- Email: [email protected]
Clinical trials in stroke
CORRESPONDENCE
Differences in bleed incidence are probably the result of differences in bleed reports and definitions. Further trials of antiplatelet drugs in cardiovascular prevention should be set to define, report, and verify bleeds with greater precision than previous investigators have done. *Alberto Zanchetti, Lennart Hansson, on behalf of the HOT Executive Committee *Centro di Fisiologia Clinica e Ipertensione, University of Milan, 20122 Milan, Italy; Ospedale Maggiore and Istituto Auxologico Italiano, Milan; and Clinical Hypertension Research, Department of Geriatrics, University of Uppsala, Uppsala, Sweden 1
2
3
4
5
Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755–62. Medical Research Council General Practice Research Framework. Thrombosis prevention trial: randomised trial of lowintensity oral anticoagulation with warfarin and low dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233–41. Steering Committee of the Physicians’ Health Study Research Group. Final report of the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321: 129–35. Peto R, Gray R, Collins R, et al. Randomized trial of prophylactic daily aspirin in British male doctors. BMJ 1988; 296: 313–16. The SALT Collaborative Group. Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345–49.
Mitochondrial DNA abnormalities in hypertrophic cardiomyopathy Sir—In their Oct 10 commentary on hypertrophic cardiomyopathy, William McKenna and colleagues1 refer to seven genes that cause the disease: genes for b-myosin heavy chain, cardiac troponin T, cardiac troponin I, a-tropomyosin, cardiac myosinbinding protein C, and the essential and regulatory myosin light chains. These genes account for over 50% of all the reported cases of hypertrophic cardiomyopathy. The researchers also refer to the possibility of testing for mutations of these genes in clinical care. However, they do not comment on mitochondrial DNA (mtDNA) abnormalities as a cause of hypertrophic cardiomyopathy. Other than abnormalities of cardiac contractile and structural proteins, hypertrophic cardiomyopathy can be caused by disorders of cardiac energy metabolism, such as disorders of
150
mitochondrial oxidative phosphorylation (OXPHOS). Hypertrophic cardiomyopathy has been reported in carriers of the mtDNA mutations with or without mitochondrial myopathies. Defects of the mitochondrial respiratory chain in cardiac muscle are an important but commonly overlooked cause of hypertrophic cardiomyopathy, partly because mitochondrial gene mutations are more difficult to detect than mutations in chromosomal genes by sequencing DNA from peripheral leucocytes. Difficulties with genetic analysis result from heteroplasmic trait of mtDNA, the coexistence of normal and mutated DNA in various proportions within a given cell, and the coexistence of deleted and duplicated mtDNA sometimes make the genetic analysis difficult. The importance of mtDNA in the development of hypertrophic cardiomyopathy is not well recognised. Zeviani and colleagues2 reported that 16 of 32 analysed patients with hypertrophic cardiomyopathy showed abnormalities of the respiratory chain,2 which suggests an important role of mitochondrial abnormalities in the pathogenesis of the disease. Various cardiomyopathies associated with OXPHOS defects have been reported to be due to mutations of mtDNA,2,3 which are maternally inherited. MtDNA deletions are also detected in patients with hypertrophic cardiomyopathy,4 which are sporadic or inherited autosomal dominantly.5 These observations indicate that hypertrophic cardiomyopathy caused by mtDNA abnormalities account not only for sporadic but also for familial cases. However, data on how much mtDNA abnormalities contribute to the pathogenesis of the disease and the real prevalence of mtDNA abnormalities in patients with hypertrophic cardiomyopathy are not known. To investigate the role of mtDNA mutations in the pathogenesis of hypertrophic cardiomyopathy, we screened for three fairly common mutations, A3243G, A3260G, and G3316A of mtDNA in 46 patients with cardiomyopathy, including 25 patients with hypertrophic cardiomyopathy. The G3316A mutation was present in one (4%) of the patients with hypertrophic cardiomyopathy (unpublished observations). Although the number of patients analysed was fairly small, our findings suggest that mtDNA mutations may exist more commonly than are currently believed, if we screen for various mtDNA
abnormalities with an appropriate method. *Masato Odawara, Kamejiro Yamashita Institute of Clinical Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba-city, Ibaraki, 305-0022, Japan 1
2
3
4
5
McKenna WJ, Coccolo F, Elliott PM. Genes and disease expression in hypertrophic cardiomyopathy. Lancet 1998; 352: 1162–63. Zeviani M, Mariotti C, Antozzi C, et al. Oxphos defects and mitochondrial DNA mutations in cardiomyopathy. Muscle Nerve 1995; (suppl 3): S170–74. Zeviani M, Gellera C, Antozzi C, et al. Maternally inherited myopathy and cardiomyopathy: association with mutation in mitochondrial DNA tRNA-Leu(UUR). Lancet 1991; 338: 143–47. Ozawa T, Tanaka M, Sugiyama S, et al. Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy. Biochem Biophys Res Commun 1990; 170: 830–36. Odawara M, Yamashita K. Idiopathic cardiomyopathy. N Engl J Med 1995; 332: 1385.
Clinical trials in stroke Sir—We applaud Kennedy Lees’ statement (Oct, suppl III, p 28)1 that he would wish to take part in a randomised placebo-controlled trial of novel therapy should he have the misfortune to have a stroke. Let all those clinicians and scientists who design and conduct clinical trials take note. However, we wonder how many of us who ask our patients to take part in randomised trials would, if faced with a serious lifechanging or life-threatening situation accept the offer? Although it is appropriate to discuss the ethics of randomised trials and debate novel approaches to trial design, what is not discussed directly enough is how to encourage public participation in these trials. The history of oncology, for example, is littered with a host of trials closed prematurely became too few patients were recruited, while treatments become adopted as standard practice in the absence of evidence of benefit, apparently because the trial just cannot be done. Since every one of us is a potential participant in a clinical trial, why do we, the investigators, so frequently fail to achieve our goals? One reason was poignantly illustrated by one of us (JH) who was recently had a diagnosis of early breast cancer. Having become aware of the concept of uncertainty in medicine and the need for randomised trials at the time of her diagnosis, she asked her surgeon if she could take part in a randomised clinical trial of adjuvant treatment. She was told that she “mustn’t let academic niceties get
THE LANCET • Vol 353 • January 9, 1999
CORRESPONDENCE
in the way of the best treatment for her”.2 But what was the best treatment and what evidence was this based on? How often do clinicians act as the barrier to furthering clinical research and accumulation of the knowledge base? At a meeting in the UK in February, 1998, towards Public Understanding of Clinical Trials, there was only two clinicians represented in an audience of 100 people. Clinicians certainly seem to be failing to effectively promote clinical trials by not meeting the very people whom we invite to be the essence of our research. We challenge readers to step out of our comfort zones, put ourselves in the place of our patients and consider, how can we as a society make the whole business of clinical research more acceptable for everyone? We would be happy to hear from any enthusiastic, motivated individuals with a desire for action! *Pippa de Takats, Jayne Harrison *Oncology Centre, Addenbrooke’s Hospital, Cambridge CB2 2QQ; and *Eccleston, Chester (e-mail: [email protected]) 1 2
Lees KR. If I had a stroke . . . Lancet 1998; 352 (suppl III): 28–30. MRC News, Autumn 1998. No 79: 22–23.
Sir—We cannot agree with Kennedy Lees’ statements1 “even though the role of statins remains uncertain”, and “I can not adequately substantiate my views on treatment of cholesterol”. The evidence to justify recommending HMG-CoA reductase inhibitors (statins) to hypercholesterolaemic patients at moderate or high risk of developing a stroke is extensive and persuasive. This evidence comes from large clinical trials, carotid imaging studies, and meta-analyses. The largest clinical intervention trials showed a significant risk reduction in the development of fatal and non-fatal stroke in those treated with statins. This risk reduction was comparable to coronary artery disease risk reduction in the major lipid trials. a double-blind In LIPID,2 randomised trial in patients with a history of coronary artery disease and cholesterol concentrations between 4–7 mmol/L, pravastatin reduced plasma total cholesterol by 21% and stroke by 19% (p=0·048). The corresponding figure in the 4S study were 25% and 30% (p=0·02). In CARE, the prespecified endpoint of non-fatal and fatal stroke was reduced by 31% (p=0·03) in the pravastatin group. There was no increase in haemorrhagic stroke. In WOSCOPS, a primary prevention study, the impact of pravastatin was more moderate. Carotid imaging studies, using B-
THE LANCET • Vol 353 • January 9, 1999
mode ultrasonography, have also provided direct supportive evidence that lipid-lowering therapy by statins results in attenuation of carotid atherosclerosis. Evidence was further re-enforced with the publication of four large meta-analyses. One review of 12 trials (four primary and eight secondary) coronary artery disease prevention trials used statins as monotherapy. Analysis of combined data showed a significant 27% reduction of stroke associated with the use of statins (p=0·001). Blauw and colleagues3 reviewed 13 trials and concluded that treatment with statins prevents stroke in middle-age people. Herbert and co-workers4 in an overview of 16 trials, included 29 000 patients and revealed that patients who received statins had a 29% reduction in risk of stroke and a 22% reduction in total mortality. The largest and most recent meta-analysis by Bucher and colleagues5 included 28 trials with totals of over 49 000 patients in the intervention groups and 56 000 in the control groups. This meta-analysis established that cholesterol lowering with statins in patients with hypercholesterolaemia reduces the risk for non-fatal and fatal stroke. Other interventions including diet, fibrates, and resins had no effect on the incidence of stroke. In primary prevention, statins should be offered to patients with hypercholesterolaemia and one or more other risk factors for stroke. In secondary prevention, statins should be offered to patients who, despite suffering their first stroke, still have a reasonable life expectancy in terms of quantity and quality. Treatment should not be offered to those with other serious coexisting disorders but age alone should not be a barrier to therapy. Tackling risk factors effectively offers our best hope of reducing the enormous disability and cost from stroke. *M J Kendall, R Y Henry Clinical Pharmacology Section, Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK 1 2
3
4
Lees KR. If I had a stroke. Lancet 1998; 352 (suppl II): 28–30. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–57. Blauw GJ, Lagaay M, Smelt AHM, Westendorp RJH. Stroke, statins and cholesterol: a meta-analysis of randomized, placebo-controlled, double-blind trials with HMG Co-A reductase inhibitors. Stroke 1997; 28: 946–50. Herbert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with
5
statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA 1997; 278: 313–21. Bucher HC, Griffith LE, Gyatt GH. Effect of HMG Co-A reductase inhibitors on stroke: a meta-analysis of randomized, controlled trials. Ann Intern Med 1998; 128: 89–95.
Immediate aspirin for suspected ischaemic stroke Sir—It was inappropriate for Michael Hill and Vladimir Hachinski (Oct, suppl III, p 10)1 to compare the benefits of immediate aspirin for acute ischaemic stroke unfavourably with those of longterm aspirin in stroke survivors. The absolute benefit per month of aspirin is greatest while stroke patients are most at risk, and the risks of vascular events (and hence the benefits of aspirin) during the first month are greater than in any later month.2–4 In the two main trials of aspirin for acute stroke, the randomised treatment lasted less than 1 month (4 weeks in the Chinese Acute Stroke Trial,2 2 weeks in the International Stroke Trial3), yet the absolute risk of death or recurrent stroke was reduced by 9 per 1000 people given aspirin (9·2% vs 8·3%, p=0·001).2 In the trials of long-term antiplatelet treatment for some years after a stroke or transient ischaemic attack, however, the average monthly benefit was only 1 per 1000 people treated, even though the cumulative benefit eventually became substantial. Allocation to an average of 3 years of antiplatelet treatment produced a reduction of 38 per 1000 in risks of myocardial infarction, stroke, or vascular death (22·2% vs 18·4%, p<0·00001).4 Hence, for maximum protection, antiplatelet treatment should generally be started as early as possible after an acute ischaemic stroke and then continued for at least some years. The benefits from this are definite, and such treatment should routinely be considered for most patients with suspected ischaemic stroke. Even if such a policy results in aspirin inadvertently being given to a small proportion of patients with a misdiagnosed intracranial haemorrhage, there is no substantial hazard2,3—and, for that minority of the world’s ischaemic stroke patients who do get fibrinolytic therapy, long-term antiplatelet therapy can still be started quite early. Unfortunately, by concentrating chiefly on other therapies, Hill and Hachinski’s review of stroke treatment somewhat undervalues the
151
Differences in bleed incidence are probably the result of differences in bleed reports and definitions. Further trials of antiplatelet drugs in cardiovascular prevention should be set to define, report, and verify bleeds with greater precision than previous investigators have done. *Alberto Zanchetti, Lennart Hansson, on behalf of the HOT Executive Committee *Centro di Fisiologia Clinica e Ipertensione, University of Milan, 20122 Milan, Italy; Ospedale Maggiore and Istituto Auxologico Italiano, Milan; and Clinical Hypertension Research, Department of Geriatrics, University of Uppsala, Uppsala, Sweden 1
2
3
4
5
Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755–62. Medical Research Council General Practice Research Framework. Thrombosis prevention trial: randomised trial of lowintensity oral anticoagulation with warfarin and low dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233–41. Steering Committee of the Physicians’ Health Study Research Group. Final report of the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321: 129–35. Peto R, Gray R, Collins R, et al. Randomized trial of prophylactic daily aspirin in British male doctors. BMJ 1988; 296: 313–16. The SALT Collaborative Group. Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345–49.
Mitochondrial DNA abnormalities in hypertrophic cardiomyopathy Sir—In their Oct 10 commentary on hypertrophic cardiomyopathy, William McKenna and colleagues1 refer to seven genes that cause the disease: genes for b-myosin heavy chain, cardiac troponin T, cardiac troponin I, a-tropomyosin, cardiac myosinbinding protein C, and the essential and regulatory myosin light chains. These genes account for over 50% of all the reported cases of hypertrophic cardiomyopathy. The researchers also refer to the possibility of testing for mutations of these genes in clinical care. However, they do not comment on mitochondrial DNA (mtDNA) abnormalities as a cause of hypertrophic cardiomyopathy. Other than abnormalities of cardiac contractile and structural proteins, hypertrophic cardiomyopathy can be caused by disorders of cardiac energy metabolism, such as disorders of
150
mitochondrial oxidative phosphorylation (OXPHOS). Hypertrophic cardiomyopathy has been reported in carriers of the mtDNA mutations with or without mitochondrial myopathies. Defects of the mitochondrial respiratory chain in cardiac muscle are an important but commonly overlooked cause of hypertrophic cardiomyopathy, partly because mitochondrial gene mutations are more difficult to detect than mutations in chromosomal genes by sequencing DNA from peripheral leucocytes. Difficulties with genetic analysis result from heteroplasmic trait of mtDNA, the coexistence of normal and mutated DNA in various proportions within a given cell, and the coexistence of deleted and duplicated mtDNA sometimes make the genetic analysis difficult. The importance of mtDNA in the development of hypertrophic cardiomyopathy is not well recognised. Zeviani and colleagues2 reported that 16 of 32 analysed patients with hypertrophic cardiomyopathy showed abnormalities of the respiratory chain,2 which suggests an important role of mitochondrial abnormalities in the pathogenesis of the disease. Various cardiomyopathies associated with OXPHOS defects have been reported to be due to mutations of mtDNA,2,3 which are maternally inherited. MtDNA deletions are also detected in patients with hypertrophic cardiomyopathy,4 which are sporadic or inherited autosomal dominantly.5 These observations indicate that hypertrophic cardiomyopathy caused by mtDNA abnormalities account not only for sporadic but also for familial cases. However, data on how much mtDNA abnormalities contribute to the pathogenesis of the disease and the real prevalence of mtDNA abnormalities in patients with hypertrophic cardiomyopathy are not known. To investigate the role of mtDNA mutations in the pathogenesis of hypertrophic cardiomyopathy, we screened for three fairly common mutations, A3243G, A3260G, and G3316A of mtDNA in 46 patients with cardiomyopathy, including 25 patients with hypertrophic cardiomyopathy. The G3316A mutation was present in one (4%) of the patients with hypertrophic cardiomyopathy (unpublished observations). Although the number of patients analysed was fairly small, our findings suggest that mtDNA mutations may exist more commonly than are currently believed, if we screen for various mtDNA
abnormalities with an appropriate method. *Masato Odawara, Kamejiro Yamashita Institute of Clinical Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba-city, Ibaraki, 305-0022, Japan 1
2
3
4
5
McKenna WJ, Coccolo F, Elliott PM. Genes and disease expression in hypertrophic cardiomyopathy. Lancet 1998; 352: 1162–63. Zeviani M, Mariotti C, Antozzi C, et al. Oxphos defects and mitochondrial DNA mutations in cardiomyopathy. Muscle Nerve 1995; (suppl 3): S170–74. Zeviani M, Gellera C, Antozzi C, et al. Maternally inherited myopathy and cardiomyopathy: association with mutation in mitochondrial DNA tRNA-Leu(UUR). Lancet 1991; 338: 143–47. Ozawa T, Tanaka M, Sugiyama S, et al. Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy. Biochem Biophys Res Commun 1990; 170: 830–36. Odawara M, Yamashita K. Idiopathic cardiomyopathy. N Engl J Med 1995; 332: 1385.
Clinical trials in stroke Sir—We applaud Kennedy Lees’ statement (Oct, suppl III, p 28)1 that he would wish to take part in a randomised placebo-controlled trial of novel therapy should he have the misfortune to have a stroke. Let all those clinicians and scientists who design and conduct clinical trials take note. However, we wonder how many of us who ask our patients to take part in randomised trials would, if faced with a serious lifechanging or life-threatening situation accept the offer? Although it is appropriate to discuss the ethics of randomised trials and debate novel approaches to trial design, what is not discussed directly enough is how to encourage public participation in these trials. The history of oncology, for example, is littered with a host of trials closed prematurely became too few patients were recruited, while treatments become adopted as standard practice in the absence of evidence of benefit, apparently because the trial just cannot be done. Since every one of us is a potential participant in a clinical trial, why do we, the investigators, so frequently fail to achieve our goals? One reason was poignantly illustrated by one of us (JH) who was recently had a diagnosis of early breast cancer. Having become aware of the concept of uncertainty in medicine and the need for randomised trials at the time of her diagnosis, she asked her surgeon if she could take part in a randomised clinical trial of adjuvant treatment. She was told that she “mustn’t let academic niceties get
THE LANCET • Vol 353 • January 9, 1999
CORRESPONDENCE
in the way of the best treatment for her”.2 But what was the best treatment and what evidence was this based on? How often do clinicians act as the barrier to furthering clinical research and accumulation of the knowledge base? At a meeting in the UK in February, 1998, towards Public Understanding of Clinical Trials, there was only two clinicians represented in an audience of 100 people. Clinicians certainly seem to be failing to effectively promote clinical trials by not meeting the very people whom we invite to be the essence of our research. We challenge readers to step out of our comfort zones, put ourselves in the place of our patients and consider, how can we as a society make the whole business of clinical research more acceptable for everyone? We would be happy to hear from any enthusiastic, motivated individuals with a desire for action! *Pippa de Takats, Jayne Harrison *Oncology Centre, Addenbrooke’s Hospital, Cambridge CB2 2QQ; and *Eccleston, Chester (e-mail: [email protected]) 1 2
Lees KR. If I had a stroke . . . Lancet 1998; 352 (suppl III): 28–30. MRC News, Autumn 1998. No 79: 22–23.
Sir—We cannot agree with Kennedy Lees’ statements1 “even though the role of statins remains uncertain”, and “I can not adequately substantiate my views on treatment of cholesterol”. The evidence to justify recommending HMG-CoA reductase inhibitors (statins) to hypercholesterolaemic patients at moderate or high risk of developing a stroke is extensive and persuasive. This evidence comes from large clinical trials, carotid imaging studies, and meta-analyses. The largest clinical intervention trials showed a significant risk reduction in the development of fatal and non-fatal stroke in those treated with statins. This risk reduction was comparable to coronary artery disease risk reduction in the major lipid trials. a double-blind In LIPID,2 randomised trial in patients with a history of coronary artery disease and cholesterol concentrations between 4–7 mmol/L, pravastatin reduced plasma total cholesterol by 21% and stroke by 19% (p=0·048). The corresponding figure in the 4S study were 25% and 30% (p=0·02). In CARE, the prespecified endpoint of non-fatal and fatal stroke was reduced by 31% (p=0·03) in the pravastatin group. There was no increase in haemorrhagic stroke. In WOSCOPS, a primary prevention study, the impact of pravastatin was more moderate. Carotid imaging studies, using B-
THE LANCET • Vol 353 • January 9, 1999
mode ultrasonography, have also provided direct supportive evidence that lipid-lowering therapy by statins results in attenuation of carotid atherosclerosis. Evidence was further re-enforced with the publication of four large meta-analyses. One review of 12 trials (four primary and eight secondary) coronary artery disease prevention trials used statins as monotherapy. Analysis of combined data showed a significant 27% reduction of stroke associated with the use of statins (p=0·001). Blauw and colleagues3 reviewed 13 trials and concluded that treatment with statins prevents stroke in middle-age people. Herbert and co-workers4 in an overview of 16 trials, included 29 000 patients and revealed that patients who received statins had a 29% reduction in risk of stroke and a 22% reduction in total mortality. The largest and most recent meta-analysis by Bucher and colleagues5 included 28 trials with totals of over 49 000 patients in the intervention groups and 56 000 in the control groups. This meta-analysis established that cholesterol lowering with statins in patients with hypercholesterolaemia reduces the risk for non-fatal and fatal stroke. Other interventions including diet, fibrates, and resins had no effect on the incidence of stroke. In primary prevention, statins should be offered to patients with hypercholesterolaemia and one or more other risk factors for stroke. In secondary prevention, statins should be offered to patients who, despite suffering their first stroke, still have a reasonable life expectancy in terms of quantity and quality. Treatment should not be offered to those with other serious coexisting disorders but age alone should not be a barrier to therapy. Tackling risk factors effectively offers our best hope of reducing the enormous disability and cost from stroke. *M J Kendall, R Y Henry Clinical Pharmacology Section, Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK 1 2
3
4
Lees KR. If I had a stroke. Lancet 1998; 352 (suppl II): 28–30. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–57. Blauw GJ, Lagaay M, Smelt AHM, Westendorp RJH. Stroke, statins and cholesterol: a meta-analysis of randomized, placebo-controlled, double-blind trials with HMG Co-A reductase inhibitors. Stroke 1997; 28: 946–50. Herbert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with
5
statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA 1997; 278: 313–21. Bucher HC, Griffith LE, Gyatt GH. Effect of HMG Co-A reductase inhibitors on stroke: a meta-analysis of randomized, controlled trials. Ann Intern Med 1998; 128: 89–95.
Immediate aspirin for suspected ischaemic stroke Sir—It was inappropriate for Michael Hill and Vladimir Hachinski (Oct, suppl III, p 10)1 to compare the benefits of immediate aspirin for acute ischaemic stroke unfavourably with those of longterm aspirin in stroke survivors. The absolute benefit per month of aspirin is greatest while stroke patients are most at risk, and the risks of vascular events (and hence the benefits of aspirin) during the first month are greater than in any later month.2–4 In the two main trials of aspirin for acute stroke, the randomised treatment lasted less than 1 month (4 weeks in the Chinese Acute Stroke Trial,2 2 weeks in the International Stroke Trial3), yet the absolute risk of death or recurrent stroke was reduced by 9 per 1000 people given aspirin (9·2% vs 8·3%, p=0·001).2 In the trials of long-term antiplatelet treatment for some years after a stroke or transient ischaemic attack, however, the average monthly benefit was only 1 per 1000 people treated, even though the cumulative benefit eventually became substantial. Allocation to an average of 3 years of antiplatelet treatment produced a reduction of 38 per 1000 in risks of myocardial infarction, stroke, or vascular death (22·2% vs 18·4%, p<0·00001).4 Hence, for maximum protection, antiplatelet treatment should generally be started as early as possible after an acute ischaemic stroke and then continued for at least some years. The benefits from this are definite, and such treatment should routinely be considered for most patients with suspected ischaemic stroke. Even if such a policy results in aspirin inadvertently being given to a small proportion of patients with a misdiagnosed intracranial haemorrhage, there is no substantial hazard2,3—and, for that minority of the world’s ischaemic stroke patients who do get fibrinolytic therapy, long-term antiplatelet therapy can still be started quite early. Unfortunately, by concentrating chiefly on other therapies, Hill and Hachinski’s review of stroke treatment somewhat undervalues the
151