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Cardiac markers and risk stratification: an integrated approach
Clinica Chimica Acta 311 Ž2001. 9–17 www.elsevier.comrlocaterclinchim
Cardiac markers and risk stratification: an integrated approach Marcello Galvani a,b,) , Donatella Ferrini a,b, Francesca Ghezzi b, Filippo Ottani a,c a b
CardioÕascular Research Unit, Fondazione Sacco, Forlı, ` Italy DiÕision of Cardiology, Ospedale G.B. Morgagni, Forlı, ` Italy c DiÕision of Cardiology, Ospedale CiÕile, BentiÕoglio, Italy
Abstract Risk stratification of patients with acute coronary syndromes ŽACS. is pivotal for correct allocation of health resources and for maximizing the benefit of available treatment modalities. However, clinical and electrocardiographic indicators of high risk lack sufficient sensitivity for the detection of major cardiac events. The complementary information provided by the measurement of different biomarkers is believed to be very useful. Specifically, elevations of cardiac troponin I ŽcTnI. and T ŽcTnT. are strongly associated with a high-risk profile both at short- and long-term. This has been definitely demonstrated in many studies as well as in cumulative meta-analysis. The role of different biomarkers, such as those reflecting activation of hemostasis and the presence of inflammation, is however less defined. At the moment, no study has prospectively evaluated these biomarkers in the whole spectrum of unselected patients with ACS. It is also unclear whether these biomarkers add independent prognostic value to the clinical and electrocardiographic indicators of adverse outcome and whether they offer additional information when compared to each other. The Early Prognostic Value of Biochemical Markers of M yocardial Damage, Activation of Hemostatic Mechanism and Inflammation in Acute Ischemic Syndromes ŽEMAI. study has been prospectively designed to solve these issues. In this study, we have evaluated the prognostic value of cTnI and cTnT, D-dimer, prothrombin fragment 1 q 2 ŽF1 q 2., thrombin–antithrombin complex ŽTAT. and C-reactive protein ŽCRP. in patients with ACS at the time of admission. We have enrolled in 31 Italian Coronary Care Units 1971 patients with rest anginal pain within 12 h from admission and electrocardiographic evidence of myocardial ischemia. Of these, 730 patients resulted to have ST-segment elevation myocardial infarction eligible for a reperfusion strategy and 1241, an acute coronary syndrome without persisting ST-segment elevation. Primary outcome measure of the study is the composite of death and non-fatal MI within 30 days from admission, which has occurred in 8.9% of the study population. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Acute coronary syndromes; Outcome; Hemostatic markers; Antithrombotic drugs
1. Introduction
Corresponding author. Fondazione Cardiologica AM.Z. SaccoB —ONLUS Piazza F.lli Ruffini, 6 47100 Forlı, ` Italy. Tel.: q39-543-33283, q39-335-8184086 Žmobile.; fax: q39-54331720. E-mail address: [email protected] ŽM. Galvani.. )
The term acute coronary syndromes ŽACS. encompasses a spectrum of clinical manifestations consisting of ST-segment elevation myocardial infarction, and ACS without persistent ST-segment elevation, i.e. unstable angina ŽUA. and non-Q wave
0009-8981r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 9 - 8 9 8 1 Ž 0 1 . 0 0 5 5 2 - 6
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myocardial infarction ŽNQMI.. This paper will review the issue of early risk stratification only in the latter patient category that is characterised by a common underlying pathophysiological mechanism, represented by the rupture or erosion of an atherosclerotic coronary plaque with differing degrees of superimposed thrombosis and distal embolization w1x. Patients with ACS without persistent ST-segment elevation, even at the turn of the century, are at high risk of myocardial infarction ŽMI. and death that ranges actually from 8% to 16% at 1-month followup, resulting from a series of recent large clinical trials ŽFig. 1.. Optimal treatment of patients with ST-segment elevation myocardial infarction is clearly defined w2x. However, the management of patients with ACS without persistent ST-segment elevation remains controversial in part because of the heterogeneous nature of this condition. Recent significant advances in treatment options for these patients has occurred, mainly related to the availability of aggressive antithrombotic drugs, like GP IIBrIIIA inhibitors, and to the improvement of the techniques of percutaneous coronary intervention. However, immediate revascularization is not always feasible, and the cost and the incidence of hemorrhagic complications of the new antithrombotic therapies are not trivial. An integrated, objective and user-friendly risk stratification algorithm is therefore hardly requested to effectively identify patients that can be managed conservatively because the gain obtained from an aggressive strategy does not outweigh the risk of drug or procedure-related adverse effects, and pa-
tients who are at high risk of complications warranting an immediate aggressive treatment strategy.
2. Diagnosis and risk assessment: a contemporary action The diagnosis of an ACS is based on history, clinical presentation Žincluding chest pain evaluation and physical examination., ECG tracing on admission and evaluation of biomarkers of myocardial damage. However, it is evident that clinicians, while diagnosing, begin risk-stratifying patients, because the diagnostic tools also contain important prognostic information that may concur to delineate the individual patient risk profile. 2.1. Demographics Age and male sex are associated with more severe coronary artery disease ŽCAD. and consequently with an increased risk of an unfavourable outcome as are diabetes mellitus and hypertension. Indeed, most of the well-known risk factors for CAD are also risk indicators for a worse prognosis in unstable CAD w3,4x. Previous manifestations of CAD such as severe or long-standing angina, or previous MI are also associated with more frequent subsequent cardiac events. A history of left ventricular dysfunction or congestive heart failure is also negative prognostic indicator w1x.
Fig. 1. Short-term Ž30–43 days. incidence of cardiac events in major antithrombotic trials. Definition of myocardial infarction ŽMI. or recurrent Žre. MI varied across the trials partially explaining differences in event rates.
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3. Clinical presentation The clinical presentation of ACS encompasses a wide variety of symptoms. The AclassicB clinical features include prolonged Ž) 20 min. anginal pain at rest, new onset Žde novo. severe ŽClass III of the Canadian Cardiovascular Society wCCSx classification. effort angina, or recent destabilisation of previously stable angina with at least CCS III angina characteristics Žcrescendo angina.. However, atypical presentations of ACS without persistent ST-segment elevation are not uncommon, being usually observed in younger Ž25–40 years. and older Ž) 75 years. patients, in diabetics and in women w5x. The clinical presentation and the time elapsed since the most recent episode of ischemia, the presence of angina at rest and the response to medical treatment provide important prognostic information w6x. The classification proposed by Braunwald, based on these clinical findings, is related to clinical outcome and has been used in scientific reports to define population characteristics w7x. However, in order to select the optimal treatment, other risk indicators also need to be taken into account w1x. 4. Physical examination Physical examination is most often normal, including chest examination, auscultation and measurement of heart rate and blood pressure. The purpose of the examination is to exclude non-cardiac causes of chest pain, non-ischemic cardiac disorders Žpericarditis, valvular heart disease., potential precipitating extra cardiac causes, pneumothorax and finally, to look for signs of hemodynamic instability. The presence of hypotension andror of pulmonary rales Ži.e. a Killip class ) 1. is an unusual feature in acute coronary syndrome patients at the time of hospital admission and cannot be considered sensitive markers of poor prognosis. The presence of hemodynamic instability is however a very specific marker of an unfavourable outcome w8x. 5. Electrocardiogram The resting electrocardiogram is a key in the assessment of patients with suspected ACS. It is a
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useful screening tool to provide evidence of an alternative diagnosis such as pericarditis, pulmonary embolism or cardiomyopathy. Comparison with a previous electrocardiogram, if available, is extremely valuable, particularly in patients with co-existing cardiac pathology such as left ventricular hypertrophy or previous myocardial infarction w5x. Shifts of the ST-segment Ž) 0.5 mm. and negative T wave Ž) 1 mm. are the most reliable electrocardiographic indicators of unstable coronary disease w9x. Nonspecific ST-segment shifts and T-wave changes Ž- 1 mm. are less specific. In the Multicenter Chest Pain Study, such non-specific changes were often noted in patients in whom UA was ultimately ruled out w10x. A completely normal electrocardiogram does not exclude the possibility of an acute coronary syndrome. The electrocardiogram is fundamental not only for the diagnosis but for prognosis as well. Patients with ST-segment depression have a higher risk for subsequent cardiac events compared to those with isolated T-wave inversion, who in turn have a higher risk than those with a normal electrocardiogram on admission w11x. Almost two-thirds of all ischemic episodes in unstable CAD are silent and hence, not likely to be detected by resting electrocardiogram. Holter monitoring of the ST-segment may be valuable, but it is limited to two to three monitored leads and off-line analysis, providing the results several hours or days after the recording. On-line continuous computer-assisted 12-lead electrocardiographic monitoring is an attractive alternative for immediate prognostic stratification. Continuous ST-monitoring studies have in fact revealed that 15–30% of patients with unstable CAD have transient episodes of ST-segment changes, predominantly ST-segment depression. These patients have an increased risk of subsequent cardiac events. The ST-segment monitoring adds independent prognostic information to the resting electrocardiogram and to other common clinical parameters w12–15x. 6. Biochemical markers of myocardial damage Cardiac troponin I or troponin T ŽcTnI and cTnT. are the preferred markers of myocardial necrosis because they allow a more sensitive detection of
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Fig. 2. Meta-analysis w18x of studies on the prognostic value of cardiac troponins I and T in patients without persisting ST-segment elevation.
myocardial damage and are more specific for the myocardial tissue than the traditional Acardiac enzymesB such as creatine kinase ŽCK. or its isoenzyme MB ŽCK-MB.. The troponin complex is formed by three distinct structural proteins Žtroponin I, C and T. and is located on the thin filament of the contractile apparatus in both skeletal and cardiac muscle tissue regulating the calcium dependent interaction of myosin and actin. The cardiac isoforms of troponin T and I are exclusively expressed in cardiac myocytes, and their detection in the blood is specific for myocardial damage w16x. After myocardial infarction, the troponin rise in peripheral blood is seen after 3–4 h with persistent elevation for up to 2 weeks. The high proportional rise of troponins, reflecting the low plasma concentrations in healthy persons, allows the detection of myocardial damage in about one-third of patients with UA even in the absence of minor CK-MB elevations w17x. In order to demonstrate or to exclude myocardial damage, repeated blood sampling is required during the first 6–12 h after admission and after any further episodes of severe chest pain.
Unstable patients with elevated levels of troponin have an unfavourable short- and long-term clinical outcome when compared to those without troponin elevation according to a recent meta-analysis w18x ŽFig. 2.. Elevated troponin levels predict the risk both of cardiac death and subsequent Žre.infarction. The results of comparable analyses of prognosis in relation to CK-MB elevations have been more conflicting w19,20x. The risk of new events is correlated with the degree of troponin elevation w20,21x. The increased risk associated with elevated troponin levels is independent from other risk factors such as electrocardiographic changes observed at rest or during continuous monitoring, or markers of inflammatory activity w22,23x.
7. Markers of inflammatory activity Increased fibrinogen and C-reactive protein ŽCRP. levels have been reported as risk markers in ACS, although the data are not always consistent w23–25x. In the FRISC trial, an elevated fibrinogen level was
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associated both with the short- and the long-term risk of death andror a subsequent myocardial infarction. The prognostic importance of fibrinogen was independent from electrocardiographic findings and troponin T levels w23x. CRP is an acute-phase protein produced by the liver under cytokine stimulation. Increases were predictive of an adverse outcome in a selected population of patients with severe unstable angina w26x. In the general population of ACS patients, the extent of risk conferred by the detection of CRP elevations is smaller than that defined by troponin increases but still significant. This is partially explained by the multiple mechanisms responsible for CRP increases in unstable CAD, possibly reflecting the propensity to progression of the unstable coronary plaque, the extent of myocardial damage, both or neither w27x. Fig. 3 shows the results of the meta-analysis we have performed on available studies on CRP in unstable CAD, where the combined end-point of death and non-fatal myocardial infarction is available at 30 days. The results of the meta-analysis, which included 2141 patients with UA and NQMI, although showing some degree of heterogeneity ŽChi-square 13.8; P s 0.03., at least, partially explained by different methods for measuring CRP and different cut-off values used to detect
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elevations, clearly indicate Ž P s 0.001. that the short-term risk of death or non-fatal myocardial infarction is increased about 1.5 times when CRP is increased. Furthermore, it has been demonstrated that CRP is a strong predictor of mortality over the long-term w28x. Measurement of CRP is particularly meaningful in conjunction with troponin, since CRP elevations may detect increased risk of cardiac events in patients who present with a negative troponin test w28–30x. 8. Hemostatic markers The measurement of markers of activation of the coagulationrfibrinolytic system with clinically meaningful laboratory methods could be important for risk stratification of patients with ACS since increases of activation peptides may reflect the tendency toward the progression of coronary thrombosis, and this subject is covered in detail in this monograph. An association between increased thrombin generation and an unfavourable outcome in UA has been found in some although not all trials w31,32x. Reduced fibrinolytic capacity has been associated with an increased risk of future coronary events in community-based population studies w33x.
Fig. 3. Meta-analysis of studies on C-reactive protein in patients with non-ST-segment elevation MI infarction or unstable angina w23,28,29,45–47x where the composite end-point of death or non-fatal myocardial infarction at 30 days is available. Risk is illustrated as Peto odds ratio Žfixed. and 95% confidence intervals ŽCI..
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Increased concentrations of PAI-1 have been reported to be related to an increased risk of new coronary events in MI survivors w34x. Increased D-dimer concentrations have been reported in UA as well as in acute MI w35x. Recently, their prognostic capacity was outlined in a high-risk cohort of ACS patients w36x and in MI survivors w37x. However, largescale trials of fibrinolytic activity in unstable CAD are still lacking and, therefore, the importance of such measurements for assessing prognosis remains unsettled. Currently, hemostatic markers are not recommended for risk stratification or selection of treatment in individual patients with unstable CAD. 9. Risk-stratification: an integrated approach The number of prognostic indicators available for rapid risk stratification of patients with ACS is definitely high. As previously discussed, the list encompasses several clinical, electrocardiographic and biochemical predictors of an adverse outcome. However, the relative importance of the single risk indicator may be extremely variable, depending upon a number of factors such as the strength of the relationship between the indicator and the mechanisms responsible for the unfavourable outcome, the spe-
cific patient population under study, the number of patients included, the subjective or objective nature of the indicator, etc. Such factors may account for even marked differences in the list of prognostic indicators and in their relative prognostic power observed in different studies. There is general agreement that in patients with ACS without persisting ST-segment elevation, the most important prognostic indicators available at the time of hospital admission are age, rest pain, particularly if recent and prolonged, hemodynamic instability, ST-segment depression and CKrCKMB increases indicative of evolving MI, or troponin elevations suggestive of AminorB myocardial damage. Utilising the presence or the absence of one or more of such indicators, a risk-classification of the patients may be attempted and some empirical suggestions about treatment strategy may be outlined ŽFig. 4.. This is not, however, an evidence-based approach since it is not based on the results of prospectively designed studies aimed to assess the prognostic role of well-defined risk indicators. Recently, Boersma et al. w38x reported the relation between the baseline characteristics and the occurrence of death or death and MI at 30 days in the PURSUIT trial, which included a population that
Fig. 4. A possible risk stratification algorithm for ACS patients without persisting ST-segment elevation.
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covered a wide variety of patients, hospital settings and treatment policies, sufficiently approximating the Areal worldB. Although retrospective, this analysis represents the first attempt to systematically evaluate the independent value of each potential prognostic indicator in order to build up a simple model for risk stratification of patients with ACS without persistent ST-segment elevation. Surprisingly, the authors found a remarkable homology with ST-segment elevation patients, since prognostic factors like age, heart rate, blood pressure and signs of heart failure resulted to be strong prognostic indicators also in this population. It was moreover observed that patients with myocardial infarction on admission Ži.e. those with elevated cardiac enzymes. had worse prognosis than patients without enzyme elevations. In the framework of the uncertainties of the clinical and electrocardiographic risk stratification, the troponins have gained wide popularity because of the ease of evaluation, the sensibility and specificity for myocardial damage and the independence from subjective evaluation Žwhen measured quantitatively.. Moreover, troponins have been demonstrated in various clinical trials to be independent prognostic indicators. However, the multivariate models generated did not account for the vast majority of the aforementioned important prognostic indicators, except age ŽTable 1.. The same applies for studies assessing the prognostic role of the electrocardiographic findings or continuous ST-segment monitoring w39x. In other words, a systematic and prospective evaluation of all potential prognostic tools is still lacking, and consequently, the role of biomarkers on top of this hypothetical risk model is still incompletely defined. Such approach to risk stratification would also represent a logical method that resembles the way the
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clinicians proceed, from admission onward, to evaluate patients with ACS. The data of the Early Prognostic Value of Biochemical Markers of M yocardial Damage, Activation of Hemostatic Mechanism and Inflammation in Acute Ischemic Syndromes ŽEMAI. study recently released at the National Meeting of the Associazione Nazionale Medici Cardiologi Ospedalieri ŽANMCO. held in Florence, Italy, May 20–23, 2000, appear to overcome many of these limitations. The EMAI study was in fact designed to prospectively study the prognostic role of several biomarkers, namely cardiac troponin I and T, CRP and hemostatic markers, such as prothrombin fragment 1 q 2, thrombin–antithrombin complex and D-dimer, when used in addition to the clinical and electrocardiographic risk indicators. An important feature of the study is represented by the fact that the population included Ž1971 patients: 730 patients with STsegment elevation eligible for a reperfusion strategy, and 1241 patients without persistent ST-segment elevation. is an unselected cohort of ACS patients admitted to 31 Italian Coronary Care Units within 12 h from symptom onset with electrocardiographic evidence of myocardial ischemia. Primary outcome measure of the study is the composite of death and non-fatal MI within 30 days from admission, which has occurred in 8.9% of the study population.
10. Therapeutic implications of an early risk stratification ACS Over the last 5 years, a number of new therapeutic options has been developed for patients with
Table 1 Independent prognostic value of cTn I and T in recent antithrombotic trials Trial
Independent value of cTn
Incremental value over CKMB
Additional independent prognostic indicators
GUSTO IIB w42x TIMI IIIB w43x FRISC w20x TRIM w44x
Yes Yes Yes Yes
Yes Yes Yes –
Age, ST≠, previous CABG, chronic RI, COPD STx, age Age, hypertension, no. antianginal drugs, STx Age, ACE inhibitors
Abbreviation: CABGs coronary artery by-pass grafting; COPDs chronic obstructive pulmonary disease; RI s renal insufficiency; ST≠ s ST-segment elevation; STx s ST-segment depression.
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ST-segment elevation and without persistent ST-segment elevation ACS. Selection of appropriate therapy for individual patient needs to be based on risk stratification, since the cost of therapy may range from very few to several thousand dollars Žfor treatment with GPIIBrIIIA inhibitors, plus PTCA and stenting.. Not only the costs are of concern, but also the risks of aggressive pharmacological or interventional treatment should be balanced against the little, if any, benefit in low risk patients. On the other hand, simple clinical, electrocardiographic and biochemical data available upon admission may identify high-risk patients as candidates for aggressive pharmacological and percutaneous interventions, the combination of which have clearly demonstrated to reduce the risk of cardiac events by a magnitude of 30–40% when administered to these patients w40,41x. A prospectively validated and Auser-friendlyB risk stratification algorithm is expected as soon as the results of recently completed or ongoing studies become available. Continuous refinement of prognosis, however, in the hours or days after admission, may be achieved by continuous electrocardiographic monitoring and biomarker determinations, providing evaluation of effectiveness of initial treatment strategies and guiding subsequent care.
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Cardiac markers and risk stratification: an integrated approach Marcello Galvani a,b,) , Donatella Ferrini a,b, Francesca Ghezzi b, Filippo Ottani a,c a b
CardioÕascular Research Unit, Fondazione Sacco, Forlı, ` Italy DiÕision of Cardiology, Ospedale G.B. Morgagni, Forlı, ` Italy c DiÕision of Cardiology, Ospedale CiÕile, BentiÕoglio, Italy
Abstract Risk stratification of patients with acute coronary syndromes ŽACS. is pivotal for correct allocation of health resources and for maximizing the benefit of available treatment modalities. However, clinical and electrocardiographic indicators of high risk lack sufficient sensitivity for the detection of major cardiac events. The complementary information provided by the measurement of different biomarkers is believed to be very useful. Specifically, elevations of cardiac troponin I ŽcTnI. and T ŽcTnT. are strongly associated with a high-risk profile both at short- and long-term. This has been definitely demonstrated in many studies as well as in cumulative meta-analysis. The role of different biomarkers, such as those reflecting activation of hemostasis and the presence of inflammation, is however less defined. At the moment, no study has prospectively evaluated these biomarkers in the whole spectrum of unselected patients with ACS. It is also unclear whether these biomarkers add independent prognostic value to the clinical and electrocardiographic indicators of adverse outcome and whether they offer additional information when compared to each other. The Early Prognostic Value of Biochemical Markers of M yocardial Damage, Activation of Hemostatic Mechanism and Inflammation in Acute Ischemic Syndromes ŽEMAI. study has been prospectively designed to solve these issues. In this study, we have evaluated the prognostic value of cTnI and cTnT, D-dimer, prothrombin fragment 1 q 2 ŽF1 q 2., thrombin–antithrombin complex ŽTAT. and C-reactive protein ŽCRP. in patients with ACS at the time of admission. We have enrolled in 31 Italian Coronary Care Units 1971 patients with rest anginal pain within 12 h from admission and electrocardiographic evidence of myocardial ischemia. Of these, 730 patients resulted to have ST-segment elevation myocardial infarction eligible for a reperfusion strategy and 1241, an acute coronary syndrome without persisting ST-segment elevation. Primary outcome measure of the study is the composite of death and non-fatal MI within 30 days from admission, which has occurred in 8.9% of the study population. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Acute coronary syndromes; Outcome; Hemostatic markers; Antithrombotic drugs
1. Introduction
Corresponding author. Fondazione Cardiologica AM.Z. SaccoB —ONLUS Piazza F.lli Ruffini, 6 47100 Forlı, ` Italy. Tel.: q39-543-33283, q39-335-8184086 Žmobile.; fax: q39-54331720. E-mail address: [email protected] ŽM. Galvani.. )
The term acute coronary syndromes ŽACS. encompasses a spectrum of clinical manifestations consisting of ST-segment elevation myocardial infarction, and ACS without persistent ST-segment elevation, i.e. unstable angina ŽUA. and non-Q wave
0009-8981r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 9 - 8 9 8 1 Ž 0 1 . 0 0 5 5 2 - 6
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myocardial infarction ŽNQMI.. This paper will review the issue of early risk stratification only in the latter patient category that is characterised by a common underlying pathophysiological mechanism, represented by the rupture or erosion of an atherosclerotic coronary plaque with differing degrees of superimposed thrombosis and distal embolization w1x. Patients with ACS without persistent ST-segment elevation, even at the turn of the century, are at high risk of myocardial infarction ŽMI. and death that ranges actually from 8% to 16% at 1-month followup, resulting from a series of recent large clinical trials ŽFig. 1.. Optimal treatment of patients with ST-segment elevation myocardial infarction is clearly defined w2x. However, the management of patients with ACS without persistent ST-segment elevation remains controversial in part because of the heterogeneous nature of this condition. Recent significant advances in treatment options for these patients has occurred, mainly related to the availability of aggressive antithrombotic drugs, like GP IIBrIIIA inhibitors, and to the improvement of the techniques of percutaneous coronary intervention. However, immediate revascularization is not always feasible, and the cost and the incidence of hemorrhagic complications of the new antithrombotic therapies are not trivial. An integrated, objective and user-friendly risk stratification algorithm is therefore hardly requested to effectively identify patients that can be managed conservatively because the gain obtained from an aggressive strategy does not outweigh the risk of drug or procedure-related adverse effects, and pa-
tients who are at high risk of complications warranting an immediate aggressive treatment strategy.
2. Diagnosis and risk assessment: a contemporary action The diagnosis of an ACS is based on history, clinical presentation Žincluding chest pain evaluation and physical examination., ECG tracing on admission and evaluation of biomarkers of myocardial damage. However, it is evident that clinicians, while diagnosing, begin risk-stratifying patients, because the diagnostic tools also contain important prognostic information that may concur to delineate the individual patient risk profile. 2.1. Demographics Age and male sex are associated with more severe coronary artery disease ŽCAD. and consequently with an increased risk of an unfavourable outcome as are diabetes mellitus and hypertension. Indeed, most of the well-known risk factors for CAD are also risk indicators for a worse prognosis in unstable CAD w3,4x. Previous manifestations of CAD such as severe or long-standing angina, or previous MI are also associated with more frequent subsequent cardiac events. A history of left ventricular dysfunction or congestive heart failure is also negative prognostic indicator w1x.
Fig. 1. Short-term Ž30–43 days. incidence of cardiac events in major antithrombotic trials. Definition of myocardial infarction ŽMI. or recurrent Žre. MI varied across the trials partially explaining differences in event rates.
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3. Clinical presentation The clinical presentation of ACS encompasses a wide variety of symptoms. The AclassicB clinical features include prolonged Ž) 20 min. anginal pain at rest, new onset Žde novo. severe ŽClass III of the Canadian Cardiovascular Society wCCSx classification. effort angina, or recent destabilisation of previously stable angina with at least CCS III angina characteristics Žcrescendo angina.. However, atypical presentations of ACS without persistent ST-segment elevation are not uncommon, being usually observed in younger Ž25–40 years. and older Ž) 75 years. patients, in diabetics and in women w5x. The clinical presentation and the time elapsed since the most recent episode of ischemia, the presence of angina at rest and the response to medical treatment provide important prognostic information w6x. The classification proposed by Braunwald, based on these clinical findings, is related to clinical outcome and has been used in scientific reports to define population characteristics w7x. However, in order to select the optimal treatment, other risk indicators also need to be taken into account w1x. 4. Physical examination Physical examination is most often normal, including chest examination, auscultation and measurement of heart rate and blood pressure. The purpose of the examination is to exclude non-cardiac causes of chest pain, non-ischemic cardiac disorders Žpericarditis, valvular heart disease., potential precipitating extra cardiac causes, pneumothorax and finally, to look for signs of hemodynamic instability. The presence of hypotension andror of pulmonary rales Ži.e. a Killip class ) 1. is an unusual feature in acute coronary syndrome patients at the time of hospital admission and cannot be considered sensitive markers of poor prognosis. The presence of hemodynamic instability is however a very specific marker of an unfavourable outcome w8x. 5. Electrocardiogram The resting electrocardiogram is a key in the assessment of patients with suspected ACS. It is a
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useful screening tool to provide evidence of an alternative diagnosis such as pericarditis, pulmonary embolism or cardiomyopathy. Comparison with a previous electrocardiogram, if available, is extremely valuable, particularly in patients with co-existing cardiac pathology such as left ventricular hypertrophy or previous myocardial infarction w5x. Shifts of the ST-segment Ž) 0.5 mm. and negative T wave Ž) 1 mm. are the most reliable electrocardiographic indicators of unstable coronary disease w9x. Nonspecific ST-segment shifts and T-wave changes Ž- 1 mm. are less specific. In the Multicenter Chest Pain Study, such non-specific changes were often noted in patients in whom UA was ultimately ruled out w10x. A completely normal electrocardiogram does not exclude the possibility of an acute coronary syndrome. The electrocardiogram is fundamental not only for the diagnosis but for prognosis as well. Patients with ST-segment depression have a higher risk for subsequent cardiac events compared to those with isolated T-wave inversion, who in turn have a higher risk than those with a normal electrocardiogram on admission w11x. Almost two-thirds of all ischemic episodes in unstable CAD are silent and hence, not likely to be detected by resting electrocardiogram. Holter monitoring of the ST-segment may be valuable, but it is limited to two to three monitored leads and off-line analysis, providing the results several hours or days after the recording. On-line continuous computer-assisted 12-lead electrocardiographic monitoring is an attractive alternative for immediate prognostic stratification. Continuous ST-monitoring studies have in fact revealed that 15–30% of patients with unstable CAD have transient episodes of ST-segment changes, predominantly ST-segment depression. These patients have an increased risk of subsequent cardiac events. The ST-segment monitoring adds independent prognostic information to the resting electrocardiogram and to other common clinical parameters w12–15x. 6. Biochemical markers of myocardial damage Cardiac troponin I or troponin T ŽcTnI and cTnT. are the preferred markers of myocardial necrosis because they allow a more sensitive detection of
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Fig. 2. Meta-analysis w18x of studies on the prognostic value of cardiac troponins I and T in patients without persisting ST-segment elevation.
myocardial damage and are more specific for the myocardial tissue than the traditional Acardiac enzymesB such as creatine kinase ŽCK. or its isoenzyme MB ŽCK-MB.. The troponin complex is formed by three distinct structural proteins Žtroponin I, C and T. and is located on the thin filament of the contractile apparatus in both skeletal and cardiac muscle tissue regulating the calcium dependent interaction of myosin and actin. The cardiac isoforms of troponin T and I are exclusively expressed in cardiac myocytes, and their detection in the blood is specific for myocardial damage w16x. After myocardial infarction, the troponin rise in peripheral blood is seen after 3–4 h with persistent elevation for up to 2 weeks. The high proportional rise of troponins, reflecting the low plasma concentrations in healthy persons, allows the detection of myocardial damage in about one-third of patients with UA even in the absence of minor CK-MB elevations w17x. In order to demonstrate or to exclude myocardial damage, repeated blood sampling is required during the first 6–12 h after admission and after any further episodes of severe chest pain.
Unstable patients with elevated levels of troponin have an unfavourable short- and long-term clinical outcome when compared to those without troponin elevation according to a recent meta-analysis w18x ŽFig. 2.. Elevated troponin levels predict the risk both of cardiac death and subsequent Žre.infarction. The results of comparable analyses of prognosis in relation to CK-MB elevations have been more conflicting w19,20x. The risk of new events is correlated with the degree of troponin elevation w20,21x. The increased risk associated with elevated troponin levels is independent from other risk factors such as electrocardiographic changes observed at rest or during continuous monitoring, or markers of inflammatory activity w22,23x.
7. Markers of inflammatory activity Increased fibrinogen and C-reactive protein ŽCRP. levels have been reported as risk markers in ACS, although the data are not always consistent w23–25x. In the FRISC trial, an elevated fibrinogen level was
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associated both with the short- and the long-term risk of death andror a subsequent myocardial infarction. The prognostic importance of fibrinogen was independent from electrocardiographic findings and troponin T levels w23x. CRP is an acute-phase protein produced by the liver under cytokine stimulation. Increases were predictive of an adverse outcome in a selected population of patients with severe unstable angina w26x. In the general population of ACS patients, the extent of risk conferred by the detection of CRP elevations is smaller than that defined by troponin increases but still significant. This is partially explained by the multiple mechanisms responsible for CRP increases in unstable CAD, possibly reflecting the propensity to progression of the unstable coronary plaque, the extent of myocardial damage, both or neither w27x. Fig. 3 shows the results of the meta-analysis we have performed on available studies on CRP in unstable CAD, where the combined end-point of death and non-fatal myocardial infarction is available at 30 days. The results of the meta-analysis, which included 2141 patients with UA and NQMI, although showing some degree of heterogeneity ŽChi-square 13.8; P s 0.03., at least, partially explained by different methods for measuring CRP and different cut-off values used to detect
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elevations, clearly indicate Ž P s 0.001. that the short-term risk of death or non-fatal myocardial infarction is increased about 1.5 times when CRP is increased. Furthermore, it has been demonstrated that CRP is a strong predictor of mortality over the long-term w28x. Measurement of CRP is particularly meaningful in conjunction with troponin, since CRP elevations may detect increased risk of cardiac events in patients who present with a negative troponin test w28–30x. 8. Hemostatic markers The measurement of markers of activation of the coagulationrfibrinolytic system with clinically meaningful laboratory methods could be important for risk stratification of patients with ACS since increases of activation peptides may reflect the tendency toward the progression of coronary thrombosis, and this subject is covered in detail in this monograph. An association between increased thrombin generation and an unfavourable outcome in UA has been found in some although not all trials w31,32x. Reduced fibrinolytic capacity has been associated with an increased risk of future coronary events in community-based population studies w33x.
Fig. 3. Meta-analysis of studies on C-reactive protein in patients with non-ST-segment elevation MI infarction or unstable angina w23,28,29,45–47x where the composite end-point of death or non-fatal myocardial infarction at 30 days is available. Risk is illustrated as Peto odds ratio Žfixed. and 95% confidence intervals ŽCI..
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Increased concentrations of PAI-1 have been reported to be related to an increased risk of new coronary events in MI survivors w34x. Increased D-dimer concentrations have been reported in UA as well as in acute MI w35x. Recently, their prognostic capacity was outlined in a high-risk cohort of ACS patients w36x and in MI survivors w37x. However, largescale trials of fibrinolytic activity in unstable CAD are still lacking and, therefore, the importance of such measurements for assessing prognosis remains unsettled. Currently, hemostatic markers are not recommended for risk stratification or selection of treatment in individual patients with unstable CAD. 9. Risk-stratification: an integrated approach The number of prognostic indicators available for rapid risk stratification of patients with ACS is definitely high. As previously discussed, the list encompasses several clinical, electrocardiographic and biochemical predictors of an adverse outcome. However, the relative importance of the single risk indicator may be extremely variable, depending upon a number of factors such as the strength of the relationship between the indicator and the mechanisms responsible for the unfavourable outcome, the spe-
cific patient population under study, the number of patients included, the subjective or objective nature of the indicator, etc. Such factors may account for even marked differences in the list of prognostic indicators and in their relative prognostic power observed in different studies. There is general agreement that in patients with ACS without persisting ST-segment elevation, the most important prognostic indicators available at the time of hospital admission are age, rest pain, particularly if recent and prolonged, hemodynamic instability, ST-segment depression and CKrCKMB increases indicative of evolving MI, or troponin elevations suggestive of AminorB myocardial damage. Utilising the presence or the absence of one or more of such indicators, a risk-classification of the patients may be attempted and some empirical suggestions about treatment strategy may be outlined ŽFig. 4.. This is not, however, an evidence-based approach since it is not based on the results of prospectively designed studies aimed to assess the prognostic role of well-defined risk indicators. Recently, Boersma et al. w38x reported the relation between the baseline characteristics and the occurrence of death or death and MI at 30 days in the PURSUIT trial, which included a population that
Fig. 4. A possible risk stratification algorithm for ACS patients without persisting ST-segment elevation.
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covered a wide variety of patients, hospital settings and treatment policies, sufficiently approximating the Areal worldB. Although retrospective, this analysis represents the first attempt to systematically evaluate the independent value of each potential prognostic indicator in order to build up a simple model for risk stratification of patients with ACS without persistent ST-segment elevation. Surprisingly, the authors found a remarkable homology with ST-segment elevation patients, since prognostic factors like age, heart rate, blood pressure and signs of heart failure resulted to be strong prognostic indicators also in this population. It was moreover observed that patients with myocardial infarction on admission Ži.e. those with elevated cardiac enzymes. had worse prognosis than patients without enzyme elevations. In the framework of the uncertainties of the clinical and electrocardiographic risk stratification, the troponins have gained wide popularity because of the ease of evaluation, the sensibility and specificity for myocardial damage and the independence from subjective evaluation Žwhen measured quantitatively.. Moreover, troponins have been demonstrated in various clinical trials to be independent prognostic indicators. However, the multivariate models generated did not account for the vast majority of the aforementioned important prognostic indicators, except age ŽTable 1.. The same applies for studies assessing the prognostic role of the electrocardiographic findings or continuous ST-segment monitoring w39x. In other words, a systematic and prospective evaluation of all potential prognostic tools is still lacking, and consequently, the role of biomarkers on top of this hypothetical risk model is still incompletely defined. Such approach to risk stratification would also represent a logical method that resembles the way the
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clinicians proceed, from admission onward, to evaluate patients with ACS. The data of the Early Prognostic Value of Biochemical Markers of M yocardial Damage, Activation of Hemostatic Mechanism and Inflammation in Acute Ischemic Syndromes ŽEMAI. study recently released at the National Meeting of the Associazione Nazionale Medici Cardiologi Ospedalieri ŽANMCO. held in Florence, Italy, May 20–23, 2000, appear to overcome many of these limitations. The EMAI study was in fact designed to prospectively study the prognostic role of several biomarkers, namely cardiac troponin I and T, CRP and hemostatic markers, such as prothrombin fragment 1 q 2, thrombin–antithrombin complex and D-dimer, when used in addition to the clinical and electrocardiographic risk indicators. An important feature of the study is represented by the fact that the population included Ž1971 patients: 730 patients with STsegment elevation eligible for a reperfusion strategy, and 1241 patients without persistent ST-segment elevation. is an unselected cohort of ACS patients admitted to 31 Italian Coronary Care Units within 12 h from symptom onset with electrocardiographic evidence of myocardial ischemia. Primary outcome measure of the study is the composite of death and non-fatal MI within 30 days from admission, which has occurred in 8.9% of the study population.
10. Therapeutic implications of an early risk stratification ACS Over the last 5 years, a number of new therapeutic options has been developed for patients with
Table 1 Independent prognostic value of cTn I and T in recent antithrombotic trials Trial
Independent value of cTn
Incremental value over CKMB
Additional independent prognostic indicators
GUSTO IIB w42x TIMI IIIB w43x FRISC w20x TRIM w44x
Yes Yes Yes Yes
Yes Yes Yes –
Age, ST≠, previous CABG, chronic RI, COPD STx, age Age, hypertension, no. antianginal drugs, STx Age, ACE inhibitors
Abbreviation: CABGs coronary artery by-pass grafting; COPDs chronic obstructive pulmonary disease; RI s renal insufficiency; ST≠ s ST-segment elevation; STx s ST-segment depression.
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ST-segment elevation and without persistent ST-segment elevation ACS. Selection of appropriate therapy for individual patient needs to be based on risk stratification, since the cost of therapy may range from very few to several thousand dollars Žfor treatment with GPIIBrIIIA inhibitors, plus PTCA and stenting.. Not only the costs are of concern, but also the risks of aggressive pharmacological or interventional treatment should be balanced against the little, if any, benefit in low risk patients. On the other hand, simple clinical, electrocardiographic and biochemical data available upon admission may identify high-risk patients as candidates for aggressive pharmacological and percutaneous interventions, the combination of which have clearly demonstrated to reduce the risk of cardiac events by a magnitude of 30–40% when administered to these patients w40,41x. A prospectively validated and Auser-friendlyB risk stratification algorithm is expected as soon as the results of recently completed or ongoing studies become available. Continuous refinement of prognosis, however, in the hours or days after admission, may be achieved by continuous electrocardiographic monitoring and biomarker determinations, providing evaluation of effectiveness of initial treatment strategies and guiding subsequent care.
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