Addition of Clopidogrel to Aspirin and Fibrinolytic Therapy for Myocardial Infarction
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《新英格兰医药杂志》
To the Editor: Sabatine et al. (March 24 issue)1 demonstrated in the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–Thrombolysis in Myocardial Infarction (TIMI) 28 trial that clopidogrel added to aspirin, heparin, and thrombolytic therapy for myocardial infarction with ST-segment elevation reduced the composite end point of TIMI grade 0 or 1 flow, death from any cause, or recurrent myocardial infarction. However, the benefit in terms of this composite end point was driven by the greater TIMI flow grade achieved in the clopidogrel group than in the placebo group; there were no differences between the groups in the rates of the clinical end points of death and of recurrent myocardial infarction. Previous trials comparing reteplase with alteplase showed that better TIMI flow grades were achieved with reteplase than with alteplase, but there was no reduction in mortality with reteplase.2,3 Tenecteplase was associated with TIMI flow grades that were similar to those found with alteplase and also resulted in no difference in mortality.4,5
These conflicting results suggest that a higher TIMI flow grade is not necessarily equivalent to greater clinical and survival benefits. Previous studies of antiplatelet agents in myocardial infarction relied on clinical, rather than surrogate, outcomes. More relevant clinical end points, rather than angiographic outcomes, are needed before clopidogrel is adopted as routine adjunctive therapy with thrombolysis.
Doson Chua, Pharm.D., B.C.P.S.
St. Paul's Hospital
Vancouver, BC V6Z 1Y6, Canada
dchua@providencehealth.bc.ca
Christopher Lo, Pharm.D.
Langley Memorial Hospital
Langley, BC V3A 4H4, Canada
Elisa-Maria Babor, B.Sc.(Pharm.)
St. Paul's Hospital
Vancouver, BC V6Z 1Y6, Canada
References
Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179-1189.
Bode C, Smalling RW, Berg G, et al. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. Circulation 1996;94:891-898.
Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997;337:1118-1123.
Cannon CP, Gibson CM, McCabe CH, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Circulation 1998;98:2805-2814.
Assessment of the Safety and Efficacy of a New Thrombolytic Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999;354:716-722.
The authors reply: Chua and colleagues comment that the difference between the clopidogrel and placebo groups in the rate of the primary end point was driven primarily by differences in the patency of the infarct-related artery. This should not be surprising, since our trial was designed to test whether clopidogrel would improve patency.1 As we stated, death or myocardial infarction before angiography was included as a necessary surrogate for failed reperfusion or reocclusion. Multiple studies have validated the association between the TIMI flow grade and clinical outcomes.2,3 To that end, in CLARITY–TIMI 28 we demonstrated that clopidogrel not only improved patency, but also significantly reduced the odds of death from cardiovascular causes, recurrent myocardial infarction, or urgent revascularization through 30 days. Furthermore, we direct the attention of Chua and colleagues to the results of the Clopidogrel and Metoprolol in Myocardial Infarction Trial/Chinese Cardiac Study 2,4 which were presented alongside those of CLARITY–TIMI 28 findings and which showed that in nearly 46,000 patients with acute myocardial infarction, the addition of clopidogrel resulted in a significant, 7 percent reduction in mortality.5 Thus, the angiographic and clinical data are quite consistent in indicating that clopidogrel improves the rate of patency of the infarct-related artery and reduces the rate of adverse clinical events, including death.
Marc S. Sabatine, M.D., M.P.H.
Christopher P. Cannon, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital
Boston, MA 02115
msabatine@partners.org
for the CLARITY–TIMI 28 Investigators
References
Sabatine MS, McCabe CH, Gibson CM, Cannon CP. Design and rationale of Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28 trial. Am Heart J 2005;149:227-233.
Dalen JE, Gore JM, Braunwald E, et al. Six- and twelve-month follow-up of the phase I Thrombolysis in Myocardial Infarction (TIMI) trial. Am J Cardiol 1988;62:179-185.
The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615-1622.
Second Chinese Cardiac Study (CCS-2) Collaborative Group. Rationale, design and organization of the Second Chinese Cardiac Study (CCS-2): a randomized trial of clopidogrel plus aspirin, and of metoprolol, among patients with suspected acute myocardial infarction. J Cardiovasc Risk 2000;7:435-441.
Chen Z. COMMIT/CCS-2, 54th Scientific Session of the American College of Cardiology, Orlando, Fla., March 9, 2005.
These conflicting results suggest that a higher TIMI flow grade is not necessarily equivalent to greater clinical and survival benefits. Previous studies of antiplatelet agents in myocardial infarction relied on clinical, rather than surrogate, outcomes. More relevant clinical end points, rather than angiographic outcomes, are needed before clopidogrel is adopted as routine adjunctive therapy with thrombolysis.
Doson Chua, Pharm.D., B.C.P.S.
St. Paul's Hospital
Vancouver, BC V6Z 1Y6, Canada
dchua@providencehealth.bc.ca
Christopher Lo, Pharm.D.
Langley Memorial Hospital
Langley, BC V3A 4H4, Canada
Elisa-Maria Babor, B.Sc.(Pharm.)
St. Paul's Hospital
Vancouver, BC V6Z 1Y6, Canada
References
Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179-1189.
Bode C, Smalling RW, Berg G, et al. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. Circulation 1996;94:891-898.
Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997;337:1118-1123.
Cannon CP, Gibson CM, McCabe CH, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Circulation 1998;98:2805-2814.
Assessment of the Safety and Efficacy of a New Thrombolytic Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999;354:716-722.
The authors reply: Chua and colleagues comment that the difference between the clopidogrel and placebo groups in the rate of the primary end point was driven primarily by differences in the patency of the infarct-related artery. This should not be surprising, since our trial was designed to test whether clopidogrel would improve patency.1 As we stated, death or myocardial infarction before angiography was included as a necessary surrogate for failed reperfusion or reocclusion. Multiple studies have validated the association between the TIMI flow grade and clinical outcomes.2,3 To that end, in CLARITY–TIMI 28 we demonstrated that clopidogrel not only improved patency, but also significantly reduced the odds of death from cardiovascular causes, recurrent myocardial infarction, or urgent revascularization through 30 days. Furthermore, we direct the attention of Chua and colleagues to the results of the Clopidogrel and Metoprolol in Myocardial Infarction Trial/Chinese Cardiac Study 2,4 which were presented alongside those of CLARITY–TIMI 28 findings and which showed that in nearly 46,000 patients with acute myocardial infarction, the addition of clopidogrel resulted in a significant, 7 percent reduction in mortality.5 Thus, the angiographic and clinical data are quite consistent in indicating that clopidogrel improves the rate of patency of the infarct-related artery and reduces the rate of adverse clinical events, including death.
Marc S. Sabatine, M.D., M.P.H.
Christopher P. Cannon, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital
Boston, MA 02115
msabatine@partners.org
for the CLARITY–TIMI 28 Investigators
References
Sabatine MS, McCabe CH, Gibson CM, Cannon CP. Design and rationale of Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28 trial. Am Heart J 2005;149:227-233.
Dalen JE, Gore JM, Braunwald E, et al. Six- and twelve-month follow-up of the phase I Thrombolysis in Myocardial Infarction (TIMI) trial. Am J Cardiol 1988;62:179-185.
The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615-1622.
Second Chinese Cardiac Study (CCS-2) Collaborative Group. Rationale, design and organization of the Second Chinese Cardiac Study (CCS-2): a randomized trial of clopidogrel plus aspirin, and of metoprolol, among patients with suspected acute myocardial infarction. J Cardiovasc Risk 2000;7:435-441.
Chen Z. COMMIT/CCS-2, 54th Scientific Session of the American College of Cardiology, Orlando, Fla., March 9, 2005.