Strokes With Minor Symptoms
An Exploratory Analysis of the National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Trials
Background and Purpose—The pivotal National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator trials excluded patients with ischemic stroke with specific minor presentations or rapidly improving symptoms. The recombinant tissue plasminogen activator product label notes that its use for minor neurological deficit or rapidly improving stroke symptoms has not been evaluated. As a result, patients with low National Institutes of Health Stroke Scale scores are not commonly treated in clinical practice. We sought to further characterize the patients with minor stroke who were included in the National Institute of Neurological Disorders and Stroke trials.
Methods—Minor strokes were defined as National Institutes of Health Stroke Scale score ≤5 at baseline for this retrospective analysis, because this subgroup is most commonly excluded from treatment in clinical practice and trials. Clinical stroke syndromes were defined based on prespecified National Institutes of Health Stroke Scale item score clusters. Clinical outcomes were reviewed generally and within these cluster subgroups.
Results—Only 58 cases had National Institutes of Health Stroke Scale scores of 0 to 5 in the National Institute of Neurological Disorders and Stroke trials (42 recombinant tissue plasminogen activator and 16 placebo), and 2971 patients were excluded from the trials due to “rapidly improving” or “minor symptoms” as the primary reason. No patients were enrolled with isolated motor symptoms, isolated facial droop, isolated ataxia, dysarthria, isolated sensory symptoms, or with only symptoms/signs not captured by the National Institutes of Health Stroke Scale score (ie, National Institutes of Health Stroke Scale=0). There were ≤3 patients with each of the other isolated deficits enrolled in the trial.
Conclusions—The National Institute of Neurological Disorders and Stroke trials excluded a substantial number of strokes with minor presentations, those that were included were small in number, and conclusions about outcomes based on specific syndromes cannot be drawn. Further prospective, systematic study of this subgroup is needed.
The pivotal National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rtPA) stroke trials established intravenous rtPA as a therapy for acute ischemic strokes within 3 hours of symptom onset. The NINDS trials required exclusion of patients with ischemic stroke if they had specific minor or rapidly improving symptoms.1 This led to the rtPA (alteplase) product label broadly stating that “treatment … in patients with minor neurological deficit or with rapidly improving symptoms … has not been evaluated.” In this setting, the role of intravenous rtPA for treatment of minor stroke syndromes at acute presentation remains unclear.
The NINDS trials specifically excluded ischemic stroke cases with no measurable deficit on the National Institutes of Health Stroke Scale (NIHSS) score; rapidly improving deficit; or symptoms of isolated sensory stroke, isolated ataxia, isolated dysarthria, or isolated facial weakness.2 However, subsequent clinical guidelines have not precisely defined minor strokes or rapid improvement. For example, the American Heart Association stroke guidelines state that eligibility for rtPA requires that “neurological signs should not be minor and isolated.”3 Epidemiological studies have used the gross definition of NIHSS score ≤5 for “mild” stroke.4,5 Most recent stroke clinical trials exclude NIHSS scores of <5 or 6 from enrollment on the presumption that this represents the minor subgroup.6–9 A definition of NIHSS ≤5 for minor stroke would include all strokes explicitly excluded from the NINDS trials and 58 of the cases enrolled in the trials.
Currently, a substantial proportion (20% to 46%) of patients who present to emergency departments are not treated because their symptoms are perceived to be minor or rapidly improving.4,10–15 Furthermore, over half of all ischemic strokes in the United States have a NIHSS score ≤5.5,16
Recent data suggest that untreated patients with ischemic stroke perceived as minor (at presentation or due to improvement before the treatment decision) have substantial rates of disability. Disability or death at hospital discharge, as measured by modified Rankin Scale (mRS) score 2 to 6 or not discharged home, has been reported in the range of 25% to 64%.11,17–19 Disability or death at 90 days, as measured by mRS 2 to 6, has been reported in the range of 32% to 58%.19,20 This disability may be due to unmeasured cognitive effects of the stroke, extension of the stroke after acute presentation, or new events resulting from related comorbidities or it may be a direct result of the acutely presenting deficit. In some cases, it may be due to disability predating the incident stroke.
We sought to further characterize the minor stroke patient group with the lowest NIHSS scores (NIHSS ≤5) that was included in the NINDS rtPA Stroke Study. We reviewed their rate of inclusion in the trial, clinical presentations, and clinical outcomes in detail. This analysis was undertaken to explore the effectiveness of intravenous rtPA treatment for this subgroup of patients with stroke based on this pivotal study and to consider the need for further randomized studies.
The NINDS rtPA Stroke Study consisted of 2 randomized trials that tested the safety and efficacy of 0.9 mg/kg intravenous rtPA for acute ischemic stroke within 3 hours of symptom onset.1 Patients were excluded from the trials if they had “rapidly improving or minor symptoms.” The NINDS trialists reported the explicit exclusion of isolated symptoms of sensory loss, facial weakness, ataxia, or dysarthria, no measurable deficit on the NIHSS (ie, NIHSS=0), or a rapidly improving neurological deficit.2
For the purposes of this retrospective analysis, minor strokes were defined as NIHSS ≤5 at baseline. Clinical stroke syndromes were defined based on prespecified NIHSS item score clusters as shown in Table 1. We defined individual isolated symptoms or signs by NIHSS score and considered secondary definitions in which additional concurrent NIHSS item abnormalities were present.
Clinical outcomes were reviewed generally and within these cluster subgroups. A favorable outcome was defined as a mRS of 0 or 1 at 90 days. Poststroke intracranial hemorrhages were reviewed in each subgroup. We also investigated potential stroke extension or recurrent events as indexed by an increase in NIHSS score to >5 from baseline to 90 days or and at least a 2-point worsening in NIHSS from baseline to 2 hours and baseline to 24 hours.
Over the 4 years of the trial, 17 324 patients were excluded; according to screening logs, 52% of these were excluded due to time of presentation. Of the remaining 8315, the “primary reason” for exclusion was minor symptoms for 1039 and rapid improvement for 1732. Among 624 patients enrolled in the trials, 58 cases had NIHSS scores ≤5, of which 42 were in the rtPA group and 16 were in the placebo group.21,22
Table 2 shows characteristics of the minor stroke group (age, sex, history of diabetes mellitus, hyperlipidemia or hypertension, atrial fibrillation, presumed etiology, stroke etiology after diagnostic testing, and time to treatment) compared with the remaining cases enrolled in the study. Subjects with minor strokes were younger and more often had small-vessel etiologies than those with more severe strokes.
Table 3 shows the number of patients within each NIHSS symptom cluster; this categorization allows for the same patient to be in >1 cluster. Among the 58 cases that were enrolled, only 2 had isolated aphasias, and only 3 had isolated vision loss. No patients were enrolled with isolated motor symptoms, isolated severe limb weakness, isolated facial droop, isolated ataxia, dysarthria, isolated sensory symptoms, or isolated with only symptoms/signs not captured by the NIHSS score (ie, NIHSS=0).
The Figure shows overall distribution of 90-day mRS scores in rtPA and placebo groups. Minimal or no disability (mRS 0 or 1) was seen in 33 of 42 (78.6%; 95% CI, 63.2 to 89.7%) of rtPA cases and 13 of 16 (81.3%; 95% CI, 54.4% to 96.0%) of the placebo cases. No treatment effect (OR, 0.85; 95% CI, 0.20 to 3.63) was demonstrated when comparing favorable outcomes between the 2 arms of the trial in this underpowered (β <25%) post hoc analysis. It should be noted that 4 of the 58 minor strokes had baseline disability (mRS ≥2), and all were in the rtPA group. There was 1 symptomatic intracranial hemorrhage (2.4%) in the intravenous rtPA arm; this subject had a baseline NIHSS score of 3 due to isolated left leg weakness and subsequently died. There were no symptomatic hemorrhages in the placebo group, and there were no asymptomatic intracranial hemorrhages in either group. Neurological worsening was numerically, but nonsignificantly, less frequent in rtPA versus placebo arms based on NIHSS >5 at 90 days (6.3% versus 9.5%; see subgroups in Table 3), 2-point worsening at 2 hours (4.8% versus 18.8%), and 2-point worsening at 24 hours (11.9% versus 25%).
Among the 624 patients in the NINDS trial, only 58 (9.3%) had NIHSS scores of ≤5. Consistent with the NINDS trialists’ description of the explicit exclusions, no patients with isolated ataxia, dysarthria, facial weakness, sensory symptoms, or isolated symptoms/signs not captured by the NIHSS score (ie, NIHSS=0) were enrolled. However, there were only ≤3 patients enrolled with each of the isolated deficits that were not explicit exclusions in the NINDS trials.
The contrast between the proportion of minor strokes in the NINDS trials (9%) and recent epidemiological data that suggest that minor strokes (NIHSS <6) comprise between 20% and 46% of strokes that arrive within 3 hours to hospital emergency departments seems greater than can be readily explained by the explicit exclusions of the NINDS trials. Furthermore, our analysis of clinical syndromes enrolled in the NINDS trials suggests that many key syndromes were not well represented. Some syndromes were not included in the trial due to the explicit requirement of their exclusion, but others seen in the emergency setting (pure motor hemiparesis, isolated aphasias, isolated homonymous hemianopsia) were not included in any significant number despite no explicit exclusion from the trial.
The relative absence of minor strokes in the NINDS trials may be due, in part, to factors specific to the era of the trials (early 1990s). Emergency physicians and triage nurses may not have recognized these presentations as strokes, because the trial took place before any proven therapy for stroke that would warrant routine acute evaluations. It is also possible that there has been a shift in the proportion of patients with minor symptoms presenting early to emergency departments either due to changing characteristics of the disease over time or to increased public awareness to present to medical care emergently.
Perhaps most significantly, whereas only 58 patients with minor symptoms were enrolled, 2971 patients were excluded due to “rapidly improving” or “minor symptoms” as the primary reason.21 There may have been a perception among at least some of the NINDS trial investigators that these syndromes were unlikely to be disabling, leading to their exclusion from the trial. This conservative approach would have been reasonable at the time given rtPA’s novelty as a stroke therapy and the lack of definitive data on its benefit and safety. The current literature suggests that minor strokes are often associated with substantial disability, but the natural history of minor ischemic stroke based on specific clinical syndromes is still not known.
It has been previously reported that there were no treatment-by-stroke severity interactions in the NINDS trials, which suggests that patients with minor stroke whose symptoms match those enrolled in the NINDS study should be treated with lytic therapy.22 Of note, however, our retrospective analysis of minor stroke clinical syndromes suggests this subgroup in the NINDS study is not fully generalizable to the broader minor stroke patient group who may be encountered acutely both because of explicit exclusions and possible implicit exclusions.
The minor strokes in the NINDS trial in this analysis, defined by NIHSS ≤5, that were included did surprisingly well compared with the proportions of favorable outcomes among minor stroke subgroups recently reported.22 In addition to the possibility that the patients with minor stroke enrolled in the trial are not representative of patients now arriving in emergency departments with minor symptoms, it should be kept in mind that the small number of patients in this subgroup leads to wide 95% CIs for the rate of favorable outcome.
It should also be noted that the NINDS rtPA study investigators have previously explored 5 minor stroke definitions that are different from that examined in this analysis.2 Definition A required 0 or 1 scores on every baseline pretreatment NIHSS score item except level of consciousness, Definition B consisted of all presumed small-vessel occlusive patients, Definition C consisted of only motor deficits (including dysarthria and/or ataxia) with or without sensory deficits, Definition D required the lowest quartile of stroke severity in the NINDS trial (NIHSS <10) and no cortical or level of consciousness symptoms, and Definition E required only the lowest quartile of stroke severity in the NINDS trial (NIHSS <10). This exploratory analysis showed favorable treatment effects of rtPA across all of these definitions. However, because these definitions all included patients with NIHSS >5, they cannot be readily applied to the subgroup of interest in this analysis.
In clinical practice at this time, a large number of patients with minor stroke symptoms as defined by an NIHSS <5 are not treated with thrombolysis. For example, in the American Heart Association Get With the Guidelines Registry from 2003 to 2009, among 73 044 cases arriving to emergency departments within 2 hours and not treated with rtPA, 29 612 (41%) were not treated due to mild or improving symptoms, and 75% of these had a baseline NIHSS <5.15 Leading stroke centers vary in their approach to acute treatment of patients with minor symptoms. Many do not treat minor symptoms unless the evaluating stroke physician perceives the symptoms at presentation to be disabling for individual circumstances. Others treat minor syndromes that have proximal arterial occlusions on intracranial vascular imaging, because these are the most likely to have poor outcomes.23,24 Still others treat most minor syndromes with the rationale that risk is likely to be low, and that even small-vessel events have significant disability rates and are likely to benefit from thrombolytic treatment.1,2 The appropriate approach to strokes with low NIHSS scores is debatable.
In summary, this exploratory analysis suggests that the NINDS trials excluded a substantial number of strokes with minor presentations, those minor stroke syndromes that were included were small in number, and conclusions about outcomes based on specific clinical syndromes cannot be drawn. Further study of this subgroup is needed in larger data sets that have systematically and prospectively included minor strokes. Whether thrombolysis is of benefit to this subgroup of patients excluded from the NINDS study is uncertain.
Sources of Funding
This research was funded by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (NIH-NINDS K23NS059843) for P.K.
P.K. is on the Executive Committee of the National Institutes of Health (NIH)-funded Interventional Management of Stroke (IMS) III trial, which received drug from Genentech, Inc. J.L.S. is a scientific consultant regarding trial design and conduct to CoAxia, Concentric Medical, Talecris, Ferrer, BrainsGate, PhotoThera, and Sygnis (all modest); has received lecture honoraria from Ferrer (modest); has declined consulting/honoraria monies from Genentech since 2002; is a site investigator in the NIH MR RESCUE, CLEAR-ER, and IMS 3 multicenter clinical trials, for which the University of California (UC) Regents receive payments based on the clinical trial contracts for the number of subjects enrolled; has served as an unpaid site investigator in a multicenter trial run by Lundbeck and for which the UC Regents received payments based on the clinical trial contracts for the number of subjects enrolled; is a site investigator in a multicenter registry run by Concentric, all for which the UC Regents receive payments based on the clinical trial contracts for the number of subjects enrolled; administers stroke thrombolytic therapy in his practice (<5% of effort); is an employee of the University of California, which holds a patent on retriever devices for stroke; and is funded by NIH National Institutes of Neurological Disorders and Strokes (NINDS) awards (P50 NS044378 and U01 NS 44364). S.R.L. is supported in part from NIH grants (1R0 1 HL096944 and 1R0 1 NS052417); is associate editor of MEDLINK; is an Independent Medical/Safety Monitor for IMS 3, FAST-MAG, CLEAR-ER, INSTINCT; and is on the Acute Advisory Board, National Stroke Association. D.O.K. is on the Speaker’s Bureau of Genentech; and the National Advisory Board of Boehringer Ingelheim. Y.Y.P. is supported in part by NIH grants (U01 NS054630-04 for ALIAS and IMS III Trials, U01 NS059041 for NETT Network Statistical and Data Management Center, R01 NS062778 for POINT Trial, R01 NS062835 for PRoTECT Trial, and U01 NS061861 for ATACH II Trial); and DMC member for IMPACT (Brainsgate). E.C.J. is supported in part by NIH grants (U01 NS054630-04 for ALIAS trials U01, NS059041 for NETT Network Statistical and Data Management Center, and U 01 NS052220 for IMS III Trial). J.P.B. is Principal Investigator of NINDS-funded IMS III Trial, University of Cincinnati SPOTRIAS Center (includes NINDS-funded CLEARER and STOP-IT Clinical Trials), NINDS-funded Familial Intracranial Aneurysm (FIA) Study, and NINDS-funded T-32 Cerebrovascular Fellowship Training Program for Cerebrovascular Disease; and is coinvestigator of NINDS-funded Genetic and Environmental Risk Factors for Hemorrhagic Stroke, NINDS-funded “Comparison of Hemorrhagic and Ischemic Strokes Among Blacks and Whites,” and NINDS-funded IRIS Trial, CREST, COSS, and SWISS Studies. Genentech Inc (supplier of alteplase for NINDS-funded CLEARER and IMS III trials) supplies intra-arterial rtPA. EKOS Corporation supplies catheter devices, Concentric Inc supplies devices, and Johnson and Johnson supplies catheters for the ongoing IMS III Study. Schering Plough supplies drug for the NINDS-funded CLEARER Trial. Boehringer Ingelheim has provided honoraria for speaking fees (honorarium last received on February 15, 2008). Consulting fees and honoraria are placed in an educational/research stroke fund in the Department of Neurology.
- Received June 17, 2010.
- Accepted June 18, 2010.
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