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Prion protein in tonsil and appendix tissue
CORRESPONDENCE
these drugs was taken. Because it is easy to measure the degree of anticoagulation and is becoming possible to accurately measure platelet function,5 we argue that future trials should include a measure of anticoagulant or antiplatelet activity, so that the dose of either drug given need not be arbitrary. It would be more difficult to recruit patients to such trials, but they are more likely to produce useful answers. Anthony C Pereira, *Elizabeth Warburton Department of Clinical Neurology, Ipswich Hospital, Ipswich and Addenbrooke’s Hospital, Cambridge, UK; and “Department of Stroke Medicine, Box 135, Addenbrooke’s hospital, Cambridge CB2 2QQ, UK 1
2
3
4
5
Berge E, Adbelnoor M, Nakstad PH, Sandset PM, on behalf of the HAEST Study Group. Low-molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355: 1205–10. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–81. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin in 20 000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–49. Helgason CM, Tortorise KL, Winkler SR, et al. Aspirin and failure in cerebral infarction. Stroke 1993; 24: 345–50. Nicholson NS, Panzer-Knodle SG, Haas NF, et al. Assessment of platelet function assays [suppl]. Am Heart J 1998; 135 (2): S170–78.
Authors’ reply Sir—The correspondents present alternative explanations for the lack of effect of LMWH relative to aspirin in patients who had acute ischaemic stroke and atrial fibrillation. Danilo Toni and colleagues raise concerns that we may have falsely classified symptomatic progression as recurrent stroke. We agree that there is potential for random misclassification in our trial, but we are not confident that their conservative definition of recurrence reflects the biological reality more accurately. They suggest that the definition of recurrent stroke should be confirmed by a new, second infarction on cerebral CT scan, or by new symptoms arising from another vascular territory. In our study, these criteria were applied strictly only within the first 48 h, when the risk of symptomatic progression is highest. In our experience CT scans are not sensitive enough to detect smaller reinfarctions superimposed on more extensive changes in the acute phase (eg, hypodensity, oedema, and haemorrhage), and the delayed
THE LANCET • Vol 356 • August 5, 2000
appearance of the index infarction may falsely be interpreted as a new event. Recurrent infarctions may also occur in the same vascular territory as the index infarction, and we believe that the proposed criteria would grossly underestimate the risk of recurrent stroke. The correspondents consider the lower incidence estimates in IST1 and TOAST2 to be nearer to the true incidence of recurrent stroke. The lower incidence in these trials was not, however, a consequence of a more conservative definition. The diagnostic criteria for recurrent stroke were not even defined, but were left to the discretion of individual investigators. Moreover, the diagnosis was made in retrospect at the end of treatment, and we believe that recurrent stroke was not more validly defined or more reliably reported in these studies. Our classification may not be ideal, but provides for the first time an operational and well defined clinically based classification for use in acute stroke trials. Anthony Pereira and Elizabeth Warburton discuss the possibility that the study results are accounted for by inadequate doses of trial drugs. The LMWH dose used in our study was identical to the dose used for the treatment of venous thromboembolism,3 but slightly lower than the dose used for the treatment of acute coronary syndromes (100 U/Kg vs 120 U/kg twice daily).4 In our study, biological activity was measured after 1 week with a chromogenic method in blood samples collected 3–4 h after injection. The median anti-factor Xa activity was 0·63 U/mL (25–75 percentiles 0·44–0·78, n=152). Measurement of platelet function is not easily done in a multicentre trial. However, meta-analyses of the effect of antiplatelet therapy has shown that doses ranging from 75 mg to 325 mg are all effective,5 and although the optimum dose still needs to be established, a daily dose of 160 mg is often recommended. *Eivind Berge, Per Morten Sandset Department of Haematology, Haematological Research Laboratory, Ullevål University Hospital, N-0407 Oslo, Norway 1
2
International Stroke Trial Collaboration Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–81. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischaemic stroke: a randomized controlled trial. JAMA 1998; 279: 1265–72.
3
4
5
Leizorovicz A, Simonneau G, Decousus H, Boissel JP. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis:a meta-analysis. BMJ 1994; 309: 299–304. Fragmin during Instability in Coronary Artery Disease (FRSC) study group. Lowmolecular-weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561–68. Collaborative overview of randomised trials of antiplatelet therapy I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ 1994; 308: 81: 106.
Prion protein in tonsil and appendix tissue Sir—James Ironside and colleagues (May 13, p 1693)1 presented an interesting article on variant Creutzfeldt-Jakob disease. The unique attribute of this prion disease is its ability to be detected outside the central nervous system—specifically, in the tonsil and appendix tissue—by western blot techniques. The investigators report the results of analysing 3075 appendices and 95 tonsils for the prion. There were no cases of prion disease detected. Although this number may be plausible from a population prevalence standpoint, it is rather unusual from a statistical standpoint. This data suggest that the false positive rate is less than one (<0·025%) in 4070. Western blots are very specific tests, but one would estimate one test being positive in over 4000 tests examined. I wonder if the test is truly that accurate or if we have set our threshold too high to detect a positive test? The question of a test being more sensitive at the expense of false-positives is a natural one for a disease which has large social implications. Robert S Dieter Department of Medicine, Section of Cardiovascular Medicine, University of Wisconsin, Madison, WI 53792, USA 1
Ironside JW, Hilton DA, Ghani A, et al. Retrospective study of prion-protein accumulation in tonsil and appendix tissues. Lancet 2000; 355: 1693–94.
Sir—Although the study by James Ironside and colleagues1 showed no cases of positive immunohistochemistry for Prion Protein (PrP) amongst 3075 archived appendices, investigators acknowledged that this was likely to be a result of the sample size. PrP has been found in the archived appendix of a man who had an appendicectomy 8 months before the onset of variant CreutzfeldtJakob disease (vCJD).2 Prion protein does not respond to conventional
505
For personal use only. Not to be reproduced without permission of The Lancet.
these drugs was taken. Because it is easy to measure the degree of anticoagulation and is becoming possible to accurately measure platelet function,5 we argue that future trials should include a measure of anticoagulant or antiplatelet activity, so that the dose of either drug given need not be arbitrary. It would be more difficult to recruit patients to such trials, but they are more likely to produce useful answers. Anthony C Pereira, *Elizabeth Warburton Department of Clinical Neurology, Ipswich Hospital, Ipswich and Addenbrooke’s Hospital, Cambridge, UK; and “Department of Stroke Medicine, Box 135, Addenbrooke’s hospital, Cambridge CB2 2QQ, UK 1
2
3
4
5
Berge E, Adbelnoor M, Nakstad PH, Sandset PM, on behalf of the HAEST Study Group. Low-molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355: 1205–10. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–81. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin in 20 000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–49. Helgason CM, Tortorise KL, Winkler SR, et al. Aspirin and failure in cerebral infarction. Stroke 1993; 24: 345–50. Nicholson NS, Panzer-Knodle SG, Haas NF, et al. Assessment of platelet function assays [suppl]. Am Heart J 1998; 135 (2): S170–78.
Authors’ reply Sir—The correspondents present alternative explanations for the lack of effect of LMWH relative to aspirin in patients who had acute ischaemic stroke and atrial fibrillation. Danilo Toni and colleagues raise concerns that we may have falsely classified symptomatic progression as recurrent stroke. We agree that there is potential for random misclassification in our trial, but we are not confident that their conservative definition of recurrence reflects the biological reality more accurately. They suggest that the definition of recurrent stroke should be confirmed by a new, second infarction on cerebral CT scan, or by new symptoms arising from another vascular territory. In our study, these criteria were applied strictly only within the first 48 h, when the risk of symptomatic progression is highest. In our experience CT scans are not sensitive enough to detect smaller reinfarctions superimposed on more extensive changes in the acute phase (eg, hypodensity, oedema, and haemorrhage), and the delayed
THE LANCET • Vol 356 • August 5, 2000
appearance of the index infarction may falsely be interpreted as a new event. Recurrent infarctions may also occur in the same vascular territory as the index infarction, and we believe that the proposed criteria would grossly underestimate the risk of recurrent stroke. The correspondents consider the lower incidence estimates in IST1 and TOAST2 to be nearer to the true incidence of recurrent stroke. The lower incidence in these trials was not, however, a consequence of a more conservative definition. The diagnostic criteria for recurrent stroke were not even defined, but were left to the discretion of individual investigators. Moreover, the diagnosis was made in retrospect at the end of treatment, and we believe that recurrent stroke was not more validly defined or more reliably reported in these studies. Our classification may not be ideal, but provides for the first time an operational and well defined clinically based classification for use in acute stroke trials. Anthony Pereira and Elizabeth Warburton discuss the possibility that the study results are accounted for by inadequate doses of trial drugs. The LMWH dose used in our study was identical to the dose used for the treatment of venous thromboembolism,3 but slightly lower than the dose used for the treatment of acute coronary syndromes (100 U/Kg vs 120 U/kg twice daily).4 In our study, biological activity was measured after 1 week with a chromogenic method in blood samples collected 3–4 h after injection. The median anti-factor Xa activity was 0·63 U/mL (25–75 percentiles 0·44–0·78, n=152). Measurement of platelet function is not easily done in a multicentre trial. However, meta-analyses of the effect of antiplatelet therapy has shown that doses ranging from 75 mg to 325 mg are all effective,5 and although the optimum dose still needs to be established, a daily dose of 160 mg is often recommended. *Eivind Berge, Per Morten Sandset Department of Haematology, Haematological Research Laboratory, Ullevål University Hospital, N-0407 Oslo, Norway 1
2
International Stroke Trial Collaboration Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–81. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischaemic stroke: a randomized controlled trial. JAMA 1998; 279: 1265–72.
3
4
5
Leizorovicz A, Simonneau G, Decousus H, Boissel JP. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis:a meta-analysis. BMJ 1994; 309: 299–304. Fragmin during Instability in Coronary Artery Disease (FRSC) study group. Lowmolecular-weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561–68. Collaborative overview of randomised trials of antiplatelet therapy I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ 1994; 308: 81: 106.
Prion protein in tonsil and appendix tissue Sir—James Ironside and colleagues (May 13, p 1693)1 presented an interesting article on variant Creutzfeldt-Jakob disease. The unique attribute of this prion disease is its ability to be detected outside the central nervous system—specifically, in the tonsil and appendix tissue—by western blot techniques. The investigators report the results of analysing 3075 appendices and 95 tonsils for the prion. There were no cases of prion disease detected. Although this number may be plausible from a population prevalence standpoint, it is rather unusual from a statistical standpoint. This data suggest that the false positive rate is less than one (<0·025%) in 4070. Western blots are very specific tests, but one would estimate one test being positive in over 4000 tests examined. I wonder if the test is truly that accurate or if we have set our threshold too high to detect a positive test? The question of a test being more sensitive at the expense of false-positives is a natural one for a disease which has large social implications. Robert S Dieter Department of Medicine, Section of Cardiovascular Medicine, University of Wisconsin, Madison, WI 53792, USA 1
Ironside JW, Hilton DA, Ghani A, et al. Retrospective study of prion-protein accumulation in tonsil and appendix tissues. Lancet 2000; 355: 1693–94.
Sir—Although the study by James Ironside and colleagues1 showed no cases of positive immunohistochemistry for Prion Protein (PrP) amongst 3075 archived appendices, investigators acknowledged that this was likely to be a result of the sample size. PrP has been found in the archived appendix of a man who had an appendicectomy 8 months before the onset of variant CreutzfeldtJakob disease (vCJD).2 Prion protein does not respond to conventional
505
For personal use only. Not to be reproduced without permission of The Lancet.