Correspondence
As a MATCH investigator, I find the final interpretation that the combination of clopidogrel and aspirin is hazardous is unduly gloomy.1 This conclusion seems to be driven by the combination of two findings: first, that combined aspirin and clopidogrel did not reduce the risk of a composite ischaemic vascular outcome when compared with clopidogrel alone and, second, that there was a significant increase in life-threatening bleeding in patients who received both drugs. However, although 47 more people taking clopidogrel alone than in combination with aspirin had an ischaemic event, 40 more people in the combination group than in the singletreatment group had life-threatening bleeding. Furthermore overall deaths in both groups were identical, there was no difference in death or dependency (assessed with the modified Rankin scale, unreported data), the number of all stroke events (representing the balance between ischaemic stroke and symptomatic intracranial haemorrhage) was similar in patients who received aspirin and clopidogrel (n=349) or clopidogrel alone (n=358), and the independent data monitoring committee did not stop the trial on the grounds of safety. These factors all indicate that the combination of clopidogrel and aspirin is as safe as clopidogrel alone. Most stroke trials have a primary outcome that includes a balance between efficacy (ischaemic vascular events, or ischaemic stroke) and hazard (intracranial haemorrhage, or life-threatening or major bleeding). The primary outcome of MATCH, however, took into account only ischaemic events and haemorrhagic death. This bias could have contributed to the misperception that benefit was missing while hazard was present. Additionally, though the results of the trial suggest no benefit of combination therapy with clopidogrel and aspirin, the non-significant finding of a reduction in risk of ischaemic events with dual antiplatelet therapy is compatible with the finding of a metaanalysis2 of aspirin in patients with 1662
ischaemic stroke or transient ischaemic attack, as Hans-Christoph Diener and colleagues acknowledge. The meta-analysis remains positive after inclusion of the MATCH data. An alternative interpretation of MATCH is, therefore, that aspirin is effective and safe in preventing vascular events, whether used in combination with clopidogrel or not. This message is important since it will not confuse primary and secondary care practitioners who generally believe that aspirin is beneficial in patients at risk of ischaemic cerebrovascular disease. Whether clopidogrel-based dual antiplatelet therapy is better than aspirin alone will be determined in several ongoing trials. Furthermore, which dual antiplatelet regimen (aspirin and clopidogrel or aspirin and dipyridamole3) is superior remains to be established. Finally, using three agents together4 might be better still but needs further assessment. I was a MATCH investigator, am on the PRoFESS trial steering committee, and am a consultant for Sanofi-Synthelabo and Boehringer Ingelheim.
Philip Bath
[email protected] Institute of Neuroscience, University of Nottingham, Nottingham NG7 2UH, UK 1
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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. Algra A, van Gijn J. Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin. J Neurol Neurosurg Psychiatry 1999; 66: 255. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurological Sciences 1996; 143: 1–13. Willmot M, Zhao L, Heptinstall S, Bath P. Triple antiplatelet therapy for secondary prevention of recurrent ischemic stroke. J Stroke Cerebrovasc Dis 2004; 13: 138–40.
Authors’ reply Unfortunately, we cannot answer Geoffrey Ling’s question about the number of patients who might be aspirin resistant. We only obtained details about medication taken at the time of
randomisation, and did not do any platelet function tests. However, the overall observed bleeding rates in MATCH suggest that patients treated with aspirin in addition to clopidogrel did respond to aspirin, since the results for this group differed from those for the group treated with clopidogrel alone. Aspirin prevents only about 13% of ischaemic events.1 Accordingly, a patient who has a stroke or a transient ischaemic attack while on aspirin need not necessarily be resistant to the drug; aspirin simply cannot prevent most of the ischaemic events, meaning that better ways to prevent them are needed. Platelet aggregation studies cannot select patients who will have an ischaemic event while on a particular drug, hence the reason why such tests are not widely used in clinical practice. In response to Peter Eriksson, the MATCH study design was appropriate, since the randomised patients were selected because they were at high risk, having already had atherothrombotic events or diabetes mellitus, or both. The CHARISMA study2 will provide further data for patients with cerebrovascular complications, comparing the effectiveness of clopidogrel and placebo in combination with a low dose of aspirin. The results of the Primary Prevention Project3 indicate that in people with diabetes, low-dose aspirin monotherapy does not prevent vascular events. A high proportion of the patients enrolled to MATCH had diabetes mellitus. The reasons listed by Philip Bath, one of our investigators, as to why MATCH was undertaken as planned, are correct. However, our study population differed from those of the acute coronary ischaemia trials, and there was no positive net balance between the efficacy and hazards in favour of combined clopidogrel and aspirin versus clopidogrel alone. However, earlier initiation of therapy and a shorter treatment period than those described could have delivered different results. We cannot comment on the efficacy of aspirin monotherapy for the prevention of www.thelancet.com Vol 364 November 6, 2004
Correspondence
stroke, since we did not study this alternative regimen in MATCH.
Hans-Christoph Diener on behalf of the steering committee of MATCH
[email protected] Klinik und Poliklinik für Neurologie, Department of Neurology, Universität Essen, 45122 Essen, Germany 1
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Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 524: 71–86. Bhatt DL, Topol EJ, on behalf of the CHARISMA Executive Committee. Clopidogrel added to aspirin alone in secondary prevention and highrisk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J 2004; 148: 263–68. Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognini G, on behalf of the PPP collaborative group. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients. Diabetes Care 2003; 26: 3264–72.
P450 oxidoreductase deficiency The Mechanism of Disease article by Wiebke Arlt and colleagues (June 26, p 2128)1 on mutations of human P450 oxidoreductase (POR) confirms many of our own observations.2 However, we point out two difficulties with Arlt and colleagues’ report. First, the numbering of the mutated aminoacids is misleading. Arlt and coworkers cite GenBank accession number P16435, which derives from the SwissProt database and indicates that human POR contains 677 residues, as does rat POR. However, the NCBI database numbers for the human POR gene (NC_000007), mRNA (NM_000941), and protein (NP_ 000932) show that human POR is 680 residues long, having an N-terminal extension (Met-Ile-Asn) that was overlooked in the SwissProt entry. This difference is important if future reports of POR mutations are to use consistent terminology. Three of the four aminoacid replacement (mis-sense) mutations reported by Arlt and colleagues were previously reported in our work.2 Thus, the mutations www.thelancet.com Vol 364 November 6, 2004
Arlt and colleagues term Ala284Pro, Arg454His, and Cys566Tyr are those we called A287P, R457H, and C569Y. Second, the enzymatic activity data reported in the Lancet article are problematic. The substantial differences in the Vmax of the wild-type POR in the two reports indicates Arlt and colleagues’ use of wholly soluble POR, lacking 46 N-terminal residues, and our use of N-27 POR in association with membranes, a system that more closely resembles POR in a cell. Arlt and co-workers report Vmax/Km values for the Ala284Pro and Arg454His mutants that are 77–83% of the activity they report for the wild-type POR. This result is inconsistent with these mutants causing disease: the affected patient (number 3) harbouring both mutations would retain about 80% normal activity, whereas the father of patients 1 and 2 is heterozygous for the totally inactive Tyr178Asp mutation, and hence has only 50% activity, yet is phenotypically normal. By contrast, we noted that A287P and R457H retained only 11% and 1% of cytochrome c reduction activity, respectively.2 Furthermore, reduction of cytochrome c, which is not a substrate for POR in vivo correlates poorly with the clinical and hormonal phenotype. By contrast, the activity of full-length membrane-bound POR to support the catalytic activities of human P450c17 yields excellent correlations with the clinical phenotype. We found that the 17,20 lyase activity of human P450c17, which is needed for sex steroid synthesis, gave the best correlations between in-vitro activity and phenotype. This finding is predictable because isolated 17,20 lyase deficiency, preserving 17-hydroxylase activity, results from mutations that alter the distribution of surface charge in the POR binding site of human P450c17. 3,4 Now that POR mutations have been identified in several individuals, additional reports will soon follow. We believe the correct numbering of human POR in future reports is essential, and we urge investigators to supplement
the facile but unreliable cytochrome c reduction assay with measurements of POR-supported P450 catalysis.
*Walter L Miller, Ningwu Huang, Christa E Flück, Amit V Pandey
[email protected] *Department of Pediatrics, University of California, San Francisco, CA 94143, USA (WLM,NH,AVP); and Pediatric Endocrinology, University Children’s Hospital, Berne, Switzerland (CEF) 1
2
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Arlt W, Walker EA, Draper N, et al. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet 2004; 363: 2128–35. Flück CE, Tajima T, Pandey AV, et al. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nature Genet 2004; 36: 228–30. Geller DG, Auchus RJ, Mendonça BB, Miller WL. The genetic and functional basis of isolated 17,20 lyase deficiency. Nature Genet 1997; 17: 201–05. Geller DG, Auchus RJ, Miller WL. P450c17 mutations R347H and R358Q selectively disrupt 17,20 lyase activity by disrupting interactions with P450 oxidoreductase and cytochrome b5. Mol Endocrinol 1999; 13: 167–75.
Peripheral neuropathy Why did John England and Arthur Asbury (June 26, p 2151)1 not include statins in the lengthy list of drugs that might cause peripheral neuropathy? Many readily available reports and articles dealing with statin-associated neuropathy have been published over the past 10 years.2,3 These and others reveal that neuropathy can arise within days of starting statins, but is most often seen after long-term use. In one report,2 patients who received statins for 2 years or more had a 4–14-fold increase in risk compared with controls. All statins have been implicated, and there are no reported instances in which patients who developed neuropathy while taking one statin were successfully switched to another. In most instances, symptoms improved or disappeared within weeks or months after statins were discontinued, and duration of treatment was inversely related to the likelihood of complete recovery. Symptoms recurred or worsened in all cases in which statins were resumed. In all these instances, 1663
