- Email: [email protected]
Heparin should not be used presently for acute ischaemic stroke
160 Gerraty Gerraty/Hankey
extracranial. There was a long time window for entry into IST (48 h), and the subcutaneous heparin (25 000 U/24 h in half the heparin group) was unmonitored. It is difficult to extrapolate the results of IST when selecting patients for closely monitored i.v. heparin, starting within hours of stroke onset. Only one reported trial with appropriate end points has compared monitored i.v. heparin with control.3 There was no difference in outcome for the two groups, but the numbers were small. One randomised trial of a low molecular weight heparin did show a benefit in outcome at six months,4 but the larger international trial (FISS-bis), not yet published beyond abstract, was negative. The Cochrane reviewers attributed the initial positive study to the play of chance.1 The Trial of Org 10172 in Acute Stroke Treatment (TOAST) used an intravenous heparinoid in 1281 patients. Although the outcome at three months was not statistically different in the treatment and placebo groups, there was a trend for better outcome in those patients with suspected large artery strokes.5 Recently Adams et al. have reported a post hoc analysis of the outcome in the 229 patients with a Doppler ultrasound diagnosis of >50% carotid stenosis or occlusion. Favourable outcomes at 7 days and 3 months were significantly greater in the danaparoid treated group.6 Although there is a benefit from long term anticoagulation in patients with non-valvular atrial fibrillation (AF), no randomised trial has examined monitored i.v. heparin in the acute setting. Ischaemic stroke as a result of dissection of an extracranial cerebral artery is considered by many to be an appropriate indication for anticoagulation with heparin, due to concern about artery-toartery embolism from clot at the site of the damaged segment, but no trial has been performed. Cerebral venous sinus thrombosis is also a condition in which there is a widespread acceptance of the place of heparin, despite conflicting trial results. I would anticoagulate with i.v. heparin patients in AF presenting with transient ischaemic attack (TIA) or minor stroke who are eligible for long term anticoagulation, and particularly patients flipping in and out of AF acutely, or who are in heart failure. I would also immediately anticoagulate stroke patients with cardiomyopathy or recent myocardial infarction, who have moderate deficits and in whom the infarct on CT is not large. Young patients with TIA or minor stroke often have an identifiable cardiac or large artery source of embolism and I would anticoagulate many of these patients, pending the results of investigations.
For most extracranial dissections, I would recommend heparin anticoagulation, followed by warfarin for six months, as is the convention in many centres. Multiple TIAs are also considered an indication for intravenous heparin, again without trial evidence. Some patients will have a critical stenosis of a large artery, but in others small vessel disease is the likely explanation. Infrequently, patients will present with a succession of 10 or 20 or more stereotyped episodes lasting several minutes, which cease abruptly with intravenous heparin. This is unlikely to be a coincidence. Patients with carotid bruit or a previously known carotid stenosis and two or three TIAs or minor stroke may be at high risk of major stroke, either from further artery to artery embolism or carotid occlusion. I consider these patients for heparin anticoagulation also. The Cochrane Review showed the risk–benefit ratio to be evenly poised for anticoagulants overall. It may well be possible to tip the balance away from the undoubted potential harmful effects of acute heparin, and with careful selection of patients, achieve a nett benefit. There is a need for a multi-centre randomised trial of early monitored i.v. heparin in patients with mild or moderate acute ischaemic stroke. In the meantime, it is reasonable to continue to consider anticoagulation with heparin for selected patients. REFERENCES 1
2
3
4
5
6
Gubitz, G, Counsell C, Sandercock P, Signorini D. Anticoagulants in acute ischaemic stroke (Cochrane Review) In: The Cochrane Library, Issue 3, 1999. Oxford: Update Software International Stroke Trial Collaborative 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: 1569–1581. Duke RJ, Bloch RF, Turpie AG, Trebilcock R, Bayer N. Intravenous heparin for the prevention of stroke progression in acute partial stable stoke. Ann Intern Med 1986; 105: 825–828. Kay R, Wong KS, Yu YL, Chan YW, Tsoi TH, Ahuja AT, Chan FL, Fong KY, Law CB, Wong A, Woo J. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995; 333: 1588–1593. 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 ischemic stroke. A randomized controlled trial. JAMA 1998; 279: 1265–1272. Adams HP, Bendixen BH, Leira E, Chang KC, Davis PH, Woolson RF, Clarke WR, Hansen MD. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery. A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) Neurology 1999; 53: 122–125.
DOI: 10.1054/ jocn.1999.0216, available online at http://www.idealibrary.com on
Heparin should not be used presently for acute ischaemic stroke Graeme J. Hankey MBBS, MD, FRCP, FRCP Ed, FRACP Consultant Neurologist and Head of Stroke Unit, Royal Perth Hospital and Clinical Associate Professor, University of Western Australia, Perth, Western Australia
For decades, clinicians have varied widely in their use of heparin in the treatment of acute ischaemic stroke. Heparin is a standard therapy in Germany, it is used by about a quarter of neurologists in the USA, and about 1% of neurologists in the UK.1–3 In Australia, clinical practice also varies widely amongst clinicians and institutions. The reasons for such wide variation in practice is nearly always disagreement amongst experts which, in turn, nearly always reflects a lack of reliable evidence. Journal of Clinical Neuroscience (2000) 7(2), 159–161
In order to produce reliable evidence of the treatment effect of heparin, which is likely to be modest at best, it is crucial that studies are able to reliably exclude two potentially erroneous conclusions:(1) a false positive (or ‘Type 1’) error that heparin is better than control when, in truth, it is not; and (2) a false negative (or ‘Type II’) error that heparin is no better than control when, in truth, it is. The probability of drawing a false positive (Type I) error can be calculated before the study begins, as the α, and after © 2000 Harcourt Publishers Ltd
Heparin should not be used presently for acute ischaemic stroke 161
the study, as the P value. The probability of a false negative (Type II) error is called the β. The probability of a true positive conclusion is called the ‘power’ of the study, and can be calculated by subtracting β from 1 (i.e. 1-β). This is analagous to the sensitivity of a diagnostic test. Appropriate studies of the effectiveness of heparin should therefore concurrently compare the effects of heparin with the effects of a control. Treatment allocation to heparin or control should be free of systematic bias (by randomisation), outcome evaluation should be free of observer bias (by observers who are blinded to the treatment allocation), and random error/the play of chance should be minimised (by studying large numbers of patients and outcome events). Such level 1 evidence (data from randomised trials with low false-positive [α] and low false-negative [β] errors)4 is now available,5 at last! A systematic review of all 21 unconfounded randomised controlled trials (RCTs) comparing immediate anticoagulation with placebo or open control in 23 427 patients with acute ischaemic stroke (Table 1) has revealed that immediate anticoagulation is associated with no overall benefit.5 Anticoagulation is associated with no significant reduction in odds of death within the scheduled treatment period (20% anticoagulants, 20% control; odds ratio [OR]: 0.99, 95% confidence intervals [CI]: 0.90–1.09), and a non-significant trend toward an increase in odds of being dead or dependent, at final follow up (60% anticoagulants, 60% control; OR: 1.05, 95% Cl: 0.98–1.12).5 Although anticoagulants reduce the risk of early recurrent ischaemic stroke by 9 per 1000 treated (2.7% anticoagulants, 3.6% control, P<0.0001), the benefit is offset by a similar sized increase in risk of haemorrhagic stroke by 9 per 1000 (1.4% anticoagulants, 0.5% control, P<0.001).5 Even a variety of sensitivity analyses, restricted to studies with various different patient selection criteria (such as cardioembolic ischaemic stroke) and anticoagulant regimes, fail to identify a significant net benefit. For example, amongst patients with acute ischaemic stroke who are in atrial fibrillation (AF), immediate anticoagulation is not associated with any improvement in recurrent stroke at 14 days (4.9% anticoagulation, 5.3% control, OR 0.91, 95% Cl: 0.66 to 1.2) or death and dependency at final followup (75.0% anticoagulation, 75.7% control, OR: 0.96, 95% Cl 0.82 to 1.13). Again, this is because the benefit of anticoagulation in reducing recurrent ischaemic stroke at 14 days (2.8% anticoagulation, 4.9% control) is offset by the hazard of excess symptomatic intracranial haemorrhage at 14 days (2.1% anticoagulation, 0.4% control) among the subgroup of ischaemic stroke patients in AF. The above results, which reflect the best available evidence, do not support the use of heparin or other anticoagulants in acute ischaemic stroke or any of its subtypes, at the present time. However, the lack of evidence of proof of effectiveness should not be equated with evidence of proof of lack of effectiveness. Indeed, heparin is effective in preventing recurrent ischaemic stroke (one ischaemic stroke prevented per 100 patients treated) but its effectiveness is offset by hazards of similar magnitude (one haemorrhagic stroke per 100 patients treated). Until we can gather more evidence from large RCTs that allow us to determine which single
© 2000 Harcourt Publishers Ltd
Table 1 Randomised controlled trials of immediate anticoagulant therapy for acute ischaemic stroke Anticoagulant regimen
Trials
Patients
Deaths
Unfractionated heparin SC Heparinoid i.v. or SC Low molecular weight heparin Thrombin inhibitor Unfractionated heparin i.v. Oral anticoagulation Total
6 3 6 2 2 2 21
20 048 1413 1321 294 270 81 23 427
4349 98 292 10 27 28 4804
acute ischaemic stroke patient is likely to benefit from heparin (perhaps with large artery thrombosis – the subject of the proposed next TOAST study),6 which single patient is likely to be harmed, and the vast majority (n=98) of patients who are likely to neither benefit, nor be harmed per 100 ischaemic stroke patients treated with heparin, I do not think we can justify using such a potentially hazardous treatment outside a RCT, or a situation where the patient and family are fully informed, and accepting, of the small potential benefits (1%) and risks (1%) of anticoagulation, based on the best available evidence.7,8 Empirical use of treatments of uncertain effectiveness and safety (such as heparin in ischaemic stroke) in circumstances outside of a controlled clinical trial are merely an experiment in which the data are uninterpretable. Furthermore, the use of heparin is a pain in the arm, leg and abdomen for patients; it upsets patients when it (all too commonly) causes bruising and intravenous catheter infections, it costs the hospital and country money, and it costs nurses, pharmacists, and doctors valuable time.
REFERENCES 1.
2.
3.
4. 5.
6.
7. 8.
Marsh EE III, Adams HP Jr, Biller J et al. Use of antithrombotic drugs in the treatment of acute ischaemic stroke. A survey of neurologists in practice in the United States. Neurology 1989; 29: 1631–1634. Smith MA, Shahar E, Doliszny KM, McGovern PG, Arnett DK, Luepker RV. Trends in medical care of hospitalised stroke patients between 1980 and 1990: The Minnesota Stroke Survey. J Stroke and Cerebrovascular Diseases 1998; 7: 76–84. Lindley RI, Amayo EO, Marshall J et al. Acute stroke treatment in UK hospitals: The Stroke Association Survey of consultant opinion. J R Coll Physicians Lond 1995; 29: 479–484. Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1989; 95 (2): 2S–4S. Sandercock PAG, Gubitz G, Counsell C, Signorini D. Immediate anticoagulant therapy for acute ischaemic stroke. Part 1: A systematic review of 21 randomised-trials of anticoagulant vs control, including 23 374 patients. (abstract). Stroke 1999; 30: 248. 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 randomised controlled trial. JAMA 1998; 279: 1265–1272. Hankey GJ. Heparin in acute ischaemic stroke. The T wave is negative and its time to stop. MJA 1998; 169: 534–536. Hankey GJ. Heparin in acute ischaemic stroke. MJA 1999; 170: 567–568.
Journal of Clinical Neuroscience (2000) 7(2), 159–161
extracranial. There was a long time window for entry into IST (48 h), and the subcutaneous heparin (25 000 U/24 h in half the heparin group) was unmonitored. It is difficult to extrapolate the results of IST when selecting patients for closely monitored i.v. heparin, starting within hours of stroke onset. Only one reported trial with appropriate end points has compared monitored i.v. heparin with control.3 There was no difference in outcome for the two groups, but the numbers were small. One randomised trial of a low molecular weight heparin did show a benefit in outcome at six months,4 but the larger international trial (FISS-bis), not yet published beyond abstract, was negative. The Cochrane reviewers attributed the initial positive study to the play of chance.1 The Trial of Org 10172 in Acute Stroke Treatment (TOAST) used an intravenous heparinoid in 1281 patients. Although the outcome at three months was not statistically different in the treatment and placebo groups, there was a trend for better outcome in those patients with suspected large artery strokes.5 Recently Adams et al. have reported a post hoc analysis of the outcome in the 229 patients with a Doppler ultrasound diagnosis of >50% carotid stenosis or occlusion. Favourable outcomes at 7 days and 3 months were significantly greater in the danaparoid treated group.6 Although there is a benefit from long term anticoagulation in patients with non-valvular atrial fibrillation (AF), no randomised trial has examined monitored i.v. heparin in the acute setting. Ischaemic stroke as a result of dissection of an extracranial cerebral artery is considered by many to be an appropriate indication for anticoagulation with heparin, due to concern about artery-toartery embolism from clot at the site of the damaged segment, but no trial has been performed. Cerebral venous sinus thrombosis is also a condition in which there is a widespread acceptance of the place of heparin, despite conflicting trial results. I would anticoagulate with i.v. heparin patients in AF presenting with transient ischaemic attack (TIA) or minor stroke who are eligible for long term anticoagulation, and particularly patients flipping in and out of AF acutely, or who are in heart failure. I would also immediately anticoagulate stroke patients with cardiomyopathy or recent myocardial infarction, who have moderate deficits and in whom the infarct on CT is not large. Young patients with TIA or minor stroke often have an identifiable cardiac or large artery source of embolism and I would anticoagulate many of these patients, pending the results of investigations.
For most extracranial dissections, I would recommend heparin anticoagulation, followed by warfarin for six months, as is the convention in many centres. Multiple TIAs are also considered an indication for intravenous heparin, again without trial evidence. Some patients will have a critical stenosis of a large artery, but in others small vessel disease is the likely explanation. Infrequently, patients will present with a succession of 10 or 20 or more stereotyped episodes lasting several minutes, which cease abruptly with intravenous heparin. This is unlikely to be a coincidence. Patients with carotid bruit or a previously known carotid stenosis and two or three TIAs or minor stroke may be at high risk of major stroke, either from further artery to artery embolism or carotid occlusion. I consider these patients for heparin anticoagulation also. The Cochrane Review showed the risk–benefit ratio to be evenly poised for anticoagulants overall. It may well be possible to tip the balance away from the undoubted potential harmful effects of acute heparin, and with careful selection of patients, achieve a nett benefit. There is a need for a multi-centre randomised trial of early monitored i.v. heparin in patients with mild or moderate acute ischaemic stroke. In the meantime, it is reasonable to continue to consider anticoagulation with heparin for selected patients. REFERENCES 1
2
3
4
5
6
Gubitz, G, Counsell C, Sandercock P, Signorini D. Anticoagulants in acute ischaemic stroke (Cochrane Review) In: The Cochrane Library, Issue 3, 1999. Oxford: Update Software International Stroke Trial Collaborative 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: 1569–1581. Duke RJ, Bloch RF, Turpie AG, Trebilcock R, Bayer N. Intravenous heparin for the prevention of stroke progression in acute partial stable stoke. Ann Intern Med 1986; 105: 825–828. Kay R, Wong KS, Yu YL, Chan YW, Tsoi TH, Ahuja AT, Chan FL, Fong KY, Law CB, Wong A, Woo J. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995; 333: 1588–1593. 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 ischemic stroke. A randomized controlled trial. JAMA 1998; 279: 1265–1272. Adams HP, Bendixen BH, Leira E, Chang KC, Davis PH, Woolson RF, Clarke WR, Hansen MD. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery. A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) Neurology 1999; 53: 122–125.
DOI: 10.1054/ jocn.1999.0216, available online at http://www.idealibrary.com on
Heparin should not be used presently for acute ischaemic stroke Graeme J. Hankey MBBS, MD, FRCP, FRCP Ed, FRACP Consultant Neurologist and Head of Stroke Unit, Royal Perth Hospital and Clinical Associate Professor, University of Western Australia, Perth, Western Australia
For decades, clinicians have varied widely in their use of heparin in the treatment of acute ischaemic stroke. Heparin is a standard therapy in Germany, it is used by about a quarter of neurologists in the USA, and about 1% of neurologists in the UK.1–3 In Australia, clinical practice also varies widely amongst clinicians and institutions. The reasons for such wide variation in practice is nearly always disagreement amongst experts which, in turn, nearly always reflects a lack of reliable evidence. Journal of Clinical Neuroscience (2000) 7(2), 159–161
In order to produce reliable evidence of the treatment effect of heparin, which is likely to be modest at best, it is crucial that studies are able to reliably exclude two potentially erroneous conclusions:(1) a false positive (or ‘Type 1’) error that heparin is better than control when, in truth, it is not; and (2) a false negative (or ‘Type II’) error that heparin is no better than control when, in truth, it is. The probability of drawing a false positive (Type I) error can be calculated before the study begins, as the α, and after © 2000 Harcourt Publishers Ltd
Heparin should not be used presently for acute ischaemic stroke 161
the study, as the P value. The probability of a false negative (Type II) error is called the β. The probability of a true positive conclusion is called the ‘power’ of the study, and can be calculated by subtracting β from 1 (i.e. 1-β). This is analagous to the sensitivity of a diagnostic test. Appropriate studies of the effectiveness of heparin should therefore concurrently compare the effects of heparin with the effects of a control. Treatment allocation to heparin or control should be free of systematic bias (by randomisation), outcome evaluation should be free of observer bias (by observers who are blinded to the treatment allocation), and random error/the play of chance should be minimised (by studying large numbers of patients and outcome events). Such level 1 evidence (data from randomised trials with low false-positive [α] and low false-negative [β] errors)4 is now available,5 at last! A systematic review of all 21 unconfounded randomised controlled trials (RCTs) comparing immediate anticoagulation with placebo or open control in 23 427 patients with acute ischaemic stroke (Table 1) has revealed that immediate anticoagulation is associated with no overall benefit.5 Anticoagulation is associated with no significant reduction in odds of death within the scheduled treatment period (20% anticoagulants, 20% control; odds ratio [OR]: 0.99, 95% confidence intervals [CI]: 0.90–1.09), and a non-significant trend toward an increase in odds of being dead or dependent, at final follow up (60% anticoagulants, 60% control; OR: 1.05, 95% Cl: 0.98–1.12).5 Although anticoagulants reduce the risk of early recurrent ischaemic stroke by 9 per 1000 treated (2.7% anticoagulants, 3.6% control, P<0.0001), the benefit is offset by a similar sized increase in risk of haemorrhagic stroke by 9 per 1000 (1.4% anticoagulants, 0.5% control, P<0.001).5 Even a variety of sensitivity analyses, restricted to studies with various different patient selection criteria (such as cardioembolic ischaemic stroke) and anticoagulant regimes, fail to identify a significant net benefit. For example, amongst patients with acute ischaemic stroke who are in atrial fibrillation (AF), immediate anticoagulation is not associated with any improvement in recurrent stroke at 14 days (4.9% anticoagulation, 5.3% control, OR 0.91, 95% Cl: 0.66 to 1.2) or death and dependency at final followup (75.0% anticoagulation, 75.7% control, OR: 0.96, 95% Cl 0.82 to 1.13). Again, this is because the benefit of anticoagulation in reducing recurrent ischaemic stroke at 14 days (2.8% anticoagulation, 4.9% control) is offset by the hazard of excess symptomatic intracranial haemorrhage at 14 days (2.1% anticoagulation, 0.4% control) among the subgroup of ischaemic stroke patients in AF. The above results, which reflect the best available evidence, do not support the use of heparin or other anticoagulants in acute ischaemic stroke or any of its subtypes, at the present time. However, the lack of evidence of proof of effectiveness should not be equated with evidence of proof of lack of effectiveness. Indeed, heparin is effective in preventing recurrent ischaemic stroke (one ischaemic stroke prevented per 100 patients treated) but its effectiveness is offset by hazards of similar magnitude (one haemorrhagic stroke per 100 patients treated). Until we can gather more evidence from large RCTs that allow us to determine which single
© 2000 Harcourt Publishers Ltd
Table 1 Randomised controlled trials of immediate anticoagulant therapy for acute ischaemic stroke Anticoagulant regimen
Trials
Patients
Deaths
Unfractionated heparin SC Heparinoid i.v. or SC Low molecular weight heparin Thrombin inhibitor Unfractionated heparin i.v. Oral anticoagulation Total
6 3 6 2 2 2 21
20 048 1413 1321 294 270 81 23 427
4349 98 292 10 27 28 4804
acute ischaemic stroke patient is likely to benefit from heparin (perhaps with large artery thrombosis – the subject of the proposed next TOAST study),6 which single patient is likely to be harmed, and the vast majority (n=98) of patients who are likely to neither benefit, nor be harmed per 100 ischaemic stroke patients treated with heparin, I do not think we can justify using such a potentially hazardous treatment outside a RCT, or a situation where the patient and family are fully informed, and accepting, of the small potential benefits (1%) and risks (1%) of anticoagulation, based on the best available evidence.7,8 Empirical use of treatments of uncertain effectiveness and safety (such as heparin in ischaemic stroke) in circumstances outside of a controlled clinical trial are merely an experiment in which the data are uninterpretable. Furthermore, the use of heparin is a pain in the arm, leg and abdomen for patients; it upsets patients when it (all too commonly) causes bruising and intravenous catheter infections, it costs the hospital and country money, and it costs nurses, pharmacists, and doctors valuable time.
REFERENCES 1.
2.
3.
4. 5.
6.
7. 8.
Marsh EE III, Adams HP Jr, Biller J et al. Use of antithrombotic drugs in the treatment of acute ischaemic stroke. A survey of neurologists in practice in the United States. Neurology 1989; 29: 1631–1634. Smith MA, Shahar E, Doliszny KM, McGovern PG, Arnett DK, Luepker RV. Trends in medical care of hospitalised stroke patients between 1980 and 1990: The Minnesota Stroke Survey. J Stroke and Cerebrovascular Diseases 1998; 7: 76–84. Lindley RI, Amayo EO, Marshall J et al. Acute stroke treatment in UK hospitals: The Stroke Association Survey of consultant opinion. J R Coll Physicians Lond 1995; 29: 479–484. Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1989; 95 (2): 2S–4S. Sandercock PAG, Gubitz G, Counsell C, Signorini D. Immediate anticoagulant therapy for acute ischaemic stroke. Part 1: A systematic review of 21 randomised-trials of anticoagulant vs control, including 23 374 patients. (abstract). Stroke 1999; 30: 248. 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 randomised controlled trial. JAMA 1998; 279: 1265–1272. Hankey GJ. Heparin in acute ischaemic stroke. The T wave is negative and its time to stop. MJA 1998; 169: 534–536. Hankey GJ. Heparin in acute ischaemic stroke. MJA 1999; 170: 567–568.
Journal of Clinical Neuroscience (2000) 7(2), 159–161