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 know