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Classification of myocardial infarction and unstable angina: A re-assessment
International Journal of Cardiology 167 (2013) 2387–2390
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Classification of myocardial infarction and unstable angina: A re-assessment☆ Jaap W. Deckers ⁎ Thoraxcenter, Department of Cardiology, Erasmus Medical Center, Room Bd 420, PO Box 2040, 3000 CA Rotterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 9 January 2013 Accepted 13 January 2013 Available online 4 February 2013 Keywords: Acute coronary syndrome Unstable angina Prognosis
a b s t r a c t True or impending myocardial injury is being defined as an acute coronary syndrome (ACS), and includes ST-segment elevation MI, non-ST-segment elevation MI, and unstable angina. According to the revised MI definitions, patients with ischemic symptoms but with only a minor rise and fall in any biomarker are now being classified as having true myocardial injury. Against this background, this paper re-examines the position of “unstable angina” within the ACS context. It now must be acknowledged that the most recent definition of unstable angina, from 2000, which divided patients with unstable angina in those who were troponin-positive and those that remained troponin-negative, overlaps with the current MI definition. The seminal 1989 clinical definition of unstable angina thus remains the most appropriate description of that ACS entity. This “paradigm shift” has significant bearing on both the numbers of patients with non-ST-segment elevation MI, as well as on their prognosis. The same is true for patients now being diagnosed as having “unstable angina.” To a large extent, future cardiovascular risk is determined by clinical parameters, and their proper assessment thus remains paramount. Elevated age, previous MI, diabetes and/or renal dysfunction and, in particular, the presence of recent onset of symptoms (Braunwald category IIIB) with concomitant ECG changes should identify those at high risk. Patients with such characteristics should benefit from thorough medical management, including extensive platelet inhibition in most and coronary revascularization in many. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Among the various clinical components associated with ischemic heart disease, the acute manifestations receive most attention. Of course, this is quite appropriate, since the occurrence of an acute coronary syndrome carries considerable risk and constitutes a medical emergency that requires concerted and immediate medical action. Fortunately, improved insight into the pathophysiology of a heart attack and ensuing therapeutic measures have resulted in impressive improvements in outcomes of these entities in a rather short time period: in comparison to the complicated and often fatal course of patients hospitalized with a myocardial infarction (MI) only a few decades ago, the current, often relatively benign clinical course of these patients is certainly remarkable. Of note, specific pathophysiologic processes involved in true or impending myocardial injury have required distinctive therapeutic approaches, and, thus, over time, separate categories of acute coronary syndromes (ACS) have been defined. Patients with a myocardial infarction are now systematically being subdivided into those presenting with ST-segment elevation MI and, in the absence of this characteristic, as non-ST-segment elevation MI [1,2]. Also, adapted markers of myocardial injury, much more sen☆ This article is dedicated to the memory of Dr Kenneth L. Baughman, friend and mentor. ⁎ Tel.: +31 10 703 4472(office), +31 10 703 1814(secretary), +31 65 34 89831(mobile). E-mail address: [email protected]. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.01.008
sitive than their earlier versions, are being introduced on a large scale at this very moment. Since these markers have the ability to identify increasing numbers of patients with evidence of myocardial damage, the impact of their introduction in clinical practice will be very significant, perhaps even more so than that of the first generation of troponin essays, about a decade ago. In addition, the definition of myocardial infarction itself has been adapted: according to the revised definitions, patients with ischemic symptoms but with only a minor rise and fall in any biomarker are now being classified as having true myocardial injury [3,4]. It is thus evident that the classification of patients with an acute coronary syndrome is dynamic and continues to evolve. The consequences of these developments for the diagnosis of myocardial infarction have been extensively described, but the implications of these changes for the third component of the acute coronary syndrome, that of “unstable angina,” have received little attention. However, these consequences are quite considerable. For this reason, I have tried to re-assess the position of “unstable angina” within the context of the “acute coronary syndrome.” In order to situate the current position of unstable angina in its proper context, a short description of the two other components of the acute coronary syndrome is given first. 1.1. ST-segment elevation MI ST-segment elevation MI results from the sudden, complete, and usually proximal thrombotic occlusion of one of the epicardial coronary
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J.W. Deckers / International Journal of Cardiology 167 (2013) 2387–2390
arteries [1]. Plaque rupture and subsequent platelet activation generate the thrombus that blocks the lumen of the artery, and the large ischemic myocardial zone that results from the sudden blockage of the coronary perfusion not only determines the quite homogenous clinical presentation of these patients, but may also trigger fatal arrhythmias. Therapeutic measures focus on reperfusion of the occluded artery by pharmaceutical or, preferably, mechanical (by percutaneous coronary intervention) means, as early as possible. Although the prognosis of these patients has considerably improved in the last decades, ST-segment elevation MI still carries considerable risk, certainly in its early, arrhythmogenic, phase. Nevertheless, nowadays, hospital and/or 30-day mortality should be less than 10% in most institutions. Actual individual risk can be assessed with the help of a number of algorithms, and long delay to treatment initiation, compromised hemodynamic status, elevated age, renal insufficiency, diabetes and previous cardiac disease are the major (negative) prognostic determinants. 1.2. Non-ST-segment elevation MI Non-ST-segment elevation MI typically results from more distally located coronary thrombosis, and coronary arterial blockage often is only partial [2]. On average, patients presenting with non-ST segment elevation MI are older than their counterparts presenting with ST-segment elevation. Amongst others, collateral coronary blood flow, ischemic pre-conditioning as well as concomitant preventive medication modulate the acute disease process, its clinical presentation and subsequent sequelae. Intensive platelet aggregation inhibitor and anti-coagulant therapy constitute the early therapeutic cornerstones. Given its pathophysiologic background, the clinical presentation of non-ST-segment elevation MI is somewhat less homogeneous than that of ST-segment elevation MI. Still, popular prognostic models, such as from the GRACE registry or the TIMI risk model, comprise not dissimilar parameters as in ST-elevation MI: elevated age, high heart rate, low blood pressure, renal dysfunction and previous cardiac disease carry most weight (Table 1) [5–7]. Current guidelines advocate the use of risk scores to guide the intensity of medical management, in particular early coronary angiography and subsequent revascularization in patients considered to be at high risk. Short term prognosis typically is better than in ST-segment elevation MI, and hospital or 30-day mortality in non-ST segment elevation MI should not exceed 5% in the absence of major comorbidity or in patients b 80 years of age. 1.3. Revised definition of MI While a new definition of MI was presented for the first time in 2000, the impact of the second Consensus Document (from 2007) was more significant, since that statement not only emphasized the different conditions which could lead to an MI, but also – and more importantly – highlighted the leading principle that any evidence of myocardial necrosis in the setting of myocardial ischemia should be considered a MI [8,9]. The introduction of the extremely sensitive assays for markers of myocardial necrosis necessitated the appearance of a new edition, and the Third Global MI Task Force, from 2012, Table 1 Clinical characteristics associated with adverse outcomes in patients with unstable angina and non-ST-segment elevation MI [5–7]. Elevated age Prior CAD Angina at rest ST deviation Poor hemodynamic status Renal dysfunction Diabetes
recognized that even a minor amount of myocardial injury or necrosis could be detected by biochemical markers (and/or myocardial imaging) [3]. Modern bioassays of cardiac (c) troponin, with both high myocardial tissue specificity as well as high sensitivity, are the currently preferred biomarkers for myocardial injury. Abnormal concentrations of the troponins are defined in the presence of a value exceeding the 99% percentile of the normal reference limit. Detection of a typical rise and fall of the (so called “high sensitive” or “hs”) troponin concentration is essential for the diagnosis of acute MI in a patient with a high clinical suspicion. This link between clinical presentation and laboratory findings is paramount, because troponin concentrations may be elevated in other conditions, including (acute) heart failure or myocarditis. Most often, however, these disorders lack the characteristic chest pain associated with myocardial ischemia and/or necrosis. Abnormal biomarker values, but without the characteristic rise and fall as seen in myocardial injury of sudden onset, can also be found in the presence of renal disease and chronic heart failure [3]. Interestingly, the (continuous) presence of elevated levels of hs-troponins has also been described in out-patients with severe, but stable coronary artery disease [10]. The implications of these findings are also yet unclear, but it is not unlikely that such a finding could portend a worse prognosis. 1.4. Unstable angina Among the various acute coronary disease entities that make up the “acute coronary syndrome,” unstable angina must be considered the most heterogeneous. Its pathophysiological background is not unlike that of the other two components of the acute coronary syndrome, and unstable angina can thus result from comparable mechanisms than the other components of the acute coronary syndrome. The following, mutually not exclusive causes of unstable angina have been proposed previously, and these are still very much operative today: [1] a non-occlusive thrombus on a preexisting plaque, [2] a dynamic obstruction, [3] progressive mechanical obstruction, [4] inflammation, and [5] secondary unstable angina, an imbalance between myocardial oxygen supply and demand [11,12]. Although the term “unstable angina” was already popular in the seventies, its first, seminal, classification scheme from Braunwald was published in 1989 (Table 2) [13]. In that definition of unstable angina, the severity of the clinical presentation, the clinical circumstances in which the symptoms occurred, and the presence of transient ST-T wave changes, were leading. This first definition of unstable angina was revised in 2000 [11]. Importantly, in that revision, one large group of patients with unstable angina with symptoms at rest within the past 48 hours (class IIIB) was subdivided in those who were troponin-positive and in patients who remained troponin-negative. At that time, the inclusion of these biomarkers, then described as surrogate markers of coronary thrombosis, certainly seemed appropriate, since even (minor) elevation of troponin levels was found to be accompanied with markedly increased levels of risk of myocardial infarction and death, while the risk of these complications was much lower in the absence of such elevations. Now, however, it must be acknowledged that this most recent definition of unstable angina overlaps with the currently redefined diagnosis of non-ST-segment elevation MI, and thus represent an unwelcome source for confusion for both doctors and patients. Thus, the 1989 clinical definition of unstable angina remains the most appropriate description of that ACS entity, and the statement “Back to the Future” certainly seems applicable here [13]. 1.5. From omen to nomen According to the revised MI definition, symptomatic patients with an albeit minor, but typical rise and fall of markers of myocardial necrosis, previously categorized as having “unstable angina,” must now
J.W. Deckers / International Journal of Cardiology 167 (2013) 2387–2390
2389
Table 2 Braunwald classification of unstable angina from 1989. Clinical circumstances
I — New onset of severe angina or accelerated angina, no rest pain II — Angina at rest within past month but not within the preceding 48 h (angina at rest, sub-acute) III — Angina at rest within 48 h (angina at rest, acute)
A. Secondary unstable angina Develops in the presence of extra-cardiac conditions intensifying ischemia
B. Primary unstable angina Develops in the absence of extra-cardiac conditions
C. Post-infarction unstable angina Develops within 2 weeks of acute MI
IA
IB
IC
IIA
IIB
IIC
IIIA
IIIB
IIIC
Patients may be further divided in those with and without transient ST-T wave changes during pain.
be re-classified as having non-ST-segment elevation MI. This “paradigm shift” will have significant bearing on both the numbers of patients with non-ST-segment elevation MI, as well as on their prognosis. The first issue in particular was elegantly described in a recent paper from Yeh and co-workers, who published population trends in the incidence and outcomes in over 40,000 patients hospitalized for incident myocardial infarction between 1999 and 2008 [14]. In that time period, the overall incidence (and mortality) of MI decreased significantly: however, the incidence of non-ST-segment elevation MI gradually increased until the year 2004, and only marginally decreased thereafter. This (temporary) increase could be directly linked to the introduction and more frequent clinical use of troponin testing in that specific time period. Without doubt, the increase in MI incidence following the introduction of the new troponin assays will also be very significant and clinically relevant: in recent studies, the number of patients re-classified from “unstable angina” to “non-ST-segment elevation MI,” on the basis of the lower diagnostic troponin threshold, increased the absolute number of patients with a myocardial infarction with more than 15% [15,16]. The relationship between markers of myocardial necrosis and prognosis has been firmly established, and as the prognostic gradient between patients with ST-segment elevation MI, non-ST-elevation MI and unstable angina attests, a direct relation exists between myocardial damage, troponin levels and outcome [17]. The re-classification of patients with “unstable angina” (old definition) with some troponin release to non-ST-segment elevation MI (new definition) will thus not only increase the number of patients from the latter category, but will also improve their prognosis, since this category will be “enriched” with patients with only minor biomarker release and thus “minimal” myocardial damage. In a similar vein, the prognosis of patients with (true) “unstable angina” without troponin release will improve as well, since those with the highest risk have been eliminated from this category. 1.6. Clinical implications While the extent of myocardial damage is a major prognostic factor in ACS patients, inspection of the most popular and robust prognostic models developed in unstable angina/non-ST-elevation MI shows that, in addition to the level of biomarkers, other parameters contribute also significantly to outcome. For instance, in the GRACE risk model, the presence of abnormal biomarkers contributes only 15 units in a total risk score that is generally in the order of magnitude of 100 to 150 units, e.g. an increase in risk associated with abnormal biomarkers of about 10–15% [7]. The importance of clinical parameters to prognosis thus must be acknowledged, and it is therefore appropriate to appreciate – once more – the specific clinical presentation of the patient with unstable angina. Universal clinical characteristics associated with an adverse outcome have been delineated in Table 1, and it goes without saying that the presence of a number of such parameters in a patient with
unstable angina but without troponin elevation portends a worse outcome. This then is a plea to consider the patient with clinical angina in his or hers proper clinical context, and there can be no doubt that many patients, in particular those with previous cardiac disease with recently developed chest pain but without elevation of hs-troponin, must still be considered to be high risk. It will be necessary to study the immediate clinical course and prognosis of patients with unstable angina but without abnormal hs-troponin release in order to determine how these patients must be managed best in the future [18]. Fortunately, recent reports provide some guidance. Reichlin et al. have validated the prognostic gradient associated with different concentration of troponin levels, hs-troponin included, while the recent study from Sanchis et al. confirmed that in patients with chest pain but with low levels of h-troponin, clinical characteristics and ECG findings added significant prognostic information in patients [18,19]. As matter of course, this is very much in line with the insight provided above. At this moment then, it seems reasonable to state that “unstable angina” should remain part of the ACS entity. Proper assessment of clinical characteristics associated with adverse outcome will be paramount in these patients, and parameters such as elevated age, previous cardiac disease, diabetes and/or renal dysfunction and, in particular, the presence of recent (b48 hours) onset of symptoms as in Braunwald category IIIB angina with concomitant ECG changes remain powerful predictors that should allow the proper identification of those at high risk. It is likely that these patients should benefit from thorough medical management, including more extensive medical regimen in most, and coronary revascularization in many [20].
2. Summary and conclusion Acute coronary syndromes encompass a wide spectrum of disease, from ST-segment elevation MI, to non-ST-segment elevation MI and unstable angina. As a result of revised definitions, according to which an abnormal value of the most sensitive cardiac biomarkers in a patient with a high clinical suspicion of ACS must be considered to represent myocardial necrosis and thus myocardial infarction, many ACS patients will be reclassified from unstable angina to non-ST-segment elevation. The incidence of non-ST-elevation (and thus the number of these patients) will therefore increase significantly. Because prognosis is directly linked to the amount of myocardial damage, the prognosis of patients with a non-ST-segment elevation MI will improve further. By definition, patients with unstable angina cannot be identified on the basis of currently available biomarkers, and a diagnosis of unstable angina must be based on clinical grounds. The absence of abnormal troponin levels in these patients will be associated with a relatively benign clinical course. Still, the presence of clinical parameters associated with adverse outcome, such as the worsening of symptoms in a patient with an unfavorable clinical
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profile, will identify patients at high risk who should benefit from more intensive clinical management.
[8]
Acknowledgments [9]
The author respectfully acknowledges the supportive comments of Dr. Eugene Braunwald on the first draft of this article.
[10]
References
[11]
[1] The Task Force on the Management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569–619. [2] The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2011;32(23):2999–3054. [3] Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD. The Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Eur Heart J 2012;33:2551–67. [4] Braunwald E. Unstable angina and non-ST elevation myocardial infarction. Am J Respir Crit Care Med 2012;185:924–32. [5] Boersma E, Pieper KS, Steyerberg EW, et al. For the PURSUT Investigators. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. Circulation 2006;101:2557–67. [6] Antman EM, Cohen M, Bernink PJ, 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. [7] Eagle KA, Lim MJ, Dabbous OH, et al. For the GRACE Investigators. A validated prediction model for all forms of acute coronary syndrome: estimating the risk
[12] [13] [14]
[15]
[16] [17] [18]
[19]
[20]
of 6-month postdischarge death in an international registry. JAMA 2004;291: 2727–33. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined–a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;3:959–69. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;116(22):2634–53. Ndrepepa G, Braun S, Mehili J, et al. Prognostic value of sensitive troponin T in patients with stable and unstable angina and undetectable conventional troponin. Am Heart J 2011;161:68–75. Hamm CW, Braunwald E. A classification of unstable angina revisited. Circulation 2000;102:118–22. Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation 2012;125:1147–56. Braunwald E. Unstable angina. A classification. Circulation 1989;80:410–4. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med 2010;362: 2155–65. Mills NL, Lee KK, McAllister DA, et al. Implications of lowering threshold of plasma troponin concentration in diagnosis of myocardial infarction: cohort study. BMJ 2012;344 [e1533doi]. Meune C, Balmelli C, Twerenbold R, et al. Patients with acute coronary syndrome and normal high-sensitivity troponin. Am J Med 2011;124:1151–7. Hallén J. Troponin for the estimation of infarct size: what have we learned? Cardiology 2012;121:204–12. Reichlin T, Twerenbold R, Reiter M, et al. Introduction of high-sensitivity troponin assays: impact on myocardial infarction incidence and progosis. Am J Med 2012;125:1205–13. Sanchis J, Bardaji A, Bosch X, et al. Usefulness of high-sensitivity troponin T for the evaluation of patients with acute chest pain and no or minimal myocardial damage. Am Heart J 2012;1064:194–200.e1. Fox KA, Clayton TC, Damman P, et al. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. J Am Coll Cardiol 2010;55:2435–45.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Classification of myocardial infarction and unstable angina: A re-assessment☆ Jaap W. Deckers ⁎ Thoraxcenter, Department of Cardiology, Erasmus Medical Center, Room Bd 420, PO Box 2040, 3000 CA Rotterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 9 January 2013 Accepted 13 January 2013 Available online 4 February 2013 Keywords: Acute coronary syndrome Unstable angina Prognosis
a b s t r a c t True or impending myocardial injury is being defined as an acute coronary syndrome (ACS), and includes ST-segment elevation MI, non-ST-segment elevation MI, and unstable angina. According to the revised MI definitions, patients with ischemic symptoms but with only a minor rise and fall in any biomarker are now being classified as having true myocardial injury. Against this background, this paper re-examines the position of “unstable angina” within the ACS context. It now must be acknowledged that the most recent definition of unstable angina, from 2000, which divided patients with unstable angina in those who were troponin-positive and those that remained troponin-negative, overlaps with the current MI definition. The seminal 1989 clinical definition of unstable angina thus remains the most appropriate description of that ACS entity. This “paradigm shift” has significant bearing on both the numbers of patients with non-ST-segment elevation MI, as well as on their prognosis. The same is true for patients now being diagnosed as having “unstable angina.” To a large extent, future cardiovascular risk is determined by clinical parameters, and their proper assessment thus remains paramount. Elevated age, previous MI, diabetes and/or renal dysfunction and, in particular, the presence of recent onset of symptoms (Braunwald category IIIB) with concomitant ECG changes should identify those at high risk. Patients with such characteristics should benefit from thorough medical management, including extensive platelet inhibition in most and coronary revascularization in many. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Among the various clinical components associated with ischemic heart disease, the acute manifestations receive most attention. Of course, this is quite appropriate, since the occurrence of an acute coronary syndrome carries considerable risk and constitutes a medical emergency that requires concerted and immediate medical action. Fortunately, improved insight into the pathophysiology of a heart attack and ensuing therapeutic measures have resulted in impressive improvements in outcomes of these entities in a rather short time period: in comparison to the complicated and often fatal course of patients hospitalized with a myocardial infarction (MI) only a few decades ago, the current, often relatively benign clinical course of these patients is certainly remarkable. Of note, specific pathophysiologic processes involved in true or impending myocardial injury have required distinctive therapeutic approaches, and, thus, over time, separate categories of acute coronary syndromes (ACS) have been defined. Patients with a myocardial infarction are now systematically being subdivided into those presenting with ST-segment elevation MI and, in the absence of this characteristic, as non-ST-segment elevation MI [1,2]. Also, adapted markers of myocardial injury, much more sen☆ This article is dedicated to the memory of Dr Kenneth L. Baughman, friend and mentor. ⁎ Tel.: +31 10 703 4472(office), +31 10 703 1814(secretary), +31 65 34 89831(mobile). E-mail address: [email protected]. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.01.008
sitive than their earlier versions, are being introduced on a large scale at this very moment. Since these markers have the ability to identify increasing numbers of patients with evidence of myocardial damage, the impact of their introduction in clinical practice will be very significant, perhaps even more so than that of the first generation of troponin essays, about a decade ago. In addition, the definition of myocardial infarction itself has been adapted: according to the revised definitions, patients with ischemic symptoms but with only a minor rise and fall in any biomarker are now being classified as having true myocardial injury [3,4]. It is thus evident that the classification of patients with an acute coronary syndrome is dynamic and continues to evolve. The consequences of these developments for the diagnosis of myocardial infarction have been extensively described, but the implications of these changes for the third component of the acute coronary syndrome, that of “unstable angina,” have received little attention. However, these consequences are quite considerable. For this reason, I have tried to re-assess the position of “unstable angina” within the context of the “acute coronary syndrome.” In order to situate the current position of unstable angina in its proper context, a short description of the two other components of the acute coronary syndrome is given first. 1.1. ST-segment elevation MI ST-segment elevation MI results from the sudden, complete, and usually proximal thrombotic occlusion of one of the epicardial coronary
2388
J.W. Deckers / International Journal of Cardiology 167 (2013) 2387–2390
arteries [1]. Plaque rupture and subsequent platelet activation generate the thrombus that blocks the lumen of the artery, and the large ischemic myocardial zone that results from the sudden blockage of the coronary perfusion not only determines the quite homogenous clinical presentation of these patients, but may also trigger fatal arrhythmias. Therapeutic measures focus on reperfusion of the occluded artery by pharmaceutical or, preferably, mechanical (by percutaneous coronary intervention) means, as early as possible. Although the prognosis of these patients has considerably improved in the last decades, ST-segment elevation MI still carries considerable risk, certainly in its early, arrhythmogenic, phase. Nevertheless, nowadays, hospital and/or 30-day mortality should be less than 10% in most institutions. Actual individual risk can be assessed with the help of a number of algorithms, and long delay to treatment initiation, compromised hemodynamic status, elevated age, renal insufficiency, diabetes and previous cardiac disease are the major (negative) prognostic determinants. 1.2. Non-ST-segment elevation MI Non-ST-segment elevation MI typically results from more distally located coronary thrombosis, and coronary arterial blockage often is only partial [2]. On average, patients presenting with non-ST segment elevation MI are older than their counterparts presenting with ST-segment elevation. Amongst others, collateral coronary blood flow, ischemic pre-conditioning as well as concomitant preventive medication modulate the acute disease process, its clinical presentation and subsequent sequelae. Intensive platelet aggregation inhibitor and anti-coagulant therapy constitute the early therapeutic cornerstones. Given its pathophysiologic background, the clinical presentation of non-ST-segment elevation MI is somewhat less homogeneous than that of ST-segment elevation MI. Still, popular prognostic models, such as from the GRACE registry or the TIMI risk model, comprise not dissimilar parameters as in ST-elevation MI: elevated age, high heart rate, low blood pressure, renal dysfunction and previous cardiac disease carry most weight (Table 1) [5–7]. Current guidelines advocate the use of risk scores to guide the intensity of medical management, in particular early coronary angiography and subsequent revascularization in patients considered to be at high risk. Short term prognosis typically is better than in ST-segment elevation MI, and hospital or 30-day mortality in non-ST segment elevation MI should not exceed 5% in the absence of major comorbidity or in patients b 80 years of age. 1.3. Revised definition of MI While a new definition of MI was presented for the first time in 2000, the impact of the second Consensus Document (from 2007) was more significant, since that statement not only emphasized the different conditions which could lead to an MI, but also – and more importantly – highlighted the leading principle that any evidence of myocardial necrosis in the setting of myocardial ischemia should be considered a MI [8,9]. The introduction of the extremely sensitive assays for markers of myocardial necrosis necessitated the appearance of a new edition, and the Third Global MI Task Force, from 2012, Table 1 Clinical characteristics associated with adverse outcomes in patients with unstable angina and non-ST-segment elevation MI [5–7]. Elevated age Prior CAD Angina at rest ST deviation Poor hemodynamic status Renal dysfunction Diabetes
recognized that even a minor amount of myocardial injury or necrosis could be detected by biochemical markers (and/or myocardial imaging) [3]. Modern bioassays of cardiac (c) troponin, with both high myocardial tissue specificity as well as high sensitivity, are the currently preferred biomarkers for myocardial injury. Abnormal concentrations of the troponins are defined in the presence of a value exceeding the 99% percentile of the normal reference limit. Detection of a typical rise and fall of the (so called “high sensitive” or “hs”) troponin concentration is essential for the diagnosis of acute MI in a patient with a high clinical suspicion. This link between clinical presentation and laboratory findings is paramount, because troponin concentrations may be elevated in other conditions, including (acute) heart failure or myocarditis. Most often, however, these disorders lack the characteristic chest pain associated with myocardial ischemia and/or necrosis. Abnormal biomarker values, but without the characteristic rise and fall as seen in myocardial injury of sudden onset, can also be found in the presence of renal disease and chronic heart failure [3]. Interestingly, the (continuous) presence of elevated levels of hs-troponins has also been described in out-patients with severe, but stable coronary artery disease [10]. The implications of these findings are also yet unclear, but it is not unlikely that such a finding could portend a worse prognosis. 1.4. Unstable angina Among the various acute coronary disease entities that make up the “acute coronary syndrome,” unstable angina must be considered the most heterogeneous. Its pathophysiological background is not unlike that of the other two components of the acute coronary syndrome, and unstable angina can thus result from comparable mechanisms than the other components of the acute coronary syndrome. The following, mutually not exclusive causes of unstable angina have been proposed previously, and these are still very much operative today: [1] a non-occlusive thrombus on a preexisting plaque, [2] a dynamic obstruction, [3] progressive mechanical obstruction, [4] inflammation, and [5] secondary unstable angina, an imbalance between myocardial oxygen supply and demand [11,12]. Although the term “unstable angina” was already popular in the seventies, its first, seminal, classification scheme from Braunwald was published in 1989 (Table 2) [13]. In that definition of unstable angina, the severity of the clinical presentation, the clinical circumstances in which the symptoms occurred, and the presence of transient ST-T wave changes, were leading. This first definition of unstable angina was revised in 2000 [11]. Importantly, in that revision, one large group of patients with unstable angina with symptoms at rest within the past 48 hours (class IIIB) was subdivided in those who were troponin-positive and in patients who remained troponin-negative. At that time, the inclusion of these biomarkers, then described as surrogate markers of coronary thrombosis, certainly seemed appropriate, since even (minor) elevation of troponin levels was found to be accompanied with markedly increased levels of risk of myocardial infarction and death, while the risk of these complications was much lower in the absence of such elevations. Now, however, it must be acknowledged that this most recent definition of unstable angina overlaps with the currently redefined diagnosis of non-ST-segment elevation MI, and thus represent an unwelcome source for confusion for both doctors and patients. Thus, the 1989 clinical definition of unstable angina remains the most appropriate description of that ACS entity, and the statement “Back to the Future” certainly seems applicable here [13]. 1.5. From omen to nomen According to the revised MI definition, symptomatic patients with an albeit minor, but typical rise and fall of markers of myocardial necrosis, previously categorized as having “unstable angina,” must now
J.W. Deckers / International Journal of Cardiology 167 (2013) 2387–2390
2389
Table 2 Braunwald classification of unstable angina from 1989. Clinical circumstances
I — New onset of severe angina or accelerated angina, no rest pain II — Angina at rest within past month but not within the preceding 48 h (angina at rest, sub-acute) III — Angina at rest within 48 h (angina at rest, acute)
A. Secondary unstable angina Develops in the presence of extra-cardiac conditions intensifying ischemia
B. Primary unstable angina Develops in the absence of extra-cardiac conditions
C. Post-infarction unstable angina Develops within 2 weeks of acute MI
IA
IB
IC
IIA
IIB
IIC
IIIA
IIIB
IIIC
Patients may be further divided in those with and without transient ST-T wave changes during pain.
be re-classified as having non-ST-segment elevation MI. This “paradigm shift” will have significant bearing on both the numbers of patients with non-ST-segment elevation MI, as well as on their prognosis. The first issue in particular was elegantly described in a recent paper from Yeh and co-workers, who published population trends in the incidence and outcomes in over 40,000 patients hospitalized for incident myocardial infarction between 1999 and 2008 [14]. In that time period, the overall incidence (and mortality) of MI decreased significantly: however, the incidence of non-ST-segment elevation MI gradually increased until the year 2004, and only marginally decreased thereafter. This (temporary) increase could be directly linked to the introduction and more frequent clinical use of troponin testing in that specific time period. Without doubt, the increase in MI incidence following the introduction of the new troponin assays will also be very significant and clinically relevant: in recent studies, the number of patients re-classified from “unstable angina” to “non-ST-segment elevation MI,” on the basis of the lower diagnostic troponin threshold, increased the absolute number of patients with a myocardial infarction with more than 15% [15,16]. The relationship between markers of myocardial necrosis and prognosis has been firmly established, and as the prognostic gradient between patients with ST-segment elevation MI, non-ST-elevation MI and unstable angina attests, a direct relation exists between myocardial damage, troponin levels and outcome [17]. The re-classification of patients with “unstable angina” (old definition) with some troponin release to non-ST-segment elevation MI (new definition) will thus not only increase the number of patients from the latter category, but will also improve their prognosis, since this category will be “enriched” with patients with only minor biomarker release and thus “minimal” myocardial damage. In a similar vein, the prognosis of patients with (true) “unstable angina” without troponin release will improve as well, since those with the highest risk have been eliminated from this category. 1.6. Clinical implications While the extent of myocardial damage is a major prognostic factor in ACS patients, inspection of the most popular and robust prognostic models developed in unstable angina/non-ST-elevation MI shows that, in addition to the level of biomarkers, other parameters contribute also significantly to outcome. For instance, in the GRACE risk model, the presence of abnormal biomarkers contributes only 15 units in a total risk score that is generally in the order of magnitude of 100 to 150 units, e.g. an increase in risk associated with abnormal biomarkers of about 10–15% [7]. The importance of clinical parameters to prognosis thus must be acknowledged, and it is therefore appropriate to appreciate – once more – the specific clinical presentation of the patient with unstable angina. Universal clinical characteristics associated with an adverse outcome have been delineated in Table 1, and it goes without saying that the presence of a number of such parameters in a patient with
unstable angina but without troponin elevation portends a worse outcome. This then is a plea to consider the patient with clinical angina in his or hers proper clinical context, and there can be no doubt that many patients, in particular those with previous cardiac disease with recently developed chest pain but without elevation of hs-troponin, must still be considered to be high risk. It will be necessary to study the immediate clinical course and prognosis of patients with unstable angina but without abnormal hs-troponin release in order to determine how these patients must be managed best in the future [18]. Fortunately, recent reports provide some guidance. Reichlin et al. have validated the prognostic gradient associated with different concentration of troponin levels, hs-troponin included, while the recent study from Sanchis et al. confirmed that in patients with chest pain but with low levels of h-troponin, clinical characteristics and ECG findings added significant prognostic information in patients [18,19]. As matter of course, this is very much in line with the insight provided above. At this moment then, it seems reasonable to state that “unstable angina” should remain part of the ACS entity. Proper assessment of clinical characteristics associated with adverse outcome will be paramount in these patients, and parameters such as elevated age, previous cardiac disease, diabetes and/or renal dysfunction and, in particular, the presence of recent (b48 hours) onset of symptoms as in Braunwald category IIIB angina with concomitant ECG changes remain powerful predictors that should allow the proper identification of those at high risk. It is likely that these patients should benefit from thorough medical management, including more extensive medical regimen in most, and coronary revascularization in many [20].
2. Summary and conclusion Acute coronary syndromes encompass a wide spectrum of disease, from ST-segment elevation MI, to non-ST-segment elevation MI and unstable angina. As a result of revised definitions, according to which an abnormal value of the most sensitive cardiac biomarkers in a patient with a high clinical suspicion of ACS must be considered to represent myocardial necrosis and thus myocardial infarction, many ACS patients will be reclassified from unstable angina to non-ST-segment elevation. The incidence of non-ST-elevation (and thus the number of these patients) will therefore increase significantly. Because prognosis is directly linked to the amount of myocardial damage, the prognosis of patients with a non-ST-segment elevation MI will improve further. By definition, patients with unstable angina cannot be identified on the basis of currently available biomarkers, and a diagnosis of unstable angina must be based on clinical grounds. The absence of abnormal troponin levels in these patients will be associated with a relatively benign clinical course. Still, the presence of clinical parameters associated with adverse outcome, such as the worsening of symptoms in a patient with an unfavorable clinical
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profile, will identify patients at high risk who should benefit from more intensive clinical management.
[8]
Acknowledgments [9]
The author respectfully acknowledges the supportive comments of Dr. Eugene Braunwald on the first draft of this article.
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