Clopidogrel for the Prevention of Atherothrombotic Events
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In the April 20 issue Bhatt et al. reported the results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study.1 As a vascular neurologist, I want to highlight a specific piece of information that may be missed in the wealth of data provided in the article.
Table 4 indicates that there was a marginal reduction in the risk of nonfatal stroke among patients receiving the dual antiplatelet therapy, as compared with patients receiving placebo plus aspirin, despite the fact that there were similar rates of nonfatal ischemic stroke in the two groups. Since there was no difference in the overall occurrence of primary intracranial hemorrhage, these numbers can be explained only by an excess of fatal intracerebral hemorrhages in the group receiving clopidogrel plus aspirin (nine patients, as compared with two patients in the group receiving placebo plus aspirin, according to my calculations).
Even though the incidence of fatal intracerebral hemorrhage in the total population was very low, the difference in the distribution of this complication between the two groups deserves to be noted.
Alejandro A. Rabinstein, M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
rabinstein.alejandro@mayo.edu
Dr. Rabinstein reports having received consulting fees and lecture fees from Boehringer Ingelheim and Bristol-Myers Squibb.
References
Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717.
To the Editor: The CHARISMA trial suffers from a basic methodologic limitation, also present in prior large trials of clopidogrel: the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial1 and the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study.2 In a study designed to compare the effectiveness (in terms of the prevention of thrombotic events) of one antiplatelet therapy (aspirin) with that of a second therapy (clopidogrel with or without aspirin), the results are obviously biased toward the second therapy if patients who had a thrombotic event while taking aspirin (owing to the failure of aspirin therapy) are included. From methodologic and clinical standpoints, patients with and those without a history of unsuccessful aspirin therapy can be included in the study but should be separated at randomization and in analyses.
Despite the list of analyses described in the Methods section, the results of the analysis of patients with "prior use of other antiplatelet agents" are not reported in the Results section. Analysis of the subgroup of patients with and those without a history of unsuccessful aspirin therapy is essential. Surprisingly, such analysis was also apparently not reported in the CAPRIE or CURE study.
Yoseph Rozenman, M.D.
Wolfson Medical Center
58100 Holon, Israel
rozenman@wolfson.health.gov.il
References
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
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.
To the Editor: The CHARISMA study showed no benefit of clopidogrel plus aspirin over aspirin alone with respect to the primary efficacy end point. Moreover, the rate of death from cardiovascular causes among asymptomatic patients was higher with clopidogrel plus aspirin than with aspirin alone. However, the presentation of the safety end points in the article is too brief to understand clearly. The authors should explain how many patients met each of the criteria of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial for severe bleeding.1 How many patients had moderate or severe bleeding in each treatment group, and what was the P value for the comparison of the two groups? Were patients with fatal hemorrhage and those with intracerebral hemorrhage included in the total numbers of patients who were reported to have had severe bleeding?
On the basis of the data presented in Table 4 of the article, we calculated the incidence of overall bleeding (Table 1). Our data, which combine data from patients with bleeding in each treatment group, suggest that the combination of clopidogrel plus aspirin was associated with a significantly greater incidence of overall bleeding than was aspirin alone. These rates are similar to those reported in another study of clopidogrel.2
Table 1. Incidence of Additional Safety End Points.
Subsai Kongsaengdao, M.D.
Rajavithi Hospital
Bangkok 10400, Thailand
skhongsa@gmail.com
Arkhom Arayawichanont, M.D.
Sappasithiprasong Hospital
Ubonratchatani 34000, Thailand
References
The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-682.
Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331-337.
To the Editor: In their trial, Bhatt et al. made it a point to exclude patients who were taking nonsteroidal antiinflammatory drugs and anticoagulant medications but included patients who were taking cyclooxygenase-2 (COX-2) inhibitors. The authors did not provide any data on the use of COX-2 inhibitors in their reported subgroup analyses. We would like to know what percentage of patients were taking COX-2 inhibitors and what their outcomes were, if such information is available.
Yassar Almanaseer, M.D.
Devang M. Desai, M.D.
St. John Hospital and Medical Center
Detroit, MI 48236
To the Editor: The CHARISMA trial comes at a time when a lot of physicians (including me) are prescribing an expensive drug (clopidogrel) empirically for patients at high risk in the hope of preventing cardiovascular events. The increased risk of moderate bleeding reported by Bhatt et al. should be an eye-opener, because in the United States, most physicians give patients 325 mg of aspirin rather than the 75 to 162 mg used in the study. Patients receiving the 325-mg dose might have an even greater risk of bleeding than the patients in the study. This observation raises the question as to whether there was a difference in efficacy and safety end points between the patients who received 75 mg of aspirin and those who received 162 mg of aspirin.
Masoor Kamalesh, M.D.
Indiana University Medical Center
Indianapolis, IN 46202
masoor.kamalesh@med.va.gov
The author replies: We appreciate the comments of Rabinstein and agree that there was a benefit of dual antiplatelet therapy with respect to the reduction in the rate of nonfatal stroke (2.4 percent in the group given aspirin and clopidogrel vs. 1.9 percent in the group given aspirin and placebo, P=0.03), but this was associated with a numerical, nonsignificant, excess of fatal, intracerebral hemorrhagic events (10 vs. 6).
Rozenman inquires about whether there was a difference in outcomes among patients with prior antiplatelet therapy at the time of enrollment in the CHARISMA trial. In the trial, 93 percent of patients were taking aspirin at the time of enrollment. Among the 765 patients who were receiving other types of antiplatelet therapy (ticlopidine, clopidogrel on an open-label basis, dipyridamole, or an intravenous glycoprotein IIb/IIIa antagonist) at the time of enrollment, the rate of the primary end point (death from cardiovascular causes, myocardial infarction, or stroke) was higher than that among the 14,838 patients who were not taking other antiplatelet therapy, but there was no significant benefit of dual antiplatelet therapy, irrespective of the prior use of these medications (Table 1).
Table 1. Incidence of the Primary End Point in Two Subgroups of Patients.
The combination of clopidogrel and aspirin was indeed associated with an increased incidence of bleeding complications, as compared with aspirin alone, as noted by Kongsaengdao and Arayawichanont. Their Table 1 is correct except for the double-counting of the severe and moderate bleeding complications that occurred in some patients. Fatal and intracerebral hemorrhage were tallied in the severe bleeding category. The correct point estimate for severe and moderate bleeding among patients receiving aspirin and placebo is 2.5 percent, and that for the composite of fatal bleeding, intracerebral hemorrhage, and moderate bleeding is 2.6 percent among patients receiving clopidogrel and aspirin.
Almanaseer and Desai have requested information about the prior use of COX-2 inhibitors by our patients. Among the 869 patients who were taking COX-2 inhibitors at the time of enrollment, there was no significant excess of myocardial infarction or effect on the primary end point with clopidogrel and aspirin, as compared with placebo and aspirin.
A question about the effect of the aspirin dose is raised by Kamalesh. Although there were no significant differences in the efficacy or safety end points between the group given placebo and aspirin and the group given clopidogrel and aspirin, the latter treatment showed less efficacy and a trend toward a greater risk of bleeding with doses of aspirin exceeding 100 mg. We are in the process of preparing in-depth reports on these interesting issues that pertain to the subgroups and secondary analyses of the CHARISMA trial.
Eric J. Topol, M.D.
Case Western Reserve University
Cleveland, OH 44106-4955
eric.topol@case.edu
for the CHARISMA Investigators
Table 4 indicates that there was a marginal reduction in the risk of nonfatal stroke among patients receiving the dual antiplatelet therapy, as compared with patients receiving placebo plus aspirin, despite the fact that there were similar rates of nonfatal ischemic stroke in the two groups. Since there was no difference in the overall occurrence of primary intracranial hemorrhage, these numbers can be explained only by an excess of fatal intracerebral hemorrhages in the group receiving clopidogrel plus aspirin (nine patients, as compared with two patients in the group receiving placebo plus aspirin, according to my calculations).
Even though the incidence of fatal intracerebral hemorrhage in the total population was very low, the difference in the distribution of this complication between the two groups deserves to be noted.
Alejandro A. Rabinstein, M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
rabinstein.alejandro@mayo.edu
Dr. Rabinstein reports having received consulting fees and lecture fees from Boehringer Ingelheim and Bristol-Myers Squibb.
References
Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717.
To the Editor: The CHARISMA trial suffers from a basic methodologic limitation, also present in prior large trials of clopidogrel: the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial1 and the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study.2 In a study designed to compare the effectiveness (in terms of the prevention of thrombotic events) of one antiplatelet therapy (aspirin) with that of a second therapy (clopidogrel with or without aspirin), the results are obviously biased toward the second therapy if patients who had a thrombotic event while taking aspirin (owing to the failure of aspirin therapy) are included. From methodologic and clinical standpoints, patients with and those without a history of unsuccessful aspirin therapy can be included in the study but should be separated at randomization and in analyses.
Despite the list of analyses described in the Methods section, the results of the analysis of patients with "prior use of other antiplatelet agents" are not reported in the Results section. Analysis of the subgroup of patients with and those without a history of unsuccessful aspirin therapy is essential. Surprisingly, such analysis was also apparently not reported in the CAPRIE or CURE study.
Yoseph Rozenman, M.D.
Wolfson Medical Center
58100 Holon, Israel
rozenman@wolfson.health.gov.il
References
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
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.
To the Editor: The CHARISMA study showed no benefit of clopidogrel plus aspirin over aspirin alone with respect to the primary efficacy end point. Moreover, the rate of death from cardiovascular causes among asymptomatic patients was higher with clopidogrel plus aspirin than with aspirin alone. However, the presentation of the safety end points in the article is too brief to understand clearly. The authors should explain how many patients met each of the criteria of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial for severe bleeding.1 How many patients had moderate or severe bleeding in each treatment group, and what was the P value for the comparison of the two groups? Were patients with fatal hemorrhage and those with intracerebral hemorrhage included in the total numbers of patients who were reported to have had severe bleeding?
On the basis of the data presented in Table 4 of the article, we calculated the incidence of overall bleeding (Table 1). Our data, which combine data from patients with bleeding in each treatment group, suggest that the combination of clopidogrel plus aspirin was associated with a significantly greater incidence of overall bleeding than was aspirin alone. These rates are similar to those reported in another study of clopidogrel.2
Table 1. Incidence of Additional Safety End Points.
Subsai Kongsaengdao, M.D.
Rajavithi Hospital
Bangkok 10400, Thailand
skhongsa@gmail.com
Arkhom Arayawichanont, M.D.
Sappasithiprasong Hospital
Ubonratchatani 34000, Thailand
References
The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-682.
Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331-337.
To the Editor: In their trial, Bhatt et al. made it a point to exclude patients who were taking nonsteroidal antiinflammatory drugs and anticoagulant medications but included patients who were taking cyclooxygenase-2 (COX-2) inhibitors. The authors did not provide any data on the use of COX-2 inhibitors in their reported subgroup analyses. We would like to know what percentage of patients were taking COX-2 inhibitors and what their outcomes were, if such information is available.
Yassar Almanaseer, M.D.
Devang M. Desai, M.D.
St. John Hospital and Medical Center
Detroit, MI 48236
To the Editor: The CHARISMA trial comes at a time when a lot of physicians (including me) are prescribing an expensive drug (clopidogrel) empirically for patients at high risk in the hope of preventing cardiovascular events. The increased risk of moderate bleeding reported by Bhatt et al. should be an eye-opener, because in the United States, most physicians give patients 325 mg of aspirin rather than the 75 to 162 mg used in the study. Patients receiving the 325-mg dose might have an even greater risk of bleeding than the patients in the study. This observation raises the question as to whether there was a difference in efficacy and safety end points between the patients who received 75 mg of aspirin and those who received 162 mg of aspirin.
Masoor Kamalesh, M.D.
Indiana University Medical Center
Indianapolis, IN 46202
masoor.kamalesh@med.va.gov
The author replies: We appreciate the comments of Rabinstein and agree that there was a benefit of dual antiplatelet therapy with respect to the reduction in the rate of nonfatal stroke (2.4 percent in the group given aspirin and clopidogrel vs. 1.9 percent in the group given aspirin and placebo, P=0.03), but this was associated with a numerical, nonsignificant, excess of fatal, intracerebral hemorrhagic events (10 vs. 6).
Rozenman inquires about whether there was a difference in outcomes among patients with prior antiplatelet therapy at the time of enrollment in the CHARISMA trial. In the trial, 93 percent of patients were taking aspirin at the time of enrollment. Among the 765 patients who were receiving other types of antiplatelet therapy (ticlopidine, clopidogrel on an open-label basis, dipyridamole, or an intravenous glycoprotein IIb/IIIa antagonist) at the time of enrollment, the rate of the primary end point (death from cardiovascular causes, myocardial infarction, or stroke) was higher than that among the 14,838 patients who were not taking other antiplatelet therapy, but there was no significant benefit of dual antiplatelet therapy, irrespective of the prior use of these medications (Table 1).
Table 1. Incidence of the Primary End Point in Two Subgroups of Patients.
The combination of clopidogrel and aspirin was indeed associated with an increased incidence of bleeding complications, as compared with aspirin alone, as noted by Kongsaengdao and Arayawichanont. Their Table 1 is correct except for the double-counting of the severe and moderate bleeding complications that occurred in some patients. Fatal and intracerebral hemorrhage were tallied in the severe bleeding category. The correct point estimate for severe and moderate bleeding among patients receiving aspirin and placebo is 2.5 percent, and that for the composite of fatal bleeding, intracerebral hemorrhage, and moderate bleeding is 2.6 percent among patients receiving clopidogrel and aspirin.
Almanaseer and Desai have requested information about the prior use of COX-2 inhibitors by our patients. Among the 869 patients who were taking COX-2 inhibitors at the time of enrollment, there was no significant excess of myocardial infarction or effect on the primary end point with clopidogrel and aspirin, as compared with placebo and aspirin.
A question about the effect of the aspirin dose is raised by Kamalesh. Although there were no significant differences in the efficacy or safety end points between the group given placebo and aspirin and the group given clopidogrel and aspirin, the latter treatment showed less efficacy and a trend toward a greater risk of bleeding with doses of aspirin exceeding 100 mg. We are in the process of preparing in-depth reports on these interesting issues that pertain to the subgroups and secondary analyses of the CHARISMA trial.
Eric J. Topol, M.D.
Case Western Reserve University
Cleveland, OH 44106-4955
eric.topol@case.edu
for the CHARISMA Investigators