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The results of MATCH: light or heat?
Reflection & Reaction The results of MATCH: light or heat? The recently published results of the MATCH trial1 may be construed as evidence that the combination of clopidogrel and aspirin is not effective for secondary prevention in patients with stroke or transient ischaemic attack (TIA). This would be an unfortunate and misguided conclusion. MATCH was an audacious endeavour, developed from the results of sound cardiac trials—CURE2 and CREDO3—in which the combination of clopidogrel and aspirin was better for prevention than aspirin alone in patients who received urgent treatment for acute myocardial infarction. MATCH ignited hope that combined therapy would be similarly beneficial in a much different patient population: those with stroke and TIA. Unfortunately, the chance to show the effect of combination therapy in this population was compromised by several questionable presumptions and decisions. First, MATCH sought to compare the combination of clopidogrel and aspirin with clopidogrel alone. This design was a bold departure from that of the cardiac trials, in which the benefit and safety of combined therapy had been compared with that of aspirin, the standard therapy. By adding aspirin to the more potent drug, clopidogrel, the MATCH design reduced the chance of showing a difference between the therapies from the outset. Furthermore, because 80% of enrolled patients had already been taking aspirin, and 20–30% of patients treated with aspirin are known to respond poorly,4,5 the chance of showing a significant event reduction in the group that received aspirin was additionally compromised. Second, the bleeding experienced by those in the combined therapy group was primarily a consequence of the gastrointestinal effects of aspirin. Because there was no stated requirement that patients on aspirin take medication for gastrointestinal protection, this adverse event compromised the benefit to risk ratio in a way that could have been mitigated. Third, the population studied consisted largely (53%) of those with small-vessel pathology, many of whom
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could be susceptible to brain infarction secondary to mechanical closure of vessels—something that no medication would be expected to prevent. Others (10%) in the study population had suffered cryptogenic strokes, many of which would be of venous (paradoxical) origin.6 It is possible that cryptogenic strokes would be difficult to prevent with antiplatelet therapy. Comparison of the benefit of combined therapy in the cardiac trials with that found in MATCH shows the effect of the types of vascular pathology on outcome. In CURE and CREDO, despite bleeding rates slightly higher than in MATCH, the event reductions favouring combined therapy over aspirin respectively were 20% and 27%. In MATCH, the event reduction was 6·4% for combined therapy over clopidogrel. The event reductions in the cardiac trials mostly reflect fewer coronary events and death. Thus, combination therapy can be beneficial for pathology in larger (coronary) arteries. The undermining effect of the study population on event rates and event reduction in MATCH is underscored by the results of CAPRIE.7 The CAPRIE stroke cohort was essentially the same as that of MATCH, and the event reduction for stroke, heart attack, and death was similar at 8·7%. Fourth, the timing of enrollment hindered the ability to show differences between therapies in MATCH. Differences in secondary prevention are best appreciated and most readily demonstrated when antiplatelet therapy is started early after the first event, during the hypercoagulable phase.2,3,7–9 However, of the 7599 patients who participated in MATCH, only 1441 were enrolled within 7 days of the qualifying event, and only 3754 were enrolled within 31 days. These patients had the highest risk of recurrent events, and, as expected, they were the ones in whom the combined therapy worked better than clopidogrel alone. However, nearly half of the patients in the study were enrolled more than 31 days after the qualifying event, and no benefit of combined therapy was seen in that group.
Fifth, a component of the primary outcome in MATCH was “rehospitalisation for recurrent ischaemic events”. The choice of this variable diluted the final analysis by adding 350 nonessential events to the total of 1232 events, thereby reducing the statistical capability to detect significant differences between the two therapies for clinically more important outcomes. The role of combined clopidogrel and aspirin therapy for secondary prevention in patients with stroke and TIA remains unknown. Trials such as CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance), FASTER (Fast Assessment of Stroke and Transient ischemic attack to prevent Early Recurrence), and SPS3 (Secondary Prevention of Small Subcortical Strokes pilot study), in which combination therapy is being compared with aspirin alone, should shed light where MATCH has generated heat. James L Frey Stroke Program Director, Barrow Neurological Institute, Phoenix, Arizona, USA. Email [email protected] Conflict of interest
I have no conflicts of interest. References 1
2 3
4 5 6
7
8
9
Diener H-C, 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: 331–37. CURE Trial Investigators. Clopidogrel in unstable angina to prevent recurrent events (CURE) study. N Engl J Med 2001; 345: 494–502. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288: 2411–20. Helgason CM, Bolin KM, Hoff JA, et al. Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994; 25: 2331–36. Alberts MJ, Bergman DL, Molner E, et al. Antiplatelet effect of aspirin in patients with cerebrovascular disease. Stroke 2004; 35: 175–78. Messé SR, Silverman IE, Kizer JR, et al. Practice parameter: recurrent stroke with patent foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004; 62: 1042–50. Caprie Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–39. Hass WK, Easton JD, Adams HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501–07. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345: 1444–51.
Neurology Vol 3 November 2004
http://neurology.thelancet.com
For personal use. Only reproduce with permission from Elsevier Ltd
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could be susceptible to brain infarction secondary to mechanical closure of vessels—something that no medication would be expected to prevent. Others (10%) in the study population had suffered cryptogenic strokes, many of which would be of venous (paradoxical) origin.6 It is possible that cryptogenic strokes would be difficult to prevent with antiplatelet therapy. Comparison of the benefit of combined therapy in the cardiac trials with that found in MATCH shows the effect of the types of vascular pathology on outcome. In CURE and CREDO, despite bleeding rates slightly higher than in MATCH, the event reductions favouring combined therapy over aspirin respectively were 20% and 27%. In MATCH, the event reduction was 6·4% for combined therapy over clopidogrel. The event reductions in the cardiac trials mostly reflect fewer coronary events and death. Thus, combination therapy can be beneficial for pathology in larger (coronary) arteries. The undermining effect of the study population on event rates and event reduction in MATCH is underscored by the results of CAPRIE.7 The CAPRIE stroke cohort was essentially the same as that of MATCH, and the event reduction for stroke, heart attack, and death was similar at 8·7%. Fourth, the timing of enrollment hindered the ability to show differences between therapies in MATCH. Differences in secondary prevention are best appreciated and most readily demonstrated when antiplatelet therapy is started early after the first event, during the hypercoagulable phase.2,3,7–9 However, of the 7599 patients who participated in MATCH, only 1441 were enrolled within 7 days of the qualifying event, and only 3754 were enrolled within 31 days. These patients had the highest risk of recurrent events, and, as expected, they were the ones in whom the combined therapy worked better than clopidogrel alone. However, nearly half of the patients in the study were enrolled more than 31 days after the qualifying event, and no benefit of combined therapy was seen in that group.
Fifth, a component of the primary outcome in MATCH was “rehospitalisation for recurrent ischaemic events”. The choice of this variable diluted the final analysis by adding 350 nonessential events to the total of 1232 events, thereby reducing the statistical capability to detect significant differences between the two therapies for clinically more important outcomes. The role of combined clopidogrel and aspirin therapy for secondary prevention in patients with stroke and TIA remains unknown. Trials such as CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance), FASTER (Fast Assessment of Stroke and Transient ischemic attack to prevent Early Recurrence), and SPS3 (Secondary Prevention of Small Subcortical Strokes pilot study), in which combination therapy is being compared with aspirin alone, should shed light where MATCH has generated heat. James L Frey Stroke Program Director, Barrow Neurological Institute, Phoenix, Arizona, USA. Email [email protected] Conflict of interest
I have no conflicts of interest. References 1
2 3
4 5 6
7
8
9
Diener H-C, 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: 331–37. CURE Trial Investigators. Clopidogrel in unstable angina to prevent recurrent events (CURE) study. N Engl J Med 2001; 345: 494–502. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288: 2411–20. Helgason CM, Bolin KM, Hoff JA, et al. Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994; 25: 2331–36. Alberts MJ, Bergman DL, Molner E, et al. Antiplatelet effect of aspirin in patients with cerebrovascular disease. Stroke 2004; 35: 175–78. Messé SR, Silverman IE, Kizer JR, et al. Practice parameter: recurrent stroke with patent foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004; 62: 1042–50. Caprie Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–39. Hass WK, Easton JD, Adams HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501–07. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345: 1444–51.
Neurology Vol 3 November 2004
http://neurology.thelancet.com
For personal use. Only reproduce with permission from Elsevier Ltd