Acute Coronary Syndromes without ST-Segment Elevation — What Is the Role of Early Intervention?
http://www.100md.com
《新英格兰医药杂志》
During the past 15 years, there have been important advances in both percutaneous coronary intervention (PCI) and the pharmacotherapy of acute coronary syndromes without ST-segment elevation. Several carefully designed, randomized clinical trials have evaluated prospectively two contrasting strategies for managing these syndromes (a routine early invasive strategy and a selectively invasive strategy) and their effect on short- and long-term clinical outcomes. With the early invasive strategy, all patients undergo early coronary angiography, followed by PCI if the coronary anatomy permits. With the selectively invasive strategy, angiography and PCI are reserved for those patients who have inducible ischemia on noninvasive testing before discharge or for whom initial medical therapy fails.
Because several trials have shown a significant clinical benefit with an early invasive strategy,1,2,3 guidelines of the American College of Cardiology (ACC)–American Heart Association (AHA) and the European Society of Cardiology (ESC) have endorsed this approach for the early treatment of acute coronary syndromes without ST-segment elevation, especially among patients who have indicators of high risk, such as recent angina or ischemia at rest, elevated troponin levels, new ST-segment depression, or clinical or hemodynamic instability.4,5 These treatment guidelines have been embraced by a majority of cardiologists as the sine qua non of optimal therapy and have shifted the management of acute coronary syndromes without ST-segment elevation decisively in the direction of early intervention.
A recent meta-analysis6 examined data on 9212 patients from seven trials and showed that the early invasive strategy was superior to the selectively invasive strategy in reducing myocardial infarction, severe angina, and rehospitalization during long-term follow-up (mean, 17 months) but was associated with a 60 percent increase in in-hospital mortality and a 36 percent increase in the rate of death or myocardial infarction. However, subgroup analyses of the three trials that were published after 19991,2,3 suggest a convincing relationship between the early invasive strategy and reductions in the rate of death or myocardial infarction among patients who were troponin-positive (which most cardiologists today regard as synonymous with being at high risk).6
In this issue of the Journal, de Winter and colleagues report on the provocative results of the Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial, involving 1200 high-risk patients who had acute coronary syndromes without ST-segment elevation, all of whom were troponin-positive at entry and who were randomly assigned to an early invasive strategy or a selectively invasive strategy.7 All patients received aggressive medical therapy, including aspirin, clopidogrel, enoxaparin for 48 hours, abciximab during PCI, and intensive lipid-lowering therapy.
Although the investigators hypothesized that clinical outcomes would be significantly better with the early invasive strategy, they found that, against a background of optimal medical therapy, an early invasive strategy was not superior to a selectively invasive approach in troponin-positive patients. Mortality at one year was identical in the two groups (2.5 percent in each) and remarkably low overall for a group of patients positive for biomarkers whose risk-factor profile, clinical characteristics, and electrocardiographic findings were consistent with a high-risk cohort. The rate of myocardial infarction was significantly higher in the early-invasive-strategy group (relative risk, 1.50; 95 percent confidence interval, 1.10 to 2.04), and the point estimate for the relative risk of the composite primary end point of death, myocardial infarction, or rehospitalization because of angina favored patients assigned to a selectively invasive strategy.
Several points warrant clarification and emphasis. First, in the ICTUS trial, recurrent myocardial infarction was defined as any elevation in the CK-MB level above the upper limit of normal, according to the recommendations of the Joint ESC–ACC Committee for the Redefinition of Myocardial Infarction,8 regardless of whether the myocardial infarction occurred spontaneously or was periprocedural. The 50 percent excess rate of myocardial infarction in the early-invasive-strategy group was driven largely by relatively small enzymatic events (peak CK-MB level, 1 to <3 times the upper limit of normal). The relative risk of periprocedural myocardial infarction increased by a factor of more than two (relative risk, 2.09; 95 percent confidence interval, 1.39 to 3.14), but there was a nonsignificant trend toward fewer spontaneous myocardial infarctions in the early-invasive-strategy group (relative risk, 0.80; 95 percent confidence interval, 0.46 to 1.34), suggesting that much of the risk of myocardial infarction was related to catheter-based or surgical revascularization.
In addition, since neither a core laboratory nor central adjudication seems to have been used, and since recurrent myocardial infarction was defined stringently as any subsequent reelevation in the CK-MB level above the upper limit of normal (or after a drop of 50 percent from a previous peak, if elevated at trial entry), the variability among available enzyme assays used at the 42 participating hospitals may have made it difficult to detect reliably myocardial necrosis at or near the decision limit (i.e., 1 or 2 SD above the upper limit of normal) for myocardial infarction. Thus, it could be argued that the restrictive definition of myocardial infarction used in the study by de Winter et al. may have stacked the deck against the patients assigned to an early invasive strategy, as was not the case in other trials1,2 that used a higher differential threshold for PCI-related myocardial infarction (1.5 times the upper limit of normal for CK-MB1 or 3.0 times the upper limit of normal2) than for spontaneous myocardial infarction.
However, this observation raises the following compelling corollary question: Since the guidelines of the ACC–AHA and the ESC define myocardial infarction as any elevation in CK-MB or troponin levels above the upper limit of normal, regardless of whether this occurs in the setting of PCI,8 is it appropriate simply to dismiss PCI-related elevations in biomarkers as trivial and clinically irrelevant? Increasingly, we seem to accept the notion that PCI-related troponin leaks are an expected artifact of the procedure that do not adversely affect prognosis, yet there is mounting evidence that periprocedural myocardial damage is not benign and may rival spontaneous myocardial infarction prognostically.9,10,11,12 Embolization of atherosclerotic plaque during coronary-artery instrumentation and the subsequent downstream showering of particulate atheromatous debris may cause microvascular obstruction, resulting in ischemic cell death and troponin positivity. To the extent that this occurs after PCI, it is difficult to argue that this represents a "good infarct," as opposed to a spontaneous ("bad") infarct. And since studies have shown that the subsequent risk of death or myocardial infarction, even well beyond one year of follow-up, is related to the extent of the release of biomarkers after PCI,9 the results of the ICTUS trial may actually underestimate the true prognostic effect of periprocedural myocardial infarction in such patients.
Another important finding in the study by de Winter et al. is the striking difference in the timing of the procedure between patients who underwent early PCI (median time, 23 hours) and those who underwent delayed PCI (median time, 11.8 days) and the absence of worse clinical outcomes in the latter group. Because the basis for acute ischemia is the rupture or erosion of plaque with or without severe obstructive coronary disease, it has been postulated that early revascularization in patients who have acute coronary syndromes without ST-segment elevation would prevent events and improve prognosis, yet we see no evidence that patients assigned to the selectively invasive strategy were clinically disadvantaged — either in the hospital or up to one year after randomization — despite the substantially divergent rates and timing of revascularization.
Although U.S. treatment standards preclude hospitalizing for 11 to 12 days patients with acute coronary syndromes without ST-segment elevation, as was done in the study by de Winter and colleagues, the trial suggests nonetheless that such patients, if aggressively treated pharmacologically and stratified appropriately according to risk, could be treated safely without clinical consequences with the use of a more selective approach to intervention.
The low one-year mortality rate in the entire ICTUS cohort and the unexpectedly low event rate among the patients assigned to a selectively invasive strategy underscore the critical role of adjunctive antiplatelet, antithrombin, and intensive lipid-lowering therapies. Recent clinical trials have shown convincingly the clinical benefits of aggressive statin therapy13 and the combined use of aspirin and clopidogrel.14 The patients in both groups in this trial received robust medical therapy in terms of contemporary standards, which could have mitigated risk by leveling the playing field between the two strategies.
The results of the study by de Winter and colleagues may serve as a wake-up call, telling us that a routine early invasive strategy for the treatment of patients with acute coronary syndromes without ST-segment elevation — even those who are positive for biomarkers — may not inherently be superior to a more selective approach. The absence of a clear reduction in the rate of death or myocardial infarction with either strategy, coupled with the recent meta-analysis showing both an early hazard and a late benefit associated with a routine early invasive approach,6 may prompt us to reassess what the optimal role and timing should be for early intervention, even in high-risk patients.
As practitioners, we are often inclined to dismiss the results of a given study because it does not conform to our preexisting beliefs (e.g., that a routine early invasive approach is fundamentally superior). However, the findings of de Winter et al. may challenge the current guidelines of the ACC–AHA and the ESC for the treatment of patients who have acute coronary syndromes without ST-segment elevation and elevated cardiac troponin levels. Furthermore, the findings may move us closer to a point of clinical equipoise at which physicians feel more confident that an early invasive strategy and a selectively invasive strategy are equivalent and defendable treatment options.
Source Information
From the Division of Cardiology and the Henry Low Heart Center, Hartford Hospital, Hartford, and the University of Connecticut School of Medicine, Farmington — both in Connecticut.
References
FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354:708-715.
Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879-1887.
Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial: Randomized Interventional Trial of Unstable Angina. Lancet 2002;360:743-751.
Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction -- summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2002;40:1366-1374.
Bertrand ME, Simoons ML, Fox KA, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002;23:1809-1840.
Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005;293:2908-2917.
de Winter RJ, Windhausen F, Cornel JH, et al. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005;353:1095-1104.
Alpert JS, Thygesen K, Antman E, et al. 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;36:959-969.
Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996;94:1528-1536.
Tardiff BE, Califf RM, Tcheng JE, et al. Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention. J Am Coll Cardiol 1999;33:88-96.
Cantor WJ, Newby LK, Christenson RH, et al. Prognostic significance of elevated troponin I after percutaneous coronary intervention. J Am Coll Cardiol 2002;39:1738-1744.
Roe MT, Mahaffey KW, Kilaru R, et al. Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes. Eur Heart J 2004;25:313-321.
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504.
The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.(William E. Boden, M.D.)
Because several trials have shown a significant clinical benefit with an early invasive strategy,1,2,3 guidelines of the American College of Cardiology (ACC)–American Heart Association (AHA) and the European Society of Cardiology (ESC) have endorsed this approach for the early treatment of acute coronary syndromes without ST-segment elevation, especially among patients who have indicators of high risk, such as recent angina or ischemia at rest, elevated troponin levels, new ST-segment depression, or clinical or hemodynamic instability.4,5 These treatment guidelines have been embraced by a majority of cardiologists as the sine qua non of optimal therapy and have shifted the management of acute coronary syndromes without ST-segment elevation decisively in the direction of early intervention.
A recent meta-analysis6 examined data on 9212 patients from seven trials and showed that the early invasive strategy was superior to the selectively invasive strategy in reducing myocardial infarction, severe angina, and rehospitalization during long-term follow-up (mean, 17 months) but was associated with a 60 percent increase in in-hospital mortality and a 36 percent increase in the rate of death or myocardial infarction. However, subgroup analyses of the three trials that were published after 19991,2,3 suggest a convincing relationship between the early invasive strategy and reductions in the rate of death or myocardial infarction among patients who were troponin-positive (which most cardiologists today regard as synonymous with being at high risk).6
In this issue of the Journal, de Winter and colleagues report on the provocative results of the Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial, involving 1200 high-risk patients who had acute coronary syndromes without ST-segment elevation, all of whom were troponin-positive at entry and who were randomly assigned to an early invasive strategy or a selectively invasive strategy.7 All patients received aggressive medical therapy, including aspirin, clopidogrel, enoxaparin for 48 hours, abciximab during PCI, and intensive lipid-lowering therapy.
Although the investigators hypothesized that clinical outcomes would be significantly better with the early invasive strategy, they found that, against a background of optimal medical therapy, an early invasive strategy was not superior to a selectively invasive approach in troponin-positive patients. Mortality at one year was identical in the two groups (2.5 percent in each) and remarkably low overall for a group of patients positive for biomarkers whose risk-factor profile, clinical characteristics, and electrocardiographic findings were consistent with a high-risk cohort. The rate of myocardial infarction was significantly higher in the early-invasive-strategy group (relative risk, 1.50; 95 percent confidence interval, 1.10 to 2.04), and the point estimate for the relative risk of the composite primary end point of death, myocardial infarction, or rehospitalization because of angina favored patients assigned to a selectively invasive strategy.
Several points warrant clarification and emphasis. First, in the ICTUS trial, recurrent myocardial infarction was defined as any elevation in the CK-MB level above the upper limit of normal, according to the recommendations of the Joint ESC–ACC Committee for the Redefinition of Myocardial Infarction,8 regardless of whether the myocardial infarction occurred spontaneously or was periprocedural. The 50 percent excess rate of myocardial infarction in the early-invasive-strategy group was driven largely by relatively small enzymatic events (peak CK-MB level, 1 to <3 times the upper limit of normal). The relative risk of periprocedural myocardial infarction increased by a factor of more than two (relative risk, 2.09; 95 percent confidence interval, 1.39 to 3.14), but there was a nonsignificant trend toward fewer spontaneous myocardial infarctions in the early-invasive-strategy group (relative risk, 0.80; 95 percent confidence interval, 0.46 to 1.34), suggesting that much of the risk of myocardial infarction was related to catheter-based or surgical revascularization.
In addition, since neither a core laboratory nor central adjudication seems to have been used, and since recurrent myocardial infarction was defined stringently as any subsequent reelevation in the CK-MB level above the upper limit of normal (or after a drop of 50 percent from a previous peak, if elevated at trial entry), the variability among available enzyme assays used at the 42 participating hospitals may have made it difficult to detect reliably myocardial necrosis at or near the decision limit (i.e., 1 or 2 SD above the upper limit of normal) for myocardial infarction. Thus, it could be argued that the restrictive definition of myocardial infarction used in the study by de Winter et al. may have stacked the deck against the patients assigned to an early invasive strategy, as was not the case in other trials1,2 that used a higher differential threshold for PCI-related myocardial infarction (1.5 times the upper limit of normal for CK-MB1 or 3.0 times the upper limit of normal2) than for spontaneous myocardial infarction.
However, this observation raises the following compelling corollary question: Since the guidelines of the ACC–AHA and the ESC define myocardial infarction as any elevation in CK-MB or troponin levels above the upper limit of normal, regardless of whether this occurs in the setting of PCI,8 is it appropriate simply to dismiss PCI-related elevations in biomarkers as trivial and clinically irrelevant? Increasingly, we seem to accept the notion that PCI-related troponin leaks are an expected artifact of the procedure that do not adversely affect prognosis, yet there is mounting evidence that periprocedural myocardial damage is not benign and may rival spontaneous myocardial infarction prognostically.9,10,11,12 Embolization of atherosclerotic plaque during coronary-artery instrumentation and the subsequent downstream showering of particulate atheromatous debris may cause microvascular obstruction, resulting in ischemic cell death and troponin positivity. To the extent that this occurs after PCI, it is difficult to argue that this represents a "good infarct," as opposed to a spontaneous ("bad") infarct. And since studies have shown that the subsequent risk of death or myocardial infarction, even well beyond one year of follow-up, is related to the extent of the release of biomarkers after PCI,9 the results of the ICTUS trial may actually underestimate the true prognostic effect of periprocedural myocardial infarction in such patients.
Another important finding in the study by de Winter et al. is the striking difference in the timing of the procedure between patients who underwent early PCI (median time, 23 hours) and those who underwent delayed PCI (median time, 11.8 days) and the absence of worse clinical outcomes in the latter group. Because the basis for acute ischemia is the rupture or erosion of plaque with or without severe obstructive coronary disease, it has been postulated that early revascularization in patients who have acute coronary syndromes without ST-segment elevation would prevent events and improve prognosis, yet we see no evidence that patients assigned to the selectively invasive strategy were clinically disadvantaged — either in the hospital or up to one year after randomization — despite the substantially divergent rates and timing of revascularization.
Although U.S. treatment standards preclude hospitalizing for 11 to 12 days patients with acute coronary syndromes without ST-segment elevation, as was done in the study by de Winter and colleagues, the trial suggests nonetheless that such patients, if aggressively treated pharmacologically and stratified appropriately according to risk, could be treated safely without clinical consequences with the use of a more selective approach to intervention.
The low one-year mortality rate in the entire ICTUS cohort and the unexpectedly low event rate among the patients assigned to a selectively invasive strategy underscore the critical role of adjunctive antiplatelet, antithrombin, and intensive lipid-lowering therapies. Recent clinical trials have shown convincingly the clinical benefits of aggressive statin therapy13 and the combined use of aspirin and clopidogrel.14 The patients in both groups in this trial received robust medical therapy in terms of contemporary standards, which could have mitigated risk by leveling the playing field between the two strategies.
The results of the study by de Winter and colleagues may serve as a wake-up call, telling us that a routine early invasive strategy for the treatment of patients with acute coronary syndromes without ST-segment elevation — even those who are positive for biomarkers — may not inherently be superior to a more selective approach. The absence of a clear reduction in the rate of death or myocardial infarction with either strategy, coupled with the recent meta-analysis showing both an early hazard and a late benefit associated with a routine early invasive approach,6 may prompt us to reassess what the optimal role and timing should be for early intervention, even in high-risk patients.
As practitioners, we are often inclined to dismiss the results of a given study because it does not conform to our preexisting beliefs (e.g., that a routine early invasive approach is fundamentally superior). However, the findings of de Winter et al. may challenge the current guidelines of the ACC–AHA and the ESC for the treatment of patients who have acute coronary syndromes without ST-segment elevation and elevated cardiac troponin levels. Furthermore, the findings may move us closer to a point of clinical equipoise at which physicians feel more confident that an early invasive strategy and a selectively invasive strategy are equivalent and defendable treatment options.
Source Information
From the Division of Cardiology and the Henry Low Heart Center, Hartford Hospital, Hartford, and the University of Connecticut School of Medicine, Farmington — both in Connecticut.
References
FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354:708-715.
Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879-1887.
Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial: Randomized Interventional Trial of Unstable Angina. Lancet 2002;360:743-751.
Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction -- summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2002;40:1366-1374.
Bertrand ME, Simoons ML, Fox KA, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002;23:1809-1840.
Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005;293:2908-2917.
de Winter RJ, Windhausen F, Cornel JH, et al. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005;353:1095-1104.
Alpert JS, Thygesen K, Antman E, et al. 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;36:959-969.
Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996;94:1528-1536.
Tardiff BE, Califf RM, Tcheng JE, et al. Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention. J Am Coll Cardiol 1999;33:88-96.
Cantor WJ, Newby LK, Christenson RH, et al. Prognostic significance of elevated troponin I after percutaneous coronary intervention. J Am Coll Cardiol 2002;39:1738-1744.
Roe MT, Mahaffey KW, Kilaru R, et al. Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes. Eur Heart J 2004;25:313-321.
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504.
The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.(William E. Boden, M.D.)