIRCUMSTANCE: COCAINE INDUCED

By Ashish Aneja, MD

The ACC/AHA has developed an outstanding set of guidelines about the management of patients with unstable angina/non-ST-elevation myocardial infarction. Included in the ACC/AHA 2007 guidelines is a section on the management of cocaine-induced myocardial ischemia. These guidelines address medication usage, including the controversy over using beta-blockers in these patients. In addition, the guidelines specifically suggest when to use an interventional approach versus a conservative approach. To read more about the ACC/AHA 2007 guidelines and the recommendations included, please see the article “ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction.”

Pathophysiology

Cocaine use has reached epidemic proportions in recent times. It is available as a water-soluble powder that can be taken orally, intranasally, or intravenously or in a heat-stable freebase form that can be smoked, known as crack cocaine. The use of the latter, a cheaper and more readily available form of cocaine, is especially popular in urban settings. Its use has been associated with chest pain, acute myocardial infarctions, accelerated atherosclerosis, cardiomyopathy, hypertensive crisis, aortic dissection, and endocarditis (with IV use or skin popping).1-5 Cocaine ingestion is also associated with arrhythmias such as wide-complex tachycardias and torsades de pointes, which can cause sudden cardiac death. Cocaine also causes other cardiovascular complications that can lead to arrhythmias, notably myocarditis and coronary spasm.

The mechanism of action consists of sympathetic and dopamine receptor activation by increasing the concentrations of norepinephrine and dopamine at postsynaptic receptors.6 Cocaine can also lead to an increase in the direct contractility of vascular smooth muscle.7 These effects lead to an accelerated chronotropic and blood pressure response, resulting in increased myocardial oxygen demand. Cocaine also promotes the development of a prothrombotic state by increasing platelet response to arachidonic acid, increasing thromboxane A2 production and platelet aggregation,9 and causing a reversible reduction in protein C and antithrombin III levels,10 all of which can promote coronary thrombosis.7,11,12 Cocaine can also cause marked coronary artery vasoconstriction. Thus, cocaine can result in myocardial ischemia and UA/NSTEMI with or without the presence of obstructive coronary atherosclerosis and coronary spasm.8

The route of administration determines the rapidity of onset and the duration of action. Cocaine is metabolized by plasma and liver cholinesterases and the metabolic products are excreted in the urine. Infants, elderly patients, and patients with hepatic dysfunction lack sufficient plasma cholinesterase to metabolize the drug and therefore are at high risk of adverse effects with cocaine use.13

Observation and monitoring

Biomarkers indicate evidence of a myocardial infarction in approximately 6% patients with cocaine-induced chest pain. Therefore, the vast majority of those using cocaine do not have evidence of myocardial necrosis.14,15 The management of patients with suspected cocaine-induced chest pain and a normal ECG or minimal T-wave abnormalities consists of sublingual nitroglycerin (NTG) or an oral calcium antagonist and observation. Increased muscle activity, skeletal muscle injury, and rhabdomyolysis frequently accompany cocaine use and are associated with CK and even CK-MB in the absence of MI,17 making cardiac troponin assays the mainstay of the diagnosis of MI. Patients with ST-segment changes but normal cardiac biochemical markers should be observed in the hospital in a monitored bed for 24 hours (most complications will occur within 24 hours).18 If a patient’s clinical condition and ECG remain unchanged after 24 hours of observation, the patient can be discharged.19

Treatment

In patients with suspected cocaine use and chest pain suggestive of myocardial ischemia and persistent STEMI, sublingual NTG or a calcium channel blocker (eg, diltiazem 20 mg IV) should be administered on arrival,12,20 and arrangements for an early coronary angiogram should be made. Fibrinolytic therapy has been successfully employed in patients with STEMI after cocaine use, but these patients frequently have contraindications to fibrinolytic therapy (hypertension, seizures, or aortic dissection), making PCI the preferred means of revascularization.

Bare-metal stents are preferred over drug-eluting stents in cocaine users because of higher rates of stent thrombosis with repeated cocaine use and a greater likelihood of noncompliance with extended dual antiplatelet therapy with aspirin and clopidogrel.

For patients with NSTEMI or U/A, the current ACC guidelines state that coronary angiography is probably recommended for patients with ischemic chest discomfort after cocaine use with new ST-segment depression or isolated T-wave changes and who are unresponsive to NTG and calcium antagonists.

Controversy about beta-blocker use

The use of beta-blockers in close proximity to cocaine exposure (ie, within 4-6 hours) is controversial. When used, the guidelines recommend combination alpha- and beta-blockade in addition to a vasodilator. There is no data to guide recommendations for beta-blockade later after exposure, that is, after cocaine elimination. Evidence from a single double-blind, randomized, placebo-controlled trial showed that beta-adrenergic blockade augments cocaine-induced coronary artery vasoconstriction.21 In contrast, if the patient has a high sympathetic state with sinus tachycardia and hypertension, beta-blockers can be used.7 Labetalol, an alpha- and beta-blocker, has been advocated, because it has been shown not to induce coronary artery vasoconstriction. However the beta-adrenergic-blocking action predominates over the alpha-adrenergic-blocking activity in the doses that are commonly used.22 Labetolol is currently a class 2b indication in the setting of cocaine use. Both NTG and verapamil have been shown to reverse cocaine-induced hypertension, coronary arterial vasoconstriction,20,22 and tachycardia (verapamil).

Benzodiazepine use

Benzodiazepines are recommended as first-line treatment for patients with cocaine-associated myocardial ischemia along with NTG and calcium channel blockers.19 In animal experiments, benzodiazepines attenuated the cardiac and central nervous system toxicity of cocaine.19 In addition to their anxiolytic properties, benzodiazepines reduce blood pressure and heart rate, thereby decreasing myocardial oxygen demand.19

Discharge

All patients admitted with chest pain because of cocaine use should be counseled during the hospital stay and/or at discharge regarding substance abuse and offered a referral to an outpatient drug-counseling program.

References

1. Dressler FA, Malekzadeh S, Roberts WC. Quantitative analysis of amounts of coronary arterial narrowing in cocaine addicts. Am J Cardiol. 1990;65:303-308.
2. Virmani R, Robinowitz M, Smialek JE, Smyth DF. Cardiovascular effects of cocaine: an autopsy study of 40 patients. Am Heart J. 1988;115:1068-1076.
3. Rashid J, Eisenberg MJ, Topol EJ. Cocaine-induced aortic dissection. Am Heart J. 1996;132:1301-1304.
4. Willens HJ, Chakko SC, Kessler KM. Cardiovascular manifestations of cocaine abuse: a case of recurrent dilated cardiomyopathy. Chest. 1994;106:594-600.
5. Chokshi SK, Moore R, Pandian NG, Isner JM. Reversible cardiomyopathy associated with cocaine intoxication. Ann Intern Med. 1989;111:1039-1040.
6. Lange RA, Flores ED, Cigarroa RG, Hillis LD. Cocaine-induced myocardial ischemia. Cardio. 1990;7:7578-7579.
7. Isner JM, Chokshi SK. Cardiovascular complications of cocaine. Curr Probl Cardiol. 1991;16:89-123.
8. Lange RA, Cigarroa RG, Yancy CWJ, et al. Cocaine-induced coronary-artery vasoconstriction. N Engl J Med. 1989;321:1557-1562.
9. Togna G, Tempesta E, Togna AR, Dolci N, Cebo B, Caprino L. Platelet responsiveness and biosynthesis of thromboxane and prostacyclin in response to in vitro cocaine treatment. Haemostasis. 1985;15:100-107.
10. Chokshi SK, Pitcairn LM. Cocaine and cardiovascular diseases: leading edge. Cardiol. 1989;3:1-6.
11. Zimmerman FH, Gustafson GM, Kemp HGJ. Recurrent myocardial infarction associated with cocaine abuse in a young man with normal coronary arteries: evidence for coronary artery spasm culminating in thrombosis. J Am Coll Cardiol. 1987;9:964-968.
12. Stenberg RG, Winniford, MD, Hillis LD, Dowling GP, Buja LM. Simultaneous acute thrombosis of two major coronary arteries following intravenous cocaine use. Arch Pathol Lab Med. 1989;113:521-524.
13. Loper KA. Clinical toxicology of cocaine. Med Toxicol Adverse Drug Exp. 1989;4:174-185.
14. Gitter MJ, Goldsmith SR, Dunbar DN, Sharkey SW. Cocaine and chest pain: clinical features and outcome of patients hospitalized to rule out myocardial infarction. Ann Intern Med. 1991;115:277-282.
15. Pitts WR, Lange RA, Cigarroa JE, Hillis LD. Cocaine-induced myocardial ischemia and infarction: pathophysiology, recognition, and management. Prog Cardiovasc Dis. 1997;40:65-76.
16. Nademanee K, Gorelick DA, Josephson MA, et al. Myocardial ischemia during cocaine withdrawal. Ann Intern Med. 1989;111:876-880.
17. Tokarski GF, Paganussi P, Urbanski R, Carden D, Foreback C, Tomlanovich MC. An evaluation of cocaine-induced chest pain. Ann Emerg Med. 1990;19:1088-1092.
18. Hollander JE, Hoffman RS, Gennis P, et al. Cocaine Associated Chest Pain (COCHPA) Study Group Prospective multicenter evaluation of cocaine-associated chest pain. Acad Emerg Med. 1994;1:330-339.
19. Hollander JE. The management of cocaine-associated myocardial ischemia. N Engl J Med. 1995;333:1267-1272.
20. Brogan WC, Lange RA, Kim AS, Moliterno DJ, Hillis LD. Alleviation of cocaine-induced coronary vasoconstriction by nitroglycerin. J Am Coll Cardiol. 1991;18:581-586.
21. Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine-induced coronary vasoconstriction by beta- adrenergic blockade. Ann Intern Med. 1990;112:897-903.
22. Boehrer JD, Moliterno DJ, Willard JE, Hillis LD, Lange RA. Influence of labetalol on cocaine-induced coronary vasoconstriction in humans. Am J Med. 1993;94:608-610.

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