- Email: [email protected]
Cardiac markers for decision making in acute ischemic syndromes1
RISK STRATIFICATION
elevation or depression had similar 30-day mortality, but long-term mortality in the latter was substantially higher (12.3% vs. 15.4%, p ⬍ 0.001). Angiography, performed in 57% of patients, showed the highest rate of nonsignificant coronary disease or normal coronary arteries among patients with T-wave inversion. Patients with ST-segment depression had the most extensive coronary artery disease (4). These findings emphasize the prognostic potential of the ECG for patients with ACS and show the relationship of ECG findings with disease burden. Only about 30% of patients with ACS present with STsegment elevation. The even larger cohort with ST-segment depression has the highest mortality risk, but many patients at risk have nondiagnostic baseline ECGs (5). To establish the diagnosis early in these patients or, more importantly, to identify increased risk, objective tools, such as cardiac markers, are needed.
BRIEF REVIEW
Cardiac Markers for Decision Making in Acute Ischemic Syndromes Britta U. Goldmann, MD, L. Kristin Newby, MD and E. Magnus Ohman, MD, Duke Clinical Research Institute, Durham, North Carolina ver the last decade, management of patients with acute coronary syndromes (ACS) has evolved tremendously. New therapeutic agents, including low–molecular-weight heparins and platelet glycoprotein IIb/IIIa receptor blockers, offer substantial therapeutic value. The spectrum of symptoms of active ischemic heart disease ranges from silent ischemia to acute myocardial infarction, and the spectrum of myocardial damage ranges from reversible injury to extensive necrosis. Because this disease is a continuum, it seems appropriate to identify patients with increased risk early so that effective therapies can begin as soon as possible. This review focuses on risk stratification in patients with ACS, strategies for antithrombotic treatment and the potential for revascularization in this setting.
O
Cardiac Markers for Diagnosis and Risk Stratification Over the last decade, new cardiac markers have been extensively studied for evaluation of patients with ACS, including myoglobin (molecular weight 24,000 Da), creatine kinase (CK)-MB (86,000 Da) and troponins T and I (37,000 Da and 24,000 Da, respectively). Typical rises and falls of CK-MB, as described in the World Health Organization criteria, remain the gold standard for diagnosing acute myocardial infarction (6). Serum myoglobin is a potential marker for early identification of patients with acute myocardial infarction but lacks specificity. Elevated levels often are evident in noncardiac conditions, and its negative predictive value declines rapidly due to its short half-life (7). Once cardiac isoforms of troponins were purified, antibodies for immunoassays became available. Accumulating data show troponin T and I to be the most sensitive markers for myocardial injury. Their greatest potential may lie in risk stratification because they are more closely linked to mortality than are CK-MB or myoglobin (7–9).
Assessment of Risk in Acute Coronary Syndromes In patients with ST-segment elevation myocardial infarction, the risk of mortality is highest during the first several days (1). Our understanding of patients with non–ST-segment elevation ACS has also suggested a heightened risk in the first several days. Thus, any treatment strategy is likely to have the greatest benefit if applied early, ideally within several hours after admission to the hospital. To better understand the value of new therapies in patients with acute coronary syndromes, the Duke Databank for Cardiovascular Disease was used to assess the long-term clinical outcome of more than 20,000 patients with ischemic heart disease (2). Patients with unstable angina and acute myocardial infarction had the highest risk during the first 30 days, more so for those with myocardial infarction rather than unstable angina (30-day mortality 11.2% vs. 7.1%, respectively). However, long-term survival was similar (12-year cumulative mortality 49.2% vs. 49.8%), and patients with either condition had a similar life expectancy (15.4 vs. 15.6 years) (3). Thus, any treatment must be applied early, which constitutes the focus for risk stratification. The electrocardiogram (ECG) is the first objective test available for risk stratification in ACS patients. The Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) trial investigators categorized the 12,000 admission ECGs into those showing STsegment elevation, ST-segment depression or isolated T-wave inversion (4). Patients presenting with ST-segment
The Potential for Risk Stratification About one third of unstable angina patients with myocardial infarction excluded on conventional grounds have elevated levels of troponin T or I. In 1992, Hamm et al. (8) were the first to observe that such patients were more likely to experience adverse events, such as death, myocardial infarction or urgent need for revascularization, if they had a troponin T level ⬎ 0.2 ng/mL. This seminal study raised awareness that troponin T may be a more sensitive marker of myocardial infarction than CK-MB. The GUSTO-IIa troponin substudy in patients with ACS demonstrated convincingly that the baseline serum troponin T level was the strongest univariate predictor of 30-day outcome when compared with standard 12-lead ECG and CK-MB (9). Even after adjustment for the other two compo-
ACC CURRENT JOURNAL REVIEW January/February 2000 © 2000 by the American College of Cardiology Published by Elsevier Science Inc.
43
1062-1458/00/$20.00 PII S1062-1458(99)00048-3
RISK STRATIFICATION
Table 1. RELATIVE VALUE OF SERUM MARKERS AND 12-LEAD ELECTROCARDIOGRAPHY AS PREDICTORS OF 30-DAY MORTALITY Unadjusted Analysis
Adjusted Analysis*
Predictor
2
p value
df
2
p value
df
Troponin T Electrocardiography Creatine kinase-MB
21 14.2 10.9
⬍ 0.001 0.003 0.004
3 3 2
9.2 11.5 0.7
0.027 0.009 0.717
3 3 2
*After the other two variables were forced into the model first. Reprinted with permission from Ohman et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333– 41. Copyright © 1996 by the Massachusetts Medical Society. All rights reserved.
those with ST-segment elevation who were troponin T positive in the first 24 hours had a higher 30-day and long-term mortality (13). Many factors can influence the troponin status in the setting of ST-segment elevation, with duration of symptoms being among the most important. To explore the relationships among troponin T status on admission, ST-segment elevation and 30-day mortality, the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTOIII) trial performed qualitative troponin T testing in 12,000 patients with ST-segment elevation (cutoff 0.2 ng/mL). This study again showed that baseline troponin T status is an independent predictor of 30-day mortality, even after adjusting for other important variables (Table 2) (14). A meta-analysis of 14 trials examining either troponin T or I in different conditions supports these findings. In all of the studies, an elevated troponin T or I level indicated an increased risk of death or infarction during 30-day follow-up with hazard ratios of 2.7 (95% confidence interval (CI), 2.1–3.4; 2, 66) for troponin T and 4.2 (95% CI, 2.7– 6.4; 2, 42) for troponin I (15). Thus, most investigations point to the value of troponin testing for risk stratification of patients with ACS. These findings also have been extended to lower-risk patients, such as those admitted to chest-pain units (16,17), and the value of qualitative bedside testing for these patients also has been explored (17).
nents, troponin T was a significant predictor of 30-day mortality (Table 1). As a result, the investigators suggested that the combination of a standard ECG and baseline troponin T measurement was the best combination for risk stratification. The substudy also revealed an increasing probability of 30-day mortality with increasing baseline troponin T levels, which indicates the need to know an actual value, not just a qualitative measure, at baseline (9). The added value of further troponin T sampling after baseline (8 hours, 16 hours, 24 hours) also was explored in the GUSTO-IIa study (10). On admission, 33% of patients were troponin T positive, but by 8 hours, the number had risen to 77.5%, driven mainly by patients with ST-segment elevation who were positive by the second sample in 88.7% of cases. Patients who became positive on the second or third sample had a lower 30-day mortality than those who were positive initially (5% vs. 10%). No troponin T–negative patients died, but they did have substantial morbidity, including an 8% rate of myocardial infarction and a similar rate of congestive heart failure. After 1 year, the difference in mortality between troponin-positive and troponin-negative patients was maintained (9.4% vs. 2%, p ⫽ 0.0029). Based on these results, the optimal testing strategy for short-term and long-term risk stratification by troponin T may be to obtain at least two samples during the first 24 hours (10). Antman et al. (11) noted similar findings in over 1,400 patients with unstable angina and non–Q-wave myocardial infarction participating in the Thrombolysis In Myocardial Infarction (TIMI)-IIIb trial. Troponin I–positive patients had a significantly higher mortality rate at 42 days (3.7% vs. 1%; p ⬍ 0.001), even when the CK-MB values were normal (2.5% vs 0.8%, p ⬍ 0.05) (11), and, as shown for troponin T, troponin I status was an independent predictor of 42-day mortality. Analysis of troponin I in the GUSTO-IIa study confirmed this finding (12). Most striking from previous trials is that patients with baseline ST-segment elevation and a positive troponin-T result had substantially higher mortality than those with ST-segment elevation who had a negative baseline troponin T (9 –12). In patients with ST-segment elevation, the diagnosis of myocardial infarction already is established; thus, cardiac markers would be used simply to identify any increased risk. In an unselected population of 513 patients,
Therapeutic Potential The great value of objective testing for patients with ACS, by use of ECG or cardiac markers, has led us to explore whether Table 2. INDEPENDENT PREDICTORS OF 30-DAY MORTALITY IN PATIENTS WITH ST-SEGMENT ELEVATION Age Killip class (IV vs. I) Systolic blood pressure Increased heart rate Anterior infarction Troponin T Time to thrombolysis
2*
Odds ratio (95% CI)
p value
502 123 108 69 61 46 3
2.16 (2–2.33) 7.81 (4.3–14.21) 1.43 (1.35–1.53) 1.18 (1.13–1.22) 1.83 (1.55–2.15) 2.05 (1.68–2.51) 1.04 (0.99–1.09)
0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.1158
*After adjustment for all other factors in the model. Reprinted from The American Journal of Cardiology, 84, Ohman EM, Armstrong PW, White HD, et al., Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction: A GUSTO-III substudy, 1281– 6, 1999, with permission from Excerpta Medica Inc.
ACC CURRENT JOURNAL REVIEW January/February 2000
44
RISK STRATIFICATION
more potent antithrombotic agents may be beneficial in this setting. If patients at heightened risk can be identified, newer antithrombotic therapies may be particularly advantageous in this group. Antithrombotic therapies that have been tested in conjunction with troponin T include the low– molecular-weight heparin, dalteparin, and the platelet GP IIb/IIIa receptor blockers, abciximab and tirofiban. Low–molecular-weight heparin In the FRagmin In unStable Coronary artery disease (FRISC) study, troponin T was tested prospectively to explore the value of potent antithrombotic therapy relative to troponin T status. Similar to other studies in ACS, patients who were troponin T positive in the first 24 hours had a higher rate of death or myocardial infarction during the 5-month observation period. The trial showed an overall trend toward benefit for patients randomized to dalteparin, but the effect was significantly greater in those who were troponin T positive (risk reductions of 6 –2.5%, p ⬍ 0.05 for troponin-positive and 2.4 – 0%; p ⫽ 0.12 for troponin-negative patients) (18).
Figure 1. Rates of cardiac events within 6 months after randomization to either abciximab or placebo, by troponin T level above or below the diagnostic cutoff (⬎ 0.1 ng/mL). Reprinted with permission from Ohman et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333– 41. Copyright 䊚 1996 by the Massachusetts Medical Society. All rights reserved.
Platelet GP IIb/IIIa Receptor Blockers The relationship between troponin T status and outcome after abciximab therapy was studied by Hamm et al. (8) in a substudy of the C7E3 fab AntiPlatelet Therapy in Unstable REfractory angina (CAPTURE) trial. In 890 of 1,265 patients enrolled, a baseline troponin T status was available. After coronary angiography, patients were randomized to abciximab or placebo for 24 hours and then underwent percutaneous revascularization. Treatment with abciximab significantly reduced the rate of death or infarction, but this effect was observed almost exclusively in troponin T-positive patients (odds ratio, 0.32; 95% CI, 0.14 – 0.62; p ⫽ 0.002). This benefit was maintained through 6 months (Figure 1) (19). These investigators found that troponin T-positive patients were much more likely to have intracoronary thrombus on initial angiography (15.1% vs. 4.3%). At the second angiogram (before angioplasty), this thrombus burden was significantly reduced in those receiving abciximab (20). Thus, patients who are troponin T positive may have more active coronary disease, where the platelet GP IIb/IIIa receptor blockers could be of particular value. There also is evidence from cardiac-marker studies that platelet GP IIb/IIIa receptor blockers limit myocardial damage in ACS. In a small substudy of the Platelet Receptor inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS) trial, in which troponin I was tested at baseline, when the study drug infusion was discontinued (48 hours), patients who had received tirofiban had significantly lower troponin
I values than those who had received placebo, suggesting less myocardial damage (21). Conclusions As we move into the next millennium, early risk stratification will become exceptionally valuable for patients in the heterogeneous group with acute coronary syndromes. By using objective testing, treatment strategies (and thus outcomes and costs) can be optimized, particularly with new antithrombotic agents. Positive troponin and ECG results indicate a heightened risk of 30-day and 6-month mortality, which appears to reflect a more thrombus-prone lesion. Thus, potent antithrombotic therapy would be of great therapeutic value, as has been shown in recent studies. The most important insight is that with risk stratification, potent therapies may be applied individually to patients at the highest risk for adverse events. The combination of risk stratification with excellent therapeutics likely will have a great effect on the outcomes of patients with acute coronary syndromes.
REFERENCES The authors have provided an extensive list of references that are available from the Editorial Office by FAX 317-274-4469. Address correspondence and reprint requests to E. Magnus Ohman, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715.
ACC CURRENT JOURNAL REVIEW January/February 2000
45
elevation or depression had similar 30-day mortality, but long-term mortality in the latter was substantially higher (12.3% vs. 15.4%, p ⬍ 0.001). Angiography, performed in 57% of patients, showed the highest rate of nonsignificant coronary disease or normal coronary arteries among patients with T-wave inversion. Patients with ST-segment depression had the most extensive coronary artery disease (4). These findings emphasize the prognostic potential of the ECG for patients with ACS and show the relationship of ECG findings with disease burden. Only about 30% of patients with ACS present with STsegment elevation. The even larger cohort with ST-segment depression has the highest mortality risk, but many patients at risk have nondiagnostic baseline ECGs (5). To establish the diagnosis early in these patients or, more importantly, to identify increased risk, objective tools, such as cardiac markers, are needed.
BRIEF REVIEW
Cardiac Markers for Decision Making in Acute Ischemic Syndromes Britta U. Goldmann, MD, L. Kristin Newby, MD and E. Magnus Ohman, MD, Duke Clinical Research Institute, Durham, North Carolina ver the last decade, management of patients with acute coronary syndromes (ACS) has evolved tremendously. New therapeutic agents, including low–molecular-weight heparins and platelet glycoprotein IIb/IIIa receptor blockers, offer substantial therapeutic value. The spectrum of symptoms of active ischemic heart disease ranges from silent ischemia to acute myocardial infarction, and the spectrum of myocardial damage ranges from reversible injury to extensive necrosis. Because this disease is a continuum, it seems appropriate to identify patients with increased risk early so that effective therapies can begin as soon as possible. This review focuses on risk stratification in patients with ACS, strategies for antithrombotic treatment and the potential for revascularization in this setting.
O
Cardiac Markers for Diagnosis and Risk Stratification Over the last decade, new cardiac markers have been extensively studied for evaluation of patients with ACS, including myoglobin (molecular weight 24,000 Da), creatine kinase (CK)-MB (86,000 Da) and troponins T and I (37,000 Da and 24,000 Da, respectively). Typical rises and falls of CK-MB, as described in the World Health Organization criteria, remain the gold standard for diagnosing acute myocardial infarction (6). Serum myoglobin is a potential marker for early identification of patients with acute myocardial infarction but lacks specificity. Elevated levels often are evident in noncardiac conditions, and its negative predictive value declines rapidly due to its short half-life (7). Once cardiac isoforms of troponins were purified, antibodies for immunoassays became available. Accumulating data show troponin T and I to be the most sensitive markers for myocardial injury. Their greatest potential may lie in risk stratification because they are more closely linked to mortality than are CK-MB or myoglobin (7–9).
Assessment of Risk in Acute Coronary Syndromes In patients with ST-segment elevation myocardial infarction, the risk of mortality is highest during the first several days (1). Our understanding of patients with non–ST-segment elevation ACS has also suggested a heightened risk in the first several days. Thus, any treatment strategy is likely to have the greatest benefit if applied early, ideally within several hours after admission to the hospital. To better understand the value of new therapies in patients with acute coronary syndromes, the Duke Databank for Cardiovascular Disease was used to assess the long-term clinical outcome of more than 20,000 patients with ischemic heart disease (2). Patients with unstable angina and acute myocardial infarction had the highest risk during the first 30 days, more so for those with myocardial infarction rather than unstable angina (30-day mortality 11.2% vs. 7.1%, respectively). However, long-term survival was similar (12-year cumulative mortality 49.2% vs. 49.8%), and patients with either condition had a similar life expectancy (15.4 vs. 15.6 years) (3). Thus, any treatment must be applied early, which constitutes the focus for risk stratification. The electrocardiogram (ECG) is the first objective test available for risk stratification in ACS patients. The Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) trial investigators categorized the 12,000 admission ECGs into those showing STsegment elevation, ST-segment depression or isolated T-wave inversion (4). Patients presenting with ST-segment
The Potential for Risk Stratification About one third of unstable angina patients with myocardial infarction excluded on conventional grounds have elevated levels of troponin T or I. In 1992, Hamm et al. (8) were the first to observe that such patients were more likely to experience adverse events, such as death, myocardial infarction or urgent need for revascularization, if they had a troponin T level ⬎ 0.2 ng/mL. This seminal study raised awareness that troponin T may be a more sensitive marker of myocardial infarction than CK-MB. The GUSTO-IIa troponin substudy in patients with ACS demonstrated convincingly that the baseline serum troponin T level was the strongest univariate predictor of 30-day outcome when compared with standard 12-lead ECG and CK-MB (9). Even after adjustment for the other two compo-
ACC CURRENT JOURNAL REVIEW January/February 2000 © 2000 by the American College of Cardiology Published by Elsevier Science Inc.
43
1062-1458/00/$20.00 PII S1062-1458(99)00048-3
RISK STRATIFICATION
Table 1. RELATIVE VALUE OF SERUM MARKERS AND 12-LEAD ELECTROCARDIOGRAPHY AS PREDICTORS OF 30-DAY MORTALITY Unadjusted Analysis
Adjusted Analysis*
Predictor
2
p value
df
2
p value
df
Troponin T Electrocardiography Creatine kinase-MB
21 14.2 10.9
⬍ 0.001 0.003 0.004
3 3 2
9.2 11.5 0.7
0.027 0.009 0.717
3 3 2
*After the other two variables were forced into the model first. Reprinted with permission from Ohman et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333– 41. Copyright © 1996 by the Massachusetts Medical Society. All rights reserved.
those with ST-segment elevation who were troponin T positive in the first 24 hours had a higher 30-day and long-term mortality (13). Many factors can influence the troponin status in the setting of ST-segment elevation, with duration of symptoms being among the most important. To explore the relationships among troponin T status on admission, ST-segment elevation and 30-day mortality, the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTOIII) trial performed qualitative troponin T testing in 12,000 patients with ST-segment elevation (cutoff 0.2 ng/mL). This study again showed that baseline troponin T status is an independent predictor of 30-day mortality, even after adjusting for other important variables (Table 2) (14). A meta-analysis of 14 trials examining either troponin T or I in different conditions supports these findings. In all of the studies, an elevated troponin T or I level indicated an increased risk of death or infarction during 30-day follow-up with hazard ratios of 2.7 (95% confidence interval (CI), 2.1–3.4; 2, 66) for troponin T and 4.2 (95% CI, 2.7– 6.4; 2, 42) for troponin I (15). Thus, most investigations point to the value of troponin testing for risk stratification of patients with ACS. These findings also have been extended to lower-risk patients, such as those admitted to chest-pain units (16,17), and the value of qualitative bedside testing for these patients also has been explored (17).
nents, troponin T was a significant predictor of 30-day mortality (Table 1). As a result, the investigators suggested that the combination of a standard ECG and baseline troponin T measurement was the best combination for risk stratification. The substudy also revealed an increasing probability of 30-day mortality with increasing baseline troponin T levels, which indicates the need to know an actual value, not just a qualitative measure, at baseline (9). The added value of further troponin T sampling after baseline (8 hours, 16 hours, 24 hours) also was explored in the GUSTO-IIa study (10). On admission, 33% of patients were troponin T positive, but by 8 hours, the number had risen to 77.5%, driven mainly by patients with ST-segment elevation who were positive by the second sample in 88.7% of cases. Patients who became positive on the second or third sample had a lower 30-day mortality than those who were positive initially (5% vs. 10%). No troponin T–negative patients died, but they did have substantial morbidity, including an 8% rate of myocardial infarction and a similar rate of congestive heart failure. After 1 year, the difference in mortality between troponin-positive and troponin-negative patients was maintained (9.4% vs. 2%, p ⫽ 0.0029). Based on these results, the optimal testing strategy for short-term and long-term risk stratification by troponin T may be to obtain at least two samples during the first 24 hours (10). Antman et al. (11) noted similar findings in over 1,400 patients with unstable angina and non–Q-wave myocardial infarction participating in the Thrombolysis In Myocardial Infarction (TIMI)-IIIb trial. Troponin I–positive patients had a significantly higher mortality rate at 42 days (3.7% vs. 1%; p ⬍ 0.001), even when the CK-MB values were normal (2.5% vs 0.8%, p ⬍ 0.05) (11), and, as shown for troponin T, troponin I status was an independent predictor of 42-day mortality. Analysis of troponin I in the GUSTO-IIa study confirmed this finding (12). Most striking from previous trials is that patients with baseline ST-segment elevation and a positive troponin-T result had substantially higher mortality than those with ST-segment elevation who had a negative baseline troponin T (9 –12). In patients with ST-segment elevation, the diagnosis of myocardial infarction already is established; thus, cardiac markers would be used simply to identify any increased risk. In an unselected population of 513 patients,
Therapeutic Potential The great value of objective testing for patients with ACS, by use of ECG or cardiac markers, has led us to explore whether Table 2. INDEPENDENT PREDICTORS OF 30-DAY MORTALITY IN PATIENTS WITH ST-SEGMENT ELEVATION Age Killip class (IV vs. I) Systolic blood pressure Increased heart rate Anterior infarction Troponin T Time to thrombolysis
2*
Odds ratio (95% CI)
p value
502 123 108 69 61 46 3
2.16 (2–2.33) 7.81 (4.3–14.21) 1.43 (1.35–1.53) 1.18 (1.13–1.22) 1.83 (1.55–2.15) 2.05 (1.68–2.51) 1.04 (0.99–1.09)
0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.1158
*After adjustment for all other factors in the model. Reprinted from The American Journal of Cardiology, 84, Ohman EM, Armstrong PW, White HD, et al., Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction: A GUSTO-III substudy, 1281– 6, 1999, with permission from Excerpta Medica Inc.
ACC CURRENT JOURNAL REVIEW January/February 2000
44
RISK STRATIFICATION
more potent antithrombotic agents may be beneficial in this setting. If patients at heightened risk can be identified, newer antithrombotic therapies may be particularly advantageous in this group. Antithrombotic therapies that have been tested in conjunction with troponin T include the low– molecular-weight heparin, dalteparin, and the platelet GP IIb/IIIa receptor blockers, abciximab and tirofiban. Low–molecular-weight heparin In the FRagmin In unStable Coronary artery disease (FRISC) study, troponin T was tested prospectively to explore the value of potent antithrombotic therapy relative to troponin T status. Similar to other studies in ACS, patients who were troponin T positive in the first 24 hours had a higher rate of death or myocardial infarction during the 5-month observation period. The trial showed an overall trend toward benefit for patients randomized to dalteparin, but the effect was significantly greater in those who were troponin T positive (risk reductions of 6 –2.5%, p ⬍ 0.05 for troponin-positive and 2.4 – 0%; p ⫽ 0.12 for troponin-negative patients) (18).
Figure 1. Rates of cardiac events within 6 months after randomization to either abciximab or placebo, by troponin T level above or below the diagnostic cutoff (⬎ 0.1 ng/mL). Reprinted with permission from Ohman et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333– 41. Copyright 䊚 1996 by the Massachusetts Medical Society. All rights reserved.
Platelet GP IIb/IIIa Receptor Blockers The relationship between troponin T status and outcome after abciximab therapy was studied by Hamm et al. (8) in a substudy of the C7E3 fab AntiPlatelet Therapy in Unstable REfractory angina (CAPTURE) trial. In 890 of 1,265 patients enrolled, a baseline troponin T status was available. After coronary angiography, patients were randomized to abciximab or placebo for 24 hours and then underwent percutaneous revascularization. Treatment with abciximab significantly reduced the rate of death or infarction, but this effect was observed almost exclusively in troponin T-positive patients (odds ratio, 0.32; 95% CI, 0.14 – 0.62; p ⫽ 0.002). This benefit was maintained through 6 months (Figure 1) (19). These investigators found that troponin T-positive patients were much more likely to have intracoronary thrombus on initial angiography (15.1% vs. 4.3%). At the second angiogram (before angioplasty), this thrombus burden was significantly reduced in those receiving abciximab (20). Thus, patients who are troponin T positive may have more active coronary disease, where the platelet GP IIb/IIIa receptor blockers could be of particular value. There also is evidence from cardiac-marker studies that platelet GP IIb/IIIa receptor blockers limit myocardial damage in ACS. In a small substudy of the Platelet Receptor inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS) trial, in which troponin I was tested at baseline, when the study drug infusion was discontinued (48 hours), patients who had received tirofiban had significantly lower troponin
I values than those who had received placebo, suggesting less myocardial damage (21). Conclusions As we move into the next millennium, early risk stratification will become exceptionally valuable for patients in the heterogeneous group with acute coronary syndromes. By using objective testing, treatment strategies (and thus outcomes and costs) can be optimized, particularly with new antithrombotic agents. Positive troponin and ECG results indicate a heightened risk of 30-day and 6-month mortality, which appears to reflect a more thrombus-prone lesion. Thus, potent antithrombotic therapy would be of great therapeutic value, as has been shown in recent studies. The most important insight is that with risk stratification, potent therapies may be applied individually to patients at the highest risk for adverse events. The combination of risk stratification with excellent therapeutics likely will have a great effect on the outcomes of patients with acute coronary syndromes.
REFERENCES The authors have provided an extensive list of references that are available from the Editorial Office by FAX 317-274-4469. Address correspondence and reprint requests to E. Magnus Ohman, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715.
ACC CURRENT JOURNAL REVIEW January/February 2000
45