A Lancet Issue Devoted to Stroke
Marc Fisher MD Kennedy Lees MD Section Editors:
The dominant theme of the January 27, 2007 issue of Lancet is stroke. In a new editorial policy the Lancet decided to publish themed issues of particular interest to both general clinicians and specialist researchers. Stroke is undoubtedly a disease that requires special attention: approximately 1% of the 6.5 billion people living on our planet—twice the population of Canada or 8 times the population of Switzerland—will die each year of stroke. Many of these strokes are either preventable or could be delayed to a more advanced age. Considering such figures, the Lancet editors have to be congratulated for their decision, which is an important step in the struggle to reduce the burden of stroke in our societies. They have carefully selected original articles, seminars, and reviews on stroke. In the following we will comment on the 4 original articles.
Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G, for the SITS-MOST investigators. Thrombolysis with alteplase for acute ischemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007;369:275–282.
The European Agency for the Evaluation of Medicinal Products (EMEA) mandated a postlicensing observational registry of thrombolysis use in Europe as a condition of licensing. The web-based SITS-MOST registry was launched in response to this need and collected more than 6000 patients from nearly 300 European centers.
Any European center was eligible as long as they agreed to enter all consecutive patients and agreed to site monitoring and aggregrate data reporting. Both experienced and inexperienced thrombolysis sites were eligible. The primary outcomes were safety outcomes: symptomatic ICH and death at 3 months from treatment.
Patients enrolled in the registry were typically similar to those enrolled in prior trials and stroke thrombolysis registries. The mortality rate was 11.3% and symptomatic ICH rate 7.3%. Excellent functional outcome was achieved in 39% of patients.
This experience represents the largest stroke thrombolysis registry globally. It documents the safety and effectiveness of alteplase for stroke in routine clinical practice.
The study is an important addition to the stroke literature and hopefully critical for the full licensure of alteplase for stroke in Europe. There are several important details to note about this study.
First, the EMEA regulated limits on the use of thrombolysis to those patients 80 years and younger, those without substantial early ischemic change on CT scan using the 1/3rd MCA rule, or those without very severe clinical stroke NIHSS ≤25. These limits were applicable to the SITS-MOST registry. Therefore, patients with the worst prognosis were excluded. I infer that these restrictions were very likely to account for the low mortality (6% less than mortality rates reported in randomized trials) observed in this study. It is critical to recognize that because a variable has prognostic value does not necessarily imply that a treatment effect differs according to that variable. Although it is true that older patients with more severe stroke and with early ischemic change evident on CT scan are more likely to fare poorly, it does not mean that there is no potential benefit to treatment. Excluding such patients from treatment may be justified on the basis of safety. However, several cohort studies have now shown that treating octogenarians is at least as safe as treating younger patients. The degree of ischemic change on CT does impact the safety of therapy. The balance of risk and potential benefit, to my mind, means allowing the treatment of patients over 80 and with higher NIHSS scores. Patients with very severe ischemic change (ASPECTS ≤4) probably should not be treated with thrombolysis.
Second, the rate of intracerebral hemorrhage was elucidated to be highly dependent on the definition. Various definitions are available including: (1) a radiological one—parenchymal hematoma type 2; (2) NIHSS change of 4 or more points plus the presence of any intracranial hemorrhage on follow-up imaging; (3) symptomatic worsening plus the presence of any intracranial hemorrhage on follow-up imaging. This is a critical issue when comparing various reports of the safety of thrombolysis. In our view, the definition is: intracranial hemorrhage proven by follow-up neuroimaging, which is judged by the attending neurologist to be the principal cause of either new neurological symptoms or worsening neurological status. This definition arises because many hemorrhages are remote from the infarct and continues to require clinical judgment about the nature of hemorrhage, but is not subject to arbitrary limits set by the NIHSS score or the greater sensitivity of MRI as the neuroimaging modality. It seems likely that, in the past by including “all hemorrhage” in the definition, symptomatic ICH was conservatively assessed and the 5% to 7% rate reported in randomized trials is an overestimate.
Overall, SITS-MOST is a critical and hopefully final work on the use of stroke thrombolysis in clinical routine practice. It is now time to move on and look for better thrombolytic agents, adjuvant agents, and explore the role of pharmacological and mechanical endovascular thrombolysis in stroke.
Johnston SC, Rothwell PM, Nguyen-Huynh MN, Giles MF, Elkins JS, Bernstein AL, Sidney S. Validation and refinement of scores to predict very early stroke risk after transient ischemic attack. Lancet. 2007;369:283–292.
The aim of this study was to validate 2 similar existing prognostic scores for early risk of stroke after transient ischemic attack (TIA) and to derive and validate a unified score optimized for prediction of 2-day stroke risk.
The California and ABCD scores were validated in 4 independent groups of patients (n=2893) diagnosed with TIA in emergency departments and clinics in defined populations in the USA and UK. Prognostic value was quantified with receiver operator characteristics methodology. The 2 groups used to derive the original scores (n=1916) were used to derive a new unified score based on logistic regression.
The 2 existing scores predicted the risk of stroke similarly in each of the 4 validation cohorts, for stroke risks at 2 days, 7 days, and 90 days (c statistics 0.60 to 0.81). In both derivation groups, c statistics were improved for a unified score based on 5 factors (age ≥60 years [1 point]; blood pressure ≥140/90 mm Hg ; clinical features: unilateral weakness , speech impairment without weakness ; duration ≥60 minutes  or 10 to 59 minutes ; and diabetes ). This score, ABCD2, validated well (c statistics 0.62 to 0.83); overall, 1012 (21%) of patients were classified as high risk (score 6 to 7, 8.1% 2-day risk), 2169 (45%) as moderate risk (score 4 to 5, 4.1%), and 1628 (34%) as low risk (score 0 to 3, 1.0%).
Existing prognostic scores for stroke risk after TIA validate well on multiple independent cohorts, but the unified ABCD2 score is likely to be most predictive. Patients at high risk need immediate evaluation to optimize stroke prevention.
The British and American researchers have to be congratulated for their creation of a clinical score that reliably predicts short-term risk of stroke after TIA. Such scores are especially important in developing countries with restricted access to medicine and in developed countries at times when health authorities are not willing or unable to allocate adequate resources for further investigation and treatment of such patients. However, ABCD2 cannot replace clinical judgment. After TIA, as Louis Caplan stated in an editorial decades ago, we need to address the question, “what is wrong with Mr Jones?”1 We need to address this question as soon as possible, even when Mr Jones is only 58 years old, smokes, and has high blood pressure and a left sided weakness for 30 minutes, ie, has an ABCD2 score of 3 and is at low short-term risk. The predictive capability of the ABCD2 rule, although similar to other prediction rules in other fields, remains modest. Will we settle for an approximately 70% discriminative value, meaning that some of our patients, if discharged, will suffer strokes? No, we require MRI, carotid imaging, cardiac workup, and blood examinations urgently (and often sooner than local circumstances currently permit) to investigate the cause of the TIA and to initiate treatment to avert a stroke. Nevertheless, the prognostic information derived from the ABCD2 tells us that TIA patients scoring 4 or more points are at substantial short-term risk of stroke and should preferably undergo same-day investigations and treatment. For low risk patients (ABCD2 scores <4), unless clinical judgment or results from ancillary investigations such as MRI and carotid imaging alert us differently, rapid outpatient evaluation and preventive treatment seems to be a reasonable option.
Chalela JA, Kidwell CS, Nentwich LM, Luby M, Butman JA, Demchuk AM, Hill MD, Patronas N, Latour L, Warach S. MRI and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet. 2007;369:293–298.
The use of MRI (MRI) for the diagnosis of acute stroke is increasing, but this method has not proved more effective than computed tomography (CT) in the emergency setting. The authors aimed to prospectively compare CT and MRI for emergency diagnosis of acute stroke.
Single-center, prospective, blinded comparison of noncontrast CT and MRI (with diffusion-weighted and susceptibility weighted images) in a consecutive series of patients referred for emergency assessment of suspected acute stroke. Scans were independently interpreted by 4 experts, who were unaware of clinical information, MRI-CT pairings, and follow-up imaging.
356 patients, 217 of whom had a final clinical diagnosis of acute stroke, were assessed. MRI detected acute stroke (ischemic or hemorrhagic), acute ischemic stroke, and chronic hemorrhage more frequently than did CT (P<0.0001, for all comparisons). MRI was similar to CT for the detection of acute intracranial hemorrhage. MRI detected acute ischemic stroke in 164 of 356 patients (46%; 95% CI 41% to 51%), compared with CT in 35 of 356 patients (10%; 7% to 14%). In the subset of patients scanned within 3 hours of symptom onset, MRI detected acute ischemic stroke in 41 of 90 patients (46%; 35% to 56%); CT in 6 of 90 (7%; 3% to 14%). Relative to the final clinical diagnosis, MRI had a sensitivity of 83% (181 of 217; 78% to 88%) and CT of 26% (56 of 217; 20% to 32%) for the diagnosis of any acute stroke.
MRI is better than CT for detection of acute ischemia and can detect acute and chronic hemorrhage; therefore it should be the preferred test for accurate diagnosis of patients with suspected acute stroke. Because the patient sample encompassed the range of disease that is likely to be encountered in emergency cases of suspected stroke, the authors felt that the results are directly applicable to clinical practice.
With the evolution of MR angiography and diffusion- and perfusion-weighted imaging, stroke MRI made rapid progress, enhanced our understanding of the pathophysiology of stroke tremendously, and many clinicians predicted the end of routine CT imaging. The study of Chalela et al, a single center comparison of MR and CT in acute stroke, has shown that MRI is superior to CT for confirming cerebral ischemia and as good as CT to detect intracerebral hemorrhage. In addition, MR has the advantage of detecting old hemorrhage. Nevertheless, the end of CT has not come yet. In spite of the clear advantages of MRI, its increasing availability in emergency rooms, it has not become the standard of care. The reasons are multiple: (1) More than 10% of Chalela’s patients could not be examined by MRI because of contraindications, claustrophobia, patient agitation, or medical instability, situations where CT is easier to use; (2) Cost of MRI is greater; (3) The time needed for imaging and preparing the patient for MR imaging cannot be neglected. Imaging time, unfortunately, is not reported in the study. Finally, the authors compared MRI to standard CT, whereas modern CT imaging has evolved. Multimodal CT now includes perfusion imaging and 3-dimensional pictures of the cerebral arteries, produced within seconds to a few minutes. Despite the drawbacks of the study Chalela and coworkers have to be congratulated. Their results tell us that MRI is underused in stroke medicine. For stable stroke patients, and this is the majority, much more clinically relevant information will be gained by MRI than by CT, and the increasing use of MRI will likely translate into better patient care. In the near future imaging-based and especially-MRI based selection of patients for thrombolysis beyond the 3-hour time window will most likely play an important role. For evaluation of unstable patients, however, clinical and CT information provides adequate information for acute management. Therefore, even MR afficionados will likely rely on CT as their work horse for many acute stroke patients in the next years to come.
Candelise L, Gattinoni M, Bersano A, Micieli G, Sterzi R, Morabito A, on the behalf of the PROSIT Study Group. Stroke-unit care for acute stroke patients: an observational follow-up study. Lancet. 2007;369:299–305.
Stroke units are known to improve outcome but are less commonly available in North America compared with Europe. Even in Europe, many hospitals do not provide organized stroke care. Much of the randomized stroke unit data comes from subacute or rehabilitation units where patients are admitted within 2 weeks of stroke.
The study was conducted in Italy and retrospectively analyzed stroke patients admitted to 274 hospitals. Outcomes were measured by telephone follow-up 2 years later recorded on the modified Rankin score. Analysis was clustered by hospital and sensitivity analysis was used to assess the role that missing data may have played.
Stroke units resulted in a 5% absolute reduction in in-hospital mortality and reduced death or dependence (OR 0.81). Long-term survival was also greater (HR 0.86 for death at follow-up) in the stroke unit group.
Acute stroke unit care is associated with improved outcomes and reduced short and long-term mortality.
This large study adds further observational evidence to the mountain of data supporting stroke units. The key additive finding of this work is the acute nature (within 48 hours) of the patient admissions. However, the data should be interpreted with a little bit of caution.
In any retrospective study, such as this one, the risk of residual confounding remains. Even careful control using multivariable methods does not remove the possibility of confounding. The authors examined the hospital effect and they performed some sensitivity analysis where the stroke unit effect was still evident. This provides further confidence in the results. However, it is the consistency of evidence in the literature that inspires confidence in the stroke unit effect.
Stroke units prevent disability and save lives. Why don’t we have more of them? We require proper integrated stroke units where patients can be managed acutely in an intensive care style with or without thrombolysis. The same ward should have the necessary rehabilitation style beds, a gym for physiotherapy, a kitchenette for home skills assessment, a room for early speech therapy, and meeting rooms for the multidisciplinary stroke team to work. It is very likely in our view that not only is this good for patients, it will also reduce the cost of stroke care. It is time for every stroke hospital everywhere to have this kind of facility.
- Received April 19, 2007.
- Revision received April 29, 2007.
- Accepted May 3, 2007.