- Email: [email protected]
ASPIRIN, WARFARIN, AND STROKE PREVENTION
409 The DHSS nutritional survey also found that energy intake was systematically lower than the RDA. My reluctance to take part in the television programme was only overcome by the condition that the study should be published at the same time as the programme. Since QED goes out on Wednesdays whereas The Lancet reaches most UK readers on Fridays the timing could not be exact. I agree with Dr Macfarlane that the programme should have suggested a suitable response for parents who believe that their child’s diet is deficient. The programme created unnecessary anxiety by failing to indicate the simple solution of changing the nature of one’s diet. In press and radio interviews over the past two weeks I have repeatedly suggested that the taking of pills is not the logical answer. I did warn the programme’s producer that parents would be alarmed and that a suitable response should be suggested, and I was assured that Prof Anthony Clare would deal with this point in his final comments. When I saw the programme I was unhappy that the problem had not been adequately dealt with. Larkhall Laboratories manufactured and supplied the tablets. The study was not otherwise funded by anyone. Dr Rose asks about urine colour. The colour of urine reflects many factors, including the volume of fluid consumed, the time of day, and the content of meals. We were continually alert to the possibility of differential responses to the tablets but have no evidence that any changes in urine colour were noticed. Department of Psychology, University College of Swansea, Swansea SA2 8PP
DAVID BENTON
StR,—The BBC television programme QED made the results of DrBenton and Mr Roberts’ trial "available for the first time" on Jan 20, two days before The Lancet paper appeared. There were, however, notable differences. The programme compared the nutrient intakes of four individual children with recommended dietary allowances (RDAsomething every student is warned against. The Lancet report stated that analysis of diet by RDA may be misleading because, strictly, daily allowances are intended as statements about populations rather than individuals. In the programme RDA were referred to as minimum requirements, anything under 100% being deemed a deficiency-ie, comparison with RDA can reveal deficiencies in someone’s diet. In The Lancet no such nonsensical statement
appeared. The programme referred to disturbing changes in the schoolchildren in the previous 7-8 years, with a lack of concentration, difficulty in following lessons, and irritability. The paper contained no such comments. The programme described some of the IQ tests as being specially devised; The Lancet report referred to two tests, both published in 1986. The paper did report a change in non-verbal IQ-clearly, as Benton and Roberts state, the study must now be replicated. QED claims that this has already been done in the United States. The programme stated that the pills supplied all the vitamins and minerals above "daily levels recommended for children" but they contained a remarkably unbalanced mixture. Compared with UK RDA for boys aged 12-14 years they supplied 52 % of the vitamin A, 355% Bl, 357% B,, 313% niacin, 2000% vitamin C, 2-9% calcium, and 11% iron, despite the statement that mineral intake was poorer than the vitamin intake. The programme showed that the teacher (Roberts) consumed thirteen pills at breakfast so even his informed diet must be grossly deficient. I found this contrast between BBC science and Lancet science
interesting. 2 Willow Vale,
Fetcham, Leatherhead, Surrey KT22 9TE
A. E. BENDER
ASPIRIN, WARFARIN, AND STROKE PREVENTION SIR,—The European Stroke Prevention Study (ESPS) has demonstrated a benefit for aspirin (whether with dipyridamole or not) on stroke recurrence and death in a cohort broadly classified as first strokes.! This, the most recent demonstration of a beneficial effect of aspirin, increases the appeal of this drug in comparison with other therapeutic options. Platelet antiaggregants other than aspirin have thus far failed to show benefits; warfarin use is regularly
debated yet a clinical trial in the testable setting of non-vascular atrial fibrillation was deemed impracticable, in Britain at least, because of the few eligible patients and pre-treatment scan costs;2 and trials of endarterectomy3,4 challenge a therapy that many had thought established. Are the options for medical therapy now well enough settled and limited enough for an endorsement of aspirin (with or without dipyridamole) as the one and only management step for first strokes? Should we now avoid admitting stroke patients to hospital? Should the search for cause-specific treatment be abandoned? Reasons to doubt the validity of such sweeping conclusions can be found in the ESPS results themselves. The frequency of stroke recurrence or death in the aspirin-treated group (8-10% per annum) is too high for aspirin to be accepted as definitive therapy. We suggest an aspirin-warfarin trial, long deferred, to see if risks can be reduced still further with warfarin. Warfarin remains the principal alternative to platelet antiaggregants and is popular for cardiogenic embolism, despite the deficiencies of earlier trials.5 Management dilemmas are posed daily by strokes with nonoperable stenoses or occlusions of large arteries, by difficulty in demonstrating a cardiogenic source for stroke, and by the frequency of strokes of undetermined cause.6 The low recurrence rates with warfarin therapy7-9 in some studies of cardiogenic embolism raise the possibility warfarin might in other settings reduce recurrence rates further than aspirin does. Warfarin is safe enough to permit a realistic test of the two therapies. Because of uncertainty about whether any effect of warfarin or aspirin is related to the presumed stroke mechanism, such a trial might benefit from stratification by presumed mechanism of infarction. In the ESPS, stratification by stroke subtypes was not described in detail. We presume global grouping was done to meet the sample size requirements of the study, keep study costs under
control, and provide results of general interest. Perhaps subsequent publications will detail them. Recurrence rates and stroke severity vary considerably by infarct mechanism, some approaching those of cardiogenic stroke." The high risk subgroups contain sufficient numbers of cases to make such a trial feasible. Such a trial would address an important question-namely, does warfarin offer a substantial advantage over aspirin? To show a 33 % reduction to 10% stroke recurrence or death in two years on warfarin, a trial would need 725 patients in each arm. 160 in each arm would be needed to show a 66 % reduction to 5 %. A rate of 5 % would warrant the expense of a detailed work-up for stroke and the long-term costs and risks of warfarin. If warfarin is better than aspirin for strokes in general or by subgroup, its use should be encouraged, and if no better, its use abandoned in favour of a search for newer therapies to reduce recurrence rates to acceptably low levels.
J. P. MOHR College of Physicians & Surgeons, Columbia University, New York, NY 10032
R. L. SACCO W. A. HAUSER G. W. PETTY T. K. TATEMICHI
Group. The European Stroke Prevention Study (ESPS): Principal endpoints. Lancet 1987; ii: 1351-54. Sandercock P, Warlow C, Bamford J, et al. Is a controlled trial of long-term oral anticoagulants in patients with stroke and non-rheumatic atrial fibrillation
1. The ESPS
2.
worthwhile? Lancet 1986; i: 788-92. A prospective multicenter of morbidity/mortality in carotid endarterectomies. Stroke 1986; 17: 146. 4. North American Symptomatic Carotid Endarterectomy Study Group. Carotid endarterectomy: Three critical evaluations. Stroke 1987; 18: 987-89. 5. Yatsu FM, Hart RG, Mohr JP, Grotta JC Anticoagulation of embolic strokes of cardiac origin: an update. Neurology (in press). 6. Sacco RL, Mohr JP, Tatemichi TK, et al. Reclassification of acute stroke with non-diagnostic CT and angiogram: infarction of undetermined cause m the NINCDS Stroke Data Bank Ann Neurol 1986; 20: 157-58. 7. Sixty Plus Reinfarction Study Research Group A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction. Lancet 1980; ii: 989-93. 8. Nunez L, Aguado MG, Celemin D, et al Aspirin or coumadin as the drug of choice for valve replacement with porcine bioprosthesis. Ann Thorac Surg 1982; 33: 354-58. 9. Sherman DG, Hart RG, Easton JD. The secondary prevention of stroke in patients with atrial fibrillation. Arch Neurol 1986; 43: 68-70. 10. Sacco RL, Mohr JP, Barwick J, et al Early recurrence of ischemic infarct: the NINCDS Stroke Data Bank. Stroke 1986; 17: 131. 3.
Asymptomatic Carotid Artery Stenosis Study Group. review
DAVID BENTON
StR,—The BBC television programme QED made the results of DrBenton and Mr Roberts’ trial "available for the first time" on Jan 20, two days before The Lancet paper appeared. There were, however, notable differences. The programme compared the nutrient intakes of four individual children with recommended dietary allowances (RDAsomething every student is warned against. The Lancet report stated that analysis of diet by RDA may be misleading because, strictly, daily allowances are intended as statements about populations rather than individuals. In the programme RDA were referred to as minimum requirements, anything under 100% being deemed a deficiency-ie, comparison with RDA can reveal deficiencies in someone’s diet. In The Lancet no such nonsensical statement
appeared. The programme referred to disturbing changes in the schoolchildren in the previous 7-8 years, with a lack of concentration, difficulty in following lessons, and irritability. The paper contained no such comments. The programme described some of the IQ tests as being specially devised; The Lancet report referred to two tests, both published in 1986. The paper did report a change in non-verbal IQ-clearly, as Benton and Roberts state, the study must now be replicated. QED claims that this has already been done in the United States. The programme stated that the pills supplied all the vitamins and minerals above "daily levels recommended for children" but they contained a remarkably unbalanced mixture. Compared with UK RDA for boys aged 12-14 years they supplied 52 % of the vitamin A, 355% Bl, 357% B,, 313% niacin, 2000% vitamin C, 2-9% calcium, and 11% iron, despite the statement that mineral intake was poorer than the vitamin intake. The programme showed that the teacher (Roberts) consumed thirteen pills at breakfast so even his informed diet must be grossly deficient. I found this contrast between BBC science and Lancet science
interesting. 2 Willow Vale,
Fetcham, Leatherhead, Surrey KT22 9TE
A. E. BENDER
ASPIRIN, WARFARIN, AND STROKE PREVENTION SIR,—The European Stroke Prevention Study (ESPS) has demonstrated a benefit for aspirin (whether with dipyridamole or not) on stroke recurrence and death in a cohort broadly classified as first strokes.! This, the most recent demonstration of a beneficial effect of aspirin, increases the appeal of this drug in comparison with other therapeutic options. Platelet antiaggregants other than aspirin have thus far failed to show benefits; warfarin use is regularly
debated yet a clinical trial in the testable setting of non-vascular atrial fibrillation was deemed impracticable, in Britain at least, because of the few eligible patients and pre-treatment scan costs;2 and trials of endarterectomy3,4 challenge a therapy that many had thought established. Are the options for medical therapy now well enough settled and limited enough for an endorsement of aspirin (with or without dipyridamole) as the one and only management step for first strokes? Should we now avoid admitting stroke patients to hospital? Should the search for cause-specific treatment be abandoned? Reasons to doubt the validity of such sweeping conclusions can be found in the ESPS results themselves. The frequency of stroke recurrence or death in the aspirin-treated group (8-10% per annum) is too high for aspirin to be accepted as definitive therapy. We suggest an aspirin-warfarin trial, long deferred, to see if risks can be reduced still further with warfarin. Warfarin remains the principal alternative to platelet antiaggregants and is popular for cardiogenic embolism, despite the deficiencies of earlier trials.5 Management dilemmas are posed daily by strokes with nonoperable stenoses or occlusions of large arteries, by difficulty in demonstrating a cardiogenic source for stroke, and by the frequency of strokes of undetermined cause.6 The low recurrence rates with warfarin therapy7-9 in some studies of cardiogenic embolism raise the possibility warfarin might in other settings reduce recurrence rates further than aspirin does. Warfarin is safe enough to permit a realistic test of the two therapies. Because of uncertainty about whether any effect of warfarin or aspirin is related to the presumed stroke mechanism, such a trial might benefit from stratification by presumed mechanism of infarction. In the ESPS, stratification by stroke subtypes was not described in detail. We presume global grouping was done to meet the sample size requirements of the study, keep study costs under
control, and provide results of general interest. Perhaps subsequent publications will detail them. Recurrence rates and stroke severity vary considerably by infarct mechanism, some approaching those of cardiogenic stroke." The high risk subgroups contain sufficient numbers of cases to make such a trial feasible. Such a trial would address an important question-namely, does warfarin offer a substantial advantage over aspirin? To show a 33 % reduction to 10% stroke recurrence or death in two years on warfarin, a trial would need 725 patients in each arm. 160 in each arm would be needed to show a 66 % reduction to 5 %. A rate of 5 % would warrant the expense of a detailed work-up for stroke and the long-term costs and risks of warfarin. If warfarin is better than aspirin for strokes in general or by subgroup, its use should be encouraged, and if no better, its use abandoned in favour of a search for newer therapies to reduce recurrence rates to acceptably low levels.
J. P. MOHR College of Physicians & Surgeons, Columbia University, New York, NY 10032
R. L. SACCO W. A. HAUSER G. W. PETTY T. K. TATEMICHI
Group. The European Stroke Prevention Study (ESPS): Principal endpoints. Lancet 1987; ii: 1351-54. Sandercock P, Warlow C, Bamford J, et al. Is a controlled trial of long-term oral anticoagulants in patients with stroke and non-rheumatic atrial fibrillation
1. The ESPS
2.
worthwhile? Lancet 1986; i: 788-92. A prospective multicenter of morbidity/mortality in carotid endarterectomies. Stroke 1986; 17: 146. 4. North American Symptomatic Carotid Endarterectomy Study Group. Carotid endarterectomy: Three critical evaluations. Stroke 1987; 18: 987-89. 5. Yatsu FM, Hart RG, Mohr JP, Grotta JC Anticoagulation of embolic strokes of cardiac origin: an update. Neurology (in press). 6. Sacco RL, Mohr JP, Tatemichi TK, et al. Reclassification of acute stroke with non-diagnostic CT and angiogram: infarction of undetermined cause m the NINCDS Stroke Data Bank Ann Neurol 1986; 20: 157-58. 7. Sixty Plus Reinfarction Study Research Group A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction. Lancet 1980; ii: 989-93. 8. Nunez L, Aguado MG, Celemin D, et al Aspirin or coumadin as the drug of choice for valve replacement with porcine bioprosthesis. Ann Thorac Surg 1982; 33: 354-58. 9. Sherman DG, Hart RG, Easton JD. The secondary prevention of stroke in patients with atrial fibrillation. Arch Neurol 1986; 43: 68-70. 10. Sacco RL, Mohr JP, Barwick J, et al Early recurrence of ischemic infarct: the NINCDS Stroke Data Bank. Stroke 1986; 17: 131. 3.
Asymptomatic Carotid Artery Stenosis Study Group. review