doi: 10.1161/01.STR.0000115260.19243.64
(Stroke. 2004;35:360.)
© 2004 American Heart Association, Inc.
Advances in Stroke 2003 |
Acute Neurovascular Syndromes: Hurry Up, Please, It’s Time1
From the Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
Correspondence to Dr A.M. Buchan, Stroke Research Office, Room 1162, Foothills Medical Centre, 1403 29th St NW, Calgary, Alberta, Canada T2N 2T9. E-mail abuchan{at}ucalgary.ca
Key Words: Advances in Stroke • cerebral ischemia, transient • diagnosis • stroke
A Brief History of Time
"It isn’t that they can’t see the solution. It is that they can’t see the problem."2
Less than 20 years ago, the most common cited reason for the admission of a patient with stroke to hospital was for nursing or general nonmedical care.3 Admission to make or confirm the diagnosis or for medical treatment were mentioned less than half as often. In the same study, the most common reasons for patients remaining in the community were that they had suffered a minor stroke or services were available in the community for assessment and work-up. The evidence surrounding the benefit of aspirin in acute stroke, the reduction of death and dependence with admission of patients to dedicated stroke units, and perhaps most controversially, the demonstration of the efficacy of thrombolysis, by either intravenous or intra-arterial routes, in reducing disability following acute ischemic stroke had yet to appear.4,5
This article does not seek to re-examine the debate surrounding the use of thrombolysis in acute ischemic stroke. This has been explored at length elsewhere.6–8 The aim of this article is to explore the new perspective on the treatment of hyperacute cerebral ischemia that has arisen because of the increasing use of tissue plasminogen activator (tPA), in particular the influence of time.
The organization of acute stroke services is now required to be time sensitive to ensure that the maximum number of patients eligible for thrombolysis have the greatest chance of a good neurological outcome as possible.9 As a result, patients are presenting sooner, emergency services are prioritizing the transport of these patients to hospital, and physicians are assessing these patients more quickly.10 However, thrombolysis in acute cerebral ischemia is not a panacea, just as it has not been in acute coronary syndromes. Rather, it has provided a lever for change for all patients with acute cerebral ischemia.11 It has allowed us a broader view of the whole spectrum of the biology of acute cerebral ischemia, and perhaps where new solutions may be found.
Acute Neurovascular Syndromes
Cardiology made a paradigm shift in the study of spectrum of acute coronary syndromes with the publication of Braunwald’s classification.12 It has not only allowed the standardization of patients that are entered into randomized trials, but most importantly improved clinical care. Patients with acute coronary syndromes are stratified by the presence or absence of ST-segment elevation on baseline ECG to define the risk of early recurrent ischemia.13 ST-segment elevation on presentation predicts a higher mortality rate. However, the risks of early recurrent ischemic events and long-term morbidity and mortality are lower compared with patients without ST-segment elevation at presentation. Current AHA guidelines recognize that different presentations have different prognoses requiring different therapeutic approaches.14,15 Acute neurovascular syndromes now require an analogous paradigm shift. There is a growing appreciation of the high early risk of recurrent ischemia that those with minor or recovered events face (non–ST-elevation myocardial infarction/ unstable angina equivalent) when compared with completed events (ST-elevation myocardial infarction equivalent).
The 10% incidence of stroke within 3 months of an incident transient ischemic attack (TIA) has long been understood.16 Recent data from Northern California have shown that half of this stroke risk occurs within the first 2 days after a TIA.17 Five factors were shown to independently predict the early risk of stroke: age >60 years (odds ratio [OR], 1.8 [95% CI, 1.1 to 2.7]), diabetes mellitus (OR, 2.0 [95% CI, 1.4 to 2.9]), symptom duration >10 minutes (OR, 2.3 [95% CI, 1.3 to 4.2]), weakness (OR, 1.9 [95% CI, 1.4 to 2.6]), and speech impairment (OR, 1.5 [95% CI, 1.1 to 2.1]). The other important message from this article is that these patients are not just at risk of cerebrovascular events. In the 90-day follow period following TIA, a further 2.6% experienced cardiac events requiring hospitalization and 2.6% of patients died.
Initial skepticism around these findings (due to the self-selection of the population studied) has fallen away with the reappraisal of older databases. Review of the Oxfordshire Community Stroke Project database highlighted how this problem has remained hidden from physicians’ view.18 This population-based study showed very eloquently how the model of outpatient assessment of patients with TIA ill serves those at the highest risk of stroke. The stroke risk from time of assessment by a neurologist was 1.9% at 7 days (95% CI, 0.1 to 3.8) and 4.4% (95% CI, 1.6 to 7.2) at 30 days. However, when the perspective was re-adjusted starting from the onset of the first-ever TIA, these risks rose to 8.6% (95% CI, 4.8 to 12.4) and 12.0% (95% CI, 7.6 to 16.4), respectively.
Review of patient data from the medical arm from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) trial suggested that within this population, there are patients at an even higher risk, with the risk of ipsilateral stroke after incident TIA of 8.5% at 7 days and 20.1% at 90 days.19 Contrary to the long-term risk reported in the primary analyses of the NASCET,20,21 and the pooled analysis of all the carotid endarterectomy trials for symptomatic carotid stenosis,22 this early risk was not stratified by the degree of stenosis as measured by angiography. This observation is congruent with observations from coronary artery disease, indicating that plaque activity rather than degree of stenosis may play a crucial role in determining the early risk of recurrent events.
Understanding this period of high early risk has become very important in the clinical care of patients because of the changes to the organization of acute stroke care brought about by thrombolysis. Of those presenting within 3 hours of symptom onset, the most common reasons for ineligibility for thrombolysis is that the deficit has resolved, is improving or is too mild to warrant treatment.23 However, one third of this group will be either dead or dependent at the time of discharge from hospital. New diagnostic and therapeutic strategies need assessment in this setting to identify those at risk more accurately and provide safe and effective hyperacute treatment to ameliorate this risk.
Diagnostic and Therapeutic Challenges
There is not yet enough evidence in the literature to characterize acute neurovascular syndromes in the same way that acute coronary syndromes have now been clarified with the additional information that electrocardiographic and soluble biomarkers, such as the troponins, play in determining a management plan for patients. The roles of imaging and soluble biomarkers in refining a patients’ neurovascular prognosis have yet to be defined.
The early imaging of this group of patients has been very revealing. A new ischemic lesion seen on head computed tomography scanning predicts risk of stroke in those with TIA (OR, 4.06 [95% CI, 1.16 to 14.14]).24 The use of diffusion-weighted MRI (DWI) has shown that these patients are not just at symptomatic risk. In patients who underwent DWI within 6 hours of a clinically symptomatic stroke and again within the first week afterward, 34% of patients were found to have had recurrence on imaging compared with just 2% with a clinical recurrence. Large-artery atherosclerosis was the most frequent stroke subtype associated with any lesion recurrence (P=0.026). These silent changes found on DWI highlight the early period of increased ischemic risk. It also raises the possibility of using DWI as a possible surrogate measure for recurrent stroke in future studies.25
Soluble biomarkers have been explored as a means of refining risk prediction. Unfortunately, biomarkers such as S100B, neuron specific enolase (NSE), glial fibrillary associated protein (GFAP), and myelin basic protein (MBP) when tested in stroke patients at the time of clinical presentation suffer from low sensitivity for early diagnosis (S100B and GFAP), while NSE and MBP are nonspecific.26 This may reflect the challenge that larger proteins and peptides face in crossing the blood-brain barrier, which makes it difficult to measure brain-derived proteins or peptides in the circulation. C-reactive protein, however, is showing promise as an independent predictor of risk of subsequent stroke.27
In reviewing the randomized evidence of hyperacute therapeutic interventions in these patients, there is minimal literature available. All previous stroke prevention trials have either not focused on this early period of risk, or actively precluded enrollment during this period. The only clinical trials looking at hyperacute intervention are the International Stroke Trial (IST)28 and the Chinese Acute Stroke Trial (CAST),29 which enrolled patients with acute stroke of all severities within 48 hours of symptom onset. In the combined analysis of the 2 trials (40 000 patients), there was a highly significant reduction in recurrent ischemic stroke of 7 per 1000 patients, which outweighed the increased risk of hemorrhagic stroke or hemorrhagic conversion of the original infarct (2 per 1000 patients).30 The principle of early treatment with combination antiplatelet therapies and statins has been explored in the cardiology literature31,32 and merits investigation in those with acute neurovascular syndromes to ensure that these therapies are effective and like IST/CAST, these benefits prevail over any risk of early treatment.33
Conclusion
Thrombolysis has transformed the way we look at all those with acute neurovascular syndromes. The next step is to accurately define those at high-risk using imaging and soluble biomarkers, allowing the randomization of standardized patients into clinical trials. Only then will we have the chance to realize the solutions to these newly understood problems.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
Received December 2, 2003; accepted December 3, 2003.
References
1. Eliot TS. Waste Land, pt. 2. 1922.
2. Chesterton GK. Scandal of Father Brown: Point of a Pin. 1935.
3. Bamford J, Sandercock P, Warlow C, Gray M. Why are stroke patients admitted to hospital? Br Med J (Clin Res Ed). 1986; 292: 1369–1372.[Medline] [Order article via Infotrieve]
4. The National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group. Tissue plasminogen activator for acute ischaemic stroke. N Engl J Med. 1995; 333: 1581–1587.
5. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, et al, for the PROACT Investigators. Intra-arterial prourokinase for acute ischemic stroke. JAMA. 1999; 282: 2003–2011.
6. Lindley RI. Further randomized controlled trials of tissue plasminogen activator within 3 hours are required. Stroke. 2001; 32: 2708–2709.
7. Lyden PC. Further randomized controlled trials of tPA within 3 hours are required—not! Stroke. 2001; 32: 2710–2711.
8. Donnan GA, Davis SM. When is enough enough? Stroke. 2001; 32: 2710–2711.
9. Marler JR, Tilley BC, Lu M, Brott TG, Lyden PD, Grotta JC, Broderick JP, Levine SR, Frankel MP, Horowitz SH, et al. Early stroke treatment associated with better outcome: the NINDS rt-PA Stroke Study. Neurology. 2000; 55: 1649–1655.
10. Kennedy J, Ma C, Buchan AM. Organization of regional and local stroke resources. ways to expedite acute management of stroke. Curr Neurol Neurosci Rep. 2004; 4: 13–18.[Medline] [Order article via Infotrieve]
11. Kennedy J, Buchan AM, Barnett HJM. Thrombolysis must be considered after stroke. BMJ. 2001; 323: 937.Letter.
12. Braunwald E. Unstable angina: a classification. Circulation. 1989; 80: 410–414.
13. Armstrong PW, Fu Y, Chang W-C, Topol EJ, Granger CB, Betriu A, Van de Werf F, Lee KL, Califf RM, for the GUSTO-IIb Investigators. Acute coronary syndromes in the GUSTO-IIb Trial: prognostic insights and impact of recurrent ischemia. Circulation. 1998; 98: 1860–1868.
14. Ryan TJ, Antman EM, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, Rapaport E, Riegel B, Russell RO, Smith EE III, Weaver WD. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Available at www.acc.org. Accessed on December 1, 2003.
15. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation. 2002; 106: 1893–1900.
16. Whisnant JP, Matsumoto N, Elveback LR. Transient cerebral ischemic attacks in a community. Mayo Clin Proc. 1973; 48: 194–198.[Medline] [Order article via Infotrieve]
17. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000; 284: 2901–2906.
18. Lovett JK, Dennis MS, Sandercock PA, Bamford J, Warlow CP, Rothwell PM. Very early risk of stroke after a first transient ischemic attack. Stroke. 2003; 34: e138–e40.[Medline] [Order article via Infotrieve]
19. Eliasziw M, Kennedy J, Hill MD, Buchan AM, Barnett HJM, for the North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group. Early risk of stroke after a transient ischemic attack in patients with internal carotid artery disease. Can Med Assoc J. In press.
20. NASCET Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991; 325: 445–453.[Abstract]
21. Barnett HJM, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, et al, for the NASCET Collaborators. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998; 339: 1415–1425.
22. Rothwell PM, Eliasziw M, Gutnikov SA, Fox AJ, Taylor DW, Mayberg MR, Warlow CP, Barnett HJ, for the Carotid Endarterectomy Trialists’ Collaboration. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet. 2003; 361: 107–116.[CrossRef][Medline] [Order article via Infotrieve]
23. Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology. 2001; 56: 1015–1020.
24. Douglas VC, Johnston CM, Elkins J, Sidney S, Gress DR, Johnston SC. Head computed tomography findings predict short-term stroke risk after transient ischemic attack. Stroke. 2003; 34: 2894–2899.
25. Kang DW, Latour LL, Chalela JA, Dambrosia J, Warach S. Early ischemic lesion recurrence within a week after acute ischemic stroke. Ann Neurol. 2003; 54: 66–74.[CrossRef][Medline] [Order article via Infotrieve]
26. Lamers KJ, Vos P, Verbeek MM, Rosmalen F, van Geel WJ, van Engelen BG. Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients. Brain Res Bull. 2003; 61: 261–264.[CrossRef][Medline] [Order article via Infotrieve]
27. Arenillas JF, Alvarez-Sabin J, Molina CA, Chacon P, Montaner J, Rovira A, Ibarra B, Quintana M. C-reactive protein predicts further ischemic events in first-ever transient ischemic attack or stroke patients with intracranial large-artery occlusive disease. Stroke. 2003; 34: 2463–2468.
28. International Stroke Trialists Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients. Lancet. 1997; 349: 1569–1581.[CrossRef][Medline] [Order article via Infotrieve]
29. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. Lancet. 1997; 349: 1641–1649.[CrossRef][Medline] [Order article via Infotrieve]
30. Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, Xie JX, Warlow C, Peto R. Indications for early aspirin use in acute ischemic stroke. Stroke. 2000; 31: 1240–1249.
31. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345: 494–502.
32. Schwartz GG, Olsen AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomised controlled trial. JAMA. 2001; 285: 1711–1718.
33. Kennedy J, Eliasziw M, Hill MD, Buchan AM. The Fast Assessment of Stroke and Transient ischemic attack to prevent Early Recurrence (FASTER) Trial. Semin Cerebrovasc Dis Stroke. 2003; 3/1: 25–30.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||