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Treatment and secondary prevention of stroke
CORRESPONDENCE
as first-line therapy. The CAPRIE population had a low event rate, and selection for clopidogrel treatment of a high-risk subgroup, in which such a strategy may be more cost-effective, is a rational suggestion that remains untested. For patients intolerant of aspirin, data on the comparison of clopidogrel with placebo are required, but are not (and may never be) available. Hankey and Warlow rightly make this comparison by indirect methods. Cost-effectiveness of clopidogrel can be argued in patients intolerant of aspirin when such approaches are used.4 Aspirin, rather than placebo, should be the comparator for costeffectiveness data on aspirin and dipyridamole in combination. The combination of dipyridamole and aspirin has been compared with aspirin alone in four published trials in patients with cerebrovascular events. From a meta-analysis of these data, the combined NNT (over 2 years) to prevent one stroke is 41. With a conservative estimate of stroke cost (UK £8500) and standard UK drug costs (aspirin treatment for 1 year £0·73, dipyridamole 200 mg modified release for 1 year £119), the net cost for the health gain from a stroke prevented is only £1175. Even with the upper limit of the 95% CI for the NNT derived from this meta-analysis (ie, 130), the net cost is £22 400, much less than that of some treatments currently purchased. Moreover, many estimations (including those quoted by Hankey and Warlow1) of the cost of stroke are much higher than £8500, so the calculated net cost would be much lower. These arguments militate against guidelines that recommend restriction of combination treatment to patients who suffer recurrent events on aspirin.5 Current evidence indicates that combination therapy is both effective and cost-effective as first-line therapy for secondary prevention in stroke patients. The analyses discussed are based on an unpublished cost-effectiveness review of antiplatelet therapy prepared for Greater Glasgow Health Board Area Drug and Therapeutics Committee. No pharmaceuticalcompany support was sought or received in relation to this work.
2
3
4
5
Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry 1996; 60: 197–99. CAPRIE Steering Committee. A randomised, blinded, trial of clopidrogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–39. Overell J, Walker A, Weir C, Lees K. The cost effectiveness of clopidrogrel and the combination of aspirin and dipyridamole in stroke prevention. Cerebrovasc Dis 1999; 9 (suppl 1): 66 (abstr). Antithrombotic Therapy. [Guideline] Scottish Intercollegiate Guidelines Network (SIGN) (36) 1999.
Sir—Graeme Hankey and Charles Warlow’s review article on secondary prevention of stroke1 claims that longterm use of aspirin reduces by 13% the combined risk of death and dependency from repeat stroke (their table 2). This relative risk reduction (RRR) may seem plausible enough because others have claimed even larger benefits.2 Hankey and Warlow’s arithmetic is, however, wrong, and the correct risk reduction is only a fifth of that cited. Given their starting-point data (risks of 47·0% vs 45·8% in controls vs treated; p 1458), their own method (p 1457) should yield an RRR of only 2·6%. This value is more in line with previous data from the same International Stroke Trial:3 with risks of 63·5% vs 62·3%, the RRR is 2·0%. Indeed, the detailed article3 makes distinctions that ought to affect the treatments. For certain groups in the International Stroke Trial,3 aspirin had no benefit at all—for example patients aged 75 and older, and those with a lacunar first stroke. Do Hankey and Warlow intend that antiplatelet drugs, which can cause gastric and cerebral bleeding, be given to those groups who will not benefit from them? Since antiplatelet protection against stroke is now turning out to be very slight, perhaps the emphasis should shift towards more promising strategies. Hankey and Warlow mention lifestyle (smoking cessation), but they exclude ethanol intake. This exclusion is strange because extensive data on moderate drinking point to a 20–30% risk reduction for first ischaemic strokes4 and a similar benefit after myocardial infarction has been described.5 Howard Newcombe
*James R Overell, Christopher J Weir, Andrew Walker, Kennedy R Lees
PO Box 135, Deep River, Ontario K0J 1PO, Canada
*Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK; and Greater Glasgow Health Board, Glasgow
1
1
2
Hankey GJ, Warlow CP. Treatment and secondary prevention of stroke: evidence, costs, and effects on individuals and populations. Lancet 1999; 354: 1457–63.
320
Hankey GJ, Warlow CP. Treatment and secondary prevention of stroke: evidence, costs, and effects on individuals and populations. Lancet 1999; 354: 1457–63. Reeder B, Chockalingam A, Dagenais G, et al. Heart disease and stroke in Canada. Ottawa: Heart and Stroke Foundation of Canada, 1997: 60.
3
4
5
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. Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middleaged and elderly US adults. N Engl J Med 1997; 337: 1705–14. Jeffrey S. Alcohol ban not necessary for MI victims: new study. Medical Post (Toronto) 1997; 33, no 42 (Dec 16): page 30.
Authors’ reply Sir—James Overell and colleagues are concerned that we estimated the effect of aspirin (vs control) in the secondary prevention of serious vascular events in survivors of stroke or transient ischaemic attack (TIA), but then overestimated the effect of clopidogrel (vs aspirin) by looking at all high-risk vascular patients and not just stroke survivors. We agree that a more consistent approach might have been preferable. Many argue that we should have taken the effect of aspirin (vs control) from trials in all high-risk patients, which gives a rather greater relative risk reduction (RRR) of 22% compared with 13% (or odds reduction of 25% [SD 2] compared with 17% [4] for the stroke trials in isolation).1 We did not, partly because there are a reasonable amount of data about aspirin (vs control) in stroke survivors (10 500 patients in 11 trials), and partly because we wished to be conservative in our analysis of aspirin. For the clopidogrel versus aspirin comparison, there is only the CAPRIE trial; although large, that trial was underpowered to look at the treatment effect reliably in the patients with ischaemic stroke (33% of the total).2 We therefore used the overall trial result in all high-risk patients. The RRR of 8·7% (95% CI 0·3–16·5) is very similar to that in the stroke patients only (7·3% [⫺5·7 to 18·7]) although in the latter the 95% CI is wider with the smaller numbers, and the result is not statistically significant. Nevertheless, the thienopyridines, including clopidrogrel, seem to have a clinically relevant antiplatelet effect that may be a little better than the effect of aspirin, but at very high cost.3 The argument about dipyridamole alone or combined with aspirin is much more difficult because the combination seems to be more effective in preventing stroke than other vascular events such as myocardial infarction and all vascular events combined, perhaps because dipyridamole is not acting as an antiplatelet drug but in some other way that is more stroke specific (eg,
THE LANCET • Vol 355 • January 22, 2000
as first-line therapy. The CAPRIE population had a low event rate, and selection for clopidogrel treatment of a high-risk subgroup, in which such a strategy may be more cost-effective, is a rational suggestion that remains untested. For patients intolerant of aspirin, data on the comparison of clopidogrel with placebo are required, but are not (and may never be) available. Hankey and Warlow rightly make this comparison by indirect methods. Cost-effectiveness of clopidogrel can be argued in patients intolerant of aspirin when such approaches are used.4 Aspirin, rather than placebo, should be the comparator for costeffectiveness data on aspirin and dipyridamole in combination. The combination of dipyridamole and aspirin has been compared with aspirin alone in four published trials in patients with cerebrovascular events. From a meta-analysis of these data, the combined NNT (over 2 years) to prevent one stroke is 41. With a conservative estimate of stroke cost (UK £8500) and standard UK drug costs (aspirin treatment for 1 year £0·73, dipyridamole 200 mg modified release for 1 year £119), the net cost for the health gain from a stroke prevented is only £1175. Even with the upper limit of the 95% CI for the NNT derived from this meta-analysis (ie, 130), the net cost is £22 400, much less than that of some treatments currently purchased. Moreover, many estimations (including those quoted by Hankey and Warlow1) of the cost of stroke are much higher than £8500, so the calculated net cost would be much lower. These arguments militate against guidelines that recommend restriction of combination treatment to patients who suffer recurrent events on aspirin.5 Current evidence indicates that combination therapy is both effective and cost-effective as first-line therapy for secondary prevention in stroke patients. The analyses discussed are based on an unpublished cost-effectiveness review of antiplatelet therapy prepared for Greater Glasgow Health Board Area Drug and Therapeutics Committee. No pharmaceuticalcompany support was sought or received in relation to this work.
2
3
4
5
Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry 1996; 60: 197–99. CAPRIE Steering Committee. A randomised, blinded, trial of clopidrogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–39. Overell J, Walker A, Weir C, Lees K. The cost effectiveness of clopidrogrel and the combination of aspirin and dipyridamole in stroke prevention. Cerebrovasc Dis 1999; 9 (suppl 1): 66 (abstr). Antithrombotic Therapy. [Guideline] Scottish Intercollegiate Guidelines Network (SIGN) (36) 1999.
Sir—Graeme Hankey and Charles Warlow’s review article on secondary prevention of stroke1 claims that longterm use of aspirin reduces by 13% the combined risk of death and dependency from repeat stroke (their table 2). This relative risk reduction (RRR) may seem plausible enough because others have claimed even larger benefits.2 Hankey and Warlow’s arithmetic is, however, wrong, and the correct risk reduction is only a fifth of that cited. Given their starting-point data (risks of 47·0% vs 45·8% in controls vs treated; p 1458), their own method (p 1457) should yield an RRR of only 2·6%. This value is more in line with previous data from the same International Stroke Trial:3 with risks of 63·5% vs 62·3%, the RRR is 2·0%. Indeed, the detailed article3 makes distinctions that ought to affect the treatments. For certain groups in the International Stroke Trial,3 aspirin had no benefit at all—for example patients aged 75 and older, and those with a lacunar first stroke. Do Hankey and Warlow intend that antiplatelet drugs, which can cause gastric and cerebral bleeding, be given to those groups who will not benefit from them? Since antiplatelet protection against stroke is now turning out to be very slight, perhaps the emphasis should shift towards more promising strategies. Hankey and Warlow mention lifestyle (smoking cessation), but they exclude ethanol intake. This exclusion is strange because extensive data on moderate drinking point to a 20–30% risk reduction for first ischaemic strokes4 and a similar benefit after myocardial infarction has been described.5 Howard Newcombe
*James R Overell, Christopher J Weir, Andrew Walker, Kennedy R Lees
PO Box 135, Deep River, Ontario K0J 1PO, Canada
*Acute Stroke Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK; and Greater Glasgow Health Board, Glasgow
1
1
2
Hankey GJ, Warlow CP. Treatment and secondary prevention of stroke: evidence, costs, and effects on individuals and populations. Lancet 1999; 354: 1457–63.
320
Hankey GJ, Warlow CP. Treatment and secondary prevention of stroke: evidence, costs, and effects on individuals and populations. Lancet 1999; 354: 1457–63. Reeder B, Chockalingam A, Dagenais G, et al. Heart disease and stroke in Canada. Ottawa: Heart and Stroke Foundation of Canada, 1997: 60.
3
4
5
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. Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middleaged and elderly US adults. N Engl J Med 1997; 337: 1705–14. Jeffrey S. Alcohol ban not necessary for MI victims: new study. Medical Post (Toronto) 1997; 33, no 42 (Dec 16): page 30.
Authors’ reply Sir—James Overell and colleagues are concerned that we estimated the effect of aspirin (vs control) in the secondary prevention of serious vascular events in survivors of stroke or transient ischaemic attack (TIA), but then overestimated the effect of clopidogrel (vs aspirin) by looking at all high-risk vascular patients and not just stroke survivors. We agree that a more consistent approach might have been preferable. Many argue that we should have taken the effect of aspirin (vs control) from trials in all high-risk patients, which gives a rather greater relative risk reduction (RRR) of 22% compared with 13% (or odds reduction of 25% [SD 2] compared with 17% [4] for the stroke trials in isolation).1 We did not, partly because there are a reasonable amount of data about aspirin (vs control) in stroke survivors (10 500 patients in 11 trials), and partly because we wished to be conservative in our analysis of aspirin. For the clopidogrel versus aspirin comparison, there is only the CAPRIE trial; although large, that trial was underpowered to look at the treatment effect reliably in the patients with ischaemic stroke (33% of the total).2 We therefore used the overall trial result in all high-risk patients. The RRR of 8·7% (95% CI 0·3–16·5) is very similar to that in the stroke patients only (7·3% [⫺5·7 to 18·7]) although in the latter the 95% CI is wider with the smaller numbers, and the result is not statistically significant. Nevertheless, the thienopyridines, including clopidrogrel, seem to have a clinically relevant antiplatelet effect that may be a little better than the effect of aspirin, but at very high cost.3 The argument about dipyridamole alone or combined with aspirin is much more difficult because the combination seems to be more effective in preventing stroke than other vascular events such as myocardial infarction and all vascular events combined, perhaps because dipyridamole is not acting as an antiplatelet drug but in some other way that is more stroke specific (eg,
THE LANCET • Vol 355 • January 22, 2000