- Email: [email protected]
Redefining risks after TIA and minor ischaemic stroke
Comment
Redefining risks after TIA and minor ischaemic stroke In today’s Lancet, Iris van Wijk and colleagues present new robust evidence from an almost ideal prognostic study about the chance of survival free of recurrent vascular events during the first 10 years after a transient ischaemic attack of the brain (TIA) or minor ischaemic stroke in a large population of patients. Furthermore, they report three prediction models (one based on history, a second on history and examination findings, and a third on clinical and laboratory tests) that will help clinicians estimate the prognosis of individual patients. In the panel, I list the attributes of such an ideal study.1 Until recently, the prognosis of TIA and minor ischaemic stroke was considered benign. Reported risks were 5% a year for stroke (up to 10% in the first year), 3% a year for myocardial infarction, and 7% a year for any one of stroke, myocardial infarction, or vascular death.2 However, because patients were not assessed until some time after their cerebrovascular event, the very early prognosis was missed. And, because patients were not followed-up beyond 5 years, the prognosis in the very long term was also missed. It is now known that the early risks of stroke after TIA and minor ischaemic stroke are substantially higher. Looking forward from the time of a TIA, the risk of a stroke is as high as 5% within the first 48 h, and 12% within the first 30 days.3–6 Looking back after an ischaemic stroke, 23% of patients recall a “warning” TIA before their stroke, of whom 17% report the TIA occurred on the day of their stroke, 9% on the preceding day, and 43% in the preceding week.7 The early risk of stroke after a TIA and minor stroke is not only higher than the risk of myocardial infarction in patients presenting with acute chest pain,8 but is also three times greater if the cause is large artery disease compared with other aetiological subtypes.9,10 Presumably the very high risk of stroke soon after large artery TIA and ischaemic stroke is because the symptomatic atherosclerotic plaque in large arteries is still thrombogenic, or inflamed, unstable, and prone to re-rupture.11 Understandably, the benefits of carotid endarterectomy for symptomatic carotid stenosis are greatest when endarterectomy is done very early.12 These prognostic studies, and the augmented benefit of early carotid endarterectomy12 and antiplatelet therapy,13 emphasise that TIA or minor ischaemic stroke www.thelancet.com Vol 365 June 18, 2005
is a treatable medical emergency—an acute focal ischaemic brain syndrome akin to “unstable angina” of the brain. Patients with suspected TIA and stroke should be referred, assessed, and treated with the same urgency as patients with suspected acute coronary syndrome. The risks of recurrence are as high and the potential benefits of treatment as great. van Wijk and colleagues confirm the high early risk and show that the risks of stroke and other major vascular events over 10 years after TIA and minor ischaemic stroke are also high. Less than half of patients (48%) survive 10 years free of another vascular event. Because early vascular events were probably missed in this study, the “real life” estimate may be as low as 40%. Moreover, the annual risk of vascular events is not linear; it is high early, declines to a nadir at 3 years, and then progressively increases. The decline in risk between the first few months and 3 years is also seen in patients with symptomatic carotid stenosis treated medically.14 This decline presumably reflects healing of the symptomatic plaque. The subsequent increasing risk probably reflects continued exposure to causal risk factors, an increase in atherosclerotic plaque burden, and increasing age.
See Articles page 2098
Panel: Ten criteria for ideal study of disease prognosis* ●
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Assembly of inception cohort at early and uniform time in course of disease (ie, day 1 of symptoms) Ascertainment of cases from community (providing representative sample of patients in population with all grades of disease severity and free of hospital referral bias) Large sample size (to ensure large number of outcome events and hence adequate statistical power for reliable results) Standardised diagnostic criteria for disease and outcomes Prospective assessment (permits uniform application of diagnostic criteria and acquisition of baseline data) Prospective, frequent, long-term, and complete follow-up (to maximise ascertainment of important outcomes and minimise potential bias from "drop-outs") Recording of outcomes that are important to patient, a consequence of disease, measurable, objective, valid, reliable, communicable and, if appropriate, preventable and sensitive to change Assessment and diagnosis of outcome events "blind" to knowledge of study hypothesis and any features that may be relevant to hypothesis (eg, patient’s treatment) Analysis of survival data by actuarial methods (eg, Kaplan-Meier product-limit technique) Analysis of prognostic factors by multiple regression techniques (eg, stepwise logistic regression, and stepwise Cox’s proportional hazards analysis) which adjust for potential confounding factors *Modified from reference 1.
2065
Comment
These data highlight how atherosclerosis is an acute-onchronic disease, behaving like a volcano with recurrent episodes of activity punctuated by long periods of a symptomatically “dormant” state. The implications of van Wijk and colleagues’ study, which can confidently be generalised to similar hospitalreferred patients,15 are that patients with TIA and minor ischaemic stroke should be repeatedly re-assessed (because risks can change), treated to prevent cerebrovascular and cardiovascular events, and treated longterm. However, because of the potential inconvenience, costs, and risks of long-term preventive treatments, patients and clinicians might be reluctant to comply unless motivated by knowledge of the absolute benefits. The prediction models produced by van Wijk and colleagues will help clinicians estimate the absolute benefits of treatment. The models refine calculations of the absolute long-term risk of recurrent vascular events (from the average probability of survival free of an event at 10 years and the hazard ratios for each significant prognostic factor16). This risk can then be multiplied by the relative risk reductions associated with respective treatments. The prediction models also show the predictive power of history-taking alone. Simply asking the patient their age and sex, and history of myocardial infarction, diabetes, hypertension, and peripheral artery disease, confers almost as much information about the risk of a future event as adding the results of the examination and diagnostic procedures. This is a consistent finding in other prognostic models for patients with TIA16 and coronary heart disease;17,18 most of the risk of future vascular events can be attributed to risk factors obtained from the clinical assessment and two inexpensive blood tests (cholesterol and glucose). Never before has the potential value of early and ongoing clinical assessment and management of patients with TIA and ischaemic stroke been so apparent. And, because patients with TIA and minor ischaemic stroke share the same causes and prognosis, differing only in the duration of their neurological symptoms ( or 24 h), it is not necessary to distinguish the two conditions, unless doing epidemiological studies or formulating a differential diagnosis (eg, the differential diagnosis of TIAs lasting minutes is different from that of mild stroke lasting days or weeks).19,20 Otherwise, why not consider them as an 2066
acute focal ischaemic brain syndrome and call them “unstable brain ischaemia”? Graeme J Hankey Stroke Unit, Department of Neurology, Royal Perth Hospital; and School of Medicine & Pharmacology, University of Western Australia, Perth, Australia [email protected] I declare that I have no conflict of interest. 1
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Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical epidemiology: a basic science for clinical medicine, 2nd edn. Boston: Little, Brown and Company, 1991: 176. Dennis M, Bamford J, Sandercock P, Warlow C. The prognosis of transient ischaemic attacks in the Oxfordshire community stroke project. Stroke 1990; 21: 848–53. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000; 284: 2901–06. Coull AJ, Lovett JK, Rothwell PM; Oxford Vascular Study. Population based study of early risk of stroke after transient ischemic attack or minor stroke: implications for public education and organisation of services. BMJ 2004; 328: 326–28. Hill MD, Yiannakoulias N, Jeerakathil T, et al. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology 2004; 62: 2015–20. Kleindorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis of transient ischaemic attack in a population-based study. Stroke 2005; 36: 720–24. Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: time window for prevention is very short. Neurology 2005; 64: 817–20. Rao SV, Ohman EM, Granger CB, et al. Prognostic value of isolated troponin elevation across the spectrum of chest pain syndromes. Am J Cardiol 2003; 91: 936–40. Lovett JK, Coull A, Rothwell PM, on behalf of the Oxford Vascular Study. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004; 62: 569–73. Eliasziw M, Kennedy J, Hill MD, Buchan AM, Barnett HJM. Early risk of stroke after a transient ischaemic attack in patients with internal carotid artery disease. CMAJ 2004; 170: 1105–09. Johnston SC, Leira EC, Hansen MD, Adams HP Jr. Early recovery after cerebral ischaemia and risk of subsequent neurological deterioration. Ann Neurol 2003; 54: 439–44. Rothwell PM, Eliasziw M, Gutnikov SA, for the Carotid Endarterectomy Trialists’ Collaboration. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and the timing of surgery. Lancet 2004; 363: 915–24. Sandercock P, Gubitz G, Foley P, Counsell C. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev 2003; Issue 2: CD00002. DOI:10·1002/14651858.CD00002. North American Symptomatic Carotid Endarterectomy Trial Collaborators: Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339: 1415–25. Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?” Lancet 2005; 365: 82–93. Hankey GJ, Slattery JM, Warlow CP: Transient ischaemic attacks: which patients are at high (and low) risk of serious vascular events? J Neurol Neurosurg Psychiatry 1992; 5: 640–52. Yusuf S, Hawken S, Ounpuu S, for the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937–52. Vason RS, Sullivan LM, Wilson PWF, et al. Relative importance of borderline and elevated levels of coronary heart disease risk factors. Ann Intern Med 2005; 142: 393–402. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. A comparison of risk factors and prognosis for transient ischaemic attacks and minor ischaemic strokes: the Oxfordshire Community Stroke Project. Stroke 1989: 20: 1494–99. Hankey GJ, Warlow CP. Transient ischaemic attacks of the brain and eye. London: WB Saunders/Balliere Tindall, 1994.
www.thelancet.com Vol 365 June 18, 2005
Redefining risks after TIA and minor ischaemic stroke In today’s Lancet, Iris van Wijk and colleagues present new robust evidence from an almost ideal prognostic study about the chance of survival free of recurrent vascular events during the first 10 years after a transient ischaemic attack of the brain (TIA) or minor ischaemic stroke in a large population of patients. Furthermore, they report three prediction models (one based on history, a second on history and examination findings, and a third on clinical and laboratory tests) that will help clinicians estimate the prognosis of individual patients. In the panel, I list the attributes of such an ideal study.1 Until recently, the prognosis of TIA and minor ischaemic stroke was considered benign. Reported risks were 5% a year for stroke (up to 10% in the first year), 3% a year for myocardial infarction, and 7% a year for any one of stroke, myocardial infarction, or vascular death.2 However, because patients were not assessed until some time after their cerebrovascular event, the very early prognosis was missed. And, because patients were not followed-up beyond 5 years, the prognosis in the very long term was also missed. It is now known that the early risks of stroke after TIA and minor ischaemic stroke are substantially higher. Looking forward from the time of a TIA, the risk of a stroke is as high as 5% within the first 48 h, and 12% within the first 30 days.3–6 Looking back after an ischaemic stroke, 23% of patients recall a “warning” TIA before their stroke, of whom 17% report the TIA occurred on the day of their stroke, 9% on the preceding day, and 43% in the preceding week.7 The early risk of stroke after a TIA and minor stroke is not only higher than the risk of myocardial infarction in patients presenting with acute chest pain,8 but is also three times greater if the cause is large artery disease compared with other aetiological subtypes.9,10 Presumably the very high risk of stroke soon after large artery TIA and ischaemic stroke is because the symptomatic atherosclerotic plaque in large arteries is still thrombogenic, or inflamed, unstable, and prone to re-rupture.11 Understandably, the benefits of carotid endarterectomy for symptomatic carotid stenosis are greatest when endarterectomy is done very early.12 These prognostic studies, and the augmented benefit of early carotid endarterectomy12 and antiplatelet therapy,13 emphasise that TIA or minor ischaemic stroke www.thelancet.com Vol 365 June 18, 2005
is a treatable medical emergency—an acute focal ischaemic brain syndrome akin to “unstable angina” of the brain. Patients with suspected TIA and stroke should be referred, assessed, and treated with the same urgency as patients with suspected acute coronary syndrome. The risks of recurrence are as high and the potential benefits of treatment as great. van Wijk and colleagues confirm the high early risk and show that the risks of stroke and other major vascular events over 10 years after TIA and minor ischaemic stroke are also high. Less than half of patients (48%) survive 10 years free of another vascular event. Because early vascular events were probably missed in this study, the “real life” estimate may be as low as 40%. Moreover, the annual risk of vascular events is not linear; it is high early, declines to a nadir at 3 years, and then progressively increases. The decline in risk between the first few months and 3 years is also seen in patients with symptomatic carotid stenosis treated medically.14 This decline presumably reflects healing of the symptomatic plaque. The subsequent increasing risk probably reflects continued exposure to causal risk factors, an increase in atherosclerotic plaque burden, and increasing age.
See Articles page 2098
Panel: Ten criteria for ideal study of disease prognosis* ●
●
●
● ●
●
●
●
●
●
Assembly of inception cohort at early and uniform time in course of disease (ie, day 1 of symptoms) Ascertainment of cases from community (providing representative sample of patients in population with all grades of disease severity and free of hospital referral bias) Large sample size (to ensure large number of outcome events and hence adequate statistical power for reliable results) Standardised diagnostic criteria for disease and outcomes Prospective assessment (permits uniform application of diagnostic criteria and acquisition of baseline data) Prospective, frequent, long-term, and complete follow-up (to maximise ascertainment of important outcomes and minimise potential bias from "drop-outs") Recording of outcomes that are important to patient, a consequence of disease, measurable, objective, valid, reliable, communicable and, if appropriate, preventable and sensitive to change Assessment and diagnosis of outcome events "blind" to knowledge of study hypothesis and any features that may be relevant to hypothesis (eg, patient’s treatment) Analysis of survival data by actuarial methods (eg, Kaplan-Meier product-limit technique) Analysis of prognostic factors by multiple regression techniques (eg, stepwise logistic regression, and stepwise Cox’s proportional hazards analysis) which adjust for potential confounding factors *Modified from reference 1.
2065
Comment
These data highlight how atherosclerosis is an acute-onchronic disease, behaving like a volcano with recurrent episodes of activity punctuated by long periods of a symptomatically “dormant” state. The implications of van Wijk and colleagues’ study, which can confidently be generalised to similar hospitalreferred patients,15 are that patients with TIA and minor ischaemic stroke should be repeatedly re-assessed (because risks can change), treated to prevent cerebrovascular and cardiovascular events, and treated longterm. However, because of the potential inconvenience, costs, and risks of long-term preventive treatments, patients and clinicians might be reluctant to comply unless motivated by knowledge of the absolute benefits. The prediction models produced by van Wijk and colleagues will help clinicians estimate the absolute benefits of treatment. The models refine calculations of the absolute long-term risk of recurrent vascular events (from the average probability of survival free of an event at 10 years and the hazard ratios for each significant prognostic factor16). This risk can then be multiplied by the relative risk reductions associated with respective treatments. The prediction models also show the predictive power of history-taking alone. Simply asking the patient their age and sex, and history of myocardial infarction, diabetes, hypertension, and peripheral artery disease, confers almost as much information about the risk of a future event as adding the results of the examination and diagnostic procedures. This is a consistent finding in other prognostic models for patients with TIA16 and coronary heart disease;17,18 most of the risk of future vascular events can be attributed to risk factors obtained from the clinical assessment and two inexpensive blood tests (cholesterol and glucose). Never before has the potential value of early and ongoing clinical assessment and management of patients with TIA and ischaemic stroke been so apparent. And, because patients with TIA and minor ischaemic stroke share the same causes and prognosis, differing only in the duration of their neurological symptoms ( or 24 h), it is not necessary to distinguish the two conditions, unless doing epidemiological studies or formulating a differential diagnosis (eg, the differential diagnosis of TIAs lasting minutes is different from that of mild stroke lasting days or weeks).19,20 Otherwise, why not consider them as an 2066
acute focal ischaemic brain syndrome and call them “unstable brain ischaemia”? Graeme J Hankey Stroke Unit, Department of Neurology, Royal Perth Hospital; and School of Medicine & Pharmacology, University of Western Australia, Perth, Australia [email protected] I declare that I have no conflict of interest. 1
2
3 4
5
6
7 8
9
10
11
12
13
14
15 16
17
18
19
20
Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical epidemiology: a basic science for clinical medicine, 2nd edn. Boston: Little, Brown and Company, 1991: 176. Dennis M, Bamford J, Sandercock P, Warlow C. The prognosis of transient ischaemic attacks in the Oxfordshire community stroke project. Stroke 1990; 21: 848–53. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000; 284: 2901–06. Coull AJ, Lovett JK, Rothwell PM; Oxford Vascular Study. Population based study of early risk of stroke after transient ischemic attack or minor stroke: implications for public education and organisation of services. BMJ 2004; 328: 326–28. Hill MD, Yiannakoulias N, Jeerakathil T, et al. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology 2004; 62: 2015–20. Kleindorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis of transient ischaemic attack in a population-based study. Stroke 2005; 36: 720–24. Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: time window for prevention is very short. Neurology 2005; 64: 817–20. Rao SV, Ohman EM, Granger CB, et al. Prognostic value of isolated troponin elevation across the spectrum of chest pain syndromes. Am J Cardiol 2003; 91: 936–40. Lovett JK, Coull A, Rothwell PM, on behalf of the Oxford Vascular Study. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004; 62: 569–73. Eliasziw M, Kennedy J, Hill MD, Buchan AM, Barnett HJM. Early risk of stroke after a transient ischaemic attack in patients with internal carotid artery disease. CMAJ 2004; 170: 1105–09. Johnston SC, Leira EC, Hansen MD, Adams HP Jr. Early recovery after cerebral ischaemia and risk of subsequent neurological deterioration. Ann Neurol 2003; 54: 439–44. Rothwell PM, Eliasziw M, Gutnikov SA, for the Carotid Endarterectomy Trialists’ Collaboration. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and the timing of surgery. Lancet 2004; 363: 915–24. Sandercock P, Gubitz G, Foley P, Counsell C. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev 2003; Issue 2: CD00002. DOI:10·1002/14651858.CD00002. North American Symptomatic Carotid Endarterectomy Trial Collaborators: Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339: 1415–25. Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?” Lancet 2005; 365: 82–93. Hankey GJ, Slattery JM, Warlow CP: Transient ischaemic attacks: which patients are at high (and low) risk of serious vascular events? J Neurol Neurosurg Psychiatry 1992; 5: 640–52. Yusuf S, Hawken S, Ounpuu S, for the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937–52. Vason RS, Sullivan LM, Wilson PWF, et al. Relative importance of borderline and elevated levels of coronary heart disease risk factors. Ann Intern Med 2005; 142: 393–402. Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. A comparison of risk factors and prognosis for transient ischaemic attacks and minor ischaemic strokes: the Oxfordshire Community Stroke Project. Stroke 1989: 20: 1494–99. Hankey GJ, Warlow CP. Transient ischaemic attacks of the brain and eye. London: WB Saunders/Balliere Tindall, 1994.
www.thelancet.com Vol 365 June 18, 2005