Background and purpose The use of thrombolysis in patients with minor neurological deficits and large vessel occlusion is controversial.
Methods We compared the outcome of patients with low National Institutes of Health Stroke Scale (NIHSS) scores and large vessel occlusions between thrombolysed and non-thrombolysed patients.
Results 88 (1.7%) of 5312 consecutive patients with acute (within 24 h) ischaemic stroke had occlusions of the internal carotid or the main stem of the middle cerebral artery and baseline NIHSS scores ≤5.47 (53.4%) were treated without thrombolysis, and 41 (46.6%) received intravenous thrombolysis, endovascular therapy or both. Successful recanalisation on MR or CT angiography at 24 h was more often observed in thrombolysed than in non-thrombolysed patients (78.9% versus 10.5%; p<0.001). Neurological deterioration (increase of NIHSS score ≥1 compared to baseline) was observed in 22.7% of non-thrombolysed versus 10.3% of thrombolysed after 24 h (p=0.002), in 33.3% versus 12.5% at hospital discharge (p=0.015) and in 41.4% versus 15% at 3 months (p<0.001). Symptomatic intracerebral haemorrhage occurred in two (asymptomatic in five) thrombolysed and in none (asymptomatic in three) non-thrombolysed. Thrombolysis was an independent predictor of favourable outcome (p=0.030) but not survival (p=0.606) at 3 months.
Conclusions Non-thrombolysed patients with mild deficits and large vessel occlusion deteriorated significantly more often within 3 months than thrombolysed patients. Symptomatic intracerebral haemorrhages occurred in less than 5% of patients in both groups. These data suggest that thrombolysis is safe and effective in these patients. Therefore, randomised trials in patients with large vessel occlusions and mild or rapidly improving symptoms are needed.
- CEREBROVASCULAR DISEASE
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A common reason to withhold thrombolysis in acute ischaemic stroke is mild or rapidly improving symptoms. According to current analyses, the risk–benefit ratio of thrombolysis in patients with low National Institutes of Health Stroke Scale (NIHSS) scores is uncertain.1–5 Patients with minor neurological deficits recover generally quite well and therefore have rarely been included in randomised trials. However, some patients with rapidly improving symptoms deteriorate until discharge1 ,6–9 and large vessel occlusions in these patients strongly predict neurological deterioration.9–11 In this study we therefore compared the course and outcome of patients with large vessel occlusions and mild neurological deficits (NIHSS score ≤5) who were treated with or without thrombolysis (intravenously, endovascularly or both).
Materials and methods
From January 2004 to November 2013, 5312 consecutive patients with ischaemic stroke or transient ischaemic attack (TIA) according to WHO criteria12 were admitted to our Stroke Centre. Of them, 232 patients presented later than 24 h after symptom onset and 874 patients had a TIA; these patients were excluded. Of the remaining patients, there were 439 patients with an acute occlusion of the internal carotid artery (ICA) and 490 patients with an occluded main stem of the middle cerebral artery (MCA; M1). Finally, we identified 88 (1.7%) patients with occlusions of the internal carotid or the main stem of the MCA and baseline NIHSS scores ≤5.
Demographic data, vascular risk factors and time from symptom onset to clinical evaluation were recorded. Clinical evaluation was performed by a stroke neurologist immediately after admission in the emergency room using the 15-item version of the NIHSS score.13 Stroke aetiology was classified according to Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria.14
Immediately after clinical evaluation all patients underwent CT or MRI to rule out intracranial haemorrhage and CT angiography (CTA; n=21, 23.9%) or MR angiography (MRA; n=67, 76.1%) to assess the site of vessel occlusion. If patients had both MRA and CTA, the imaging modality performed first was used for this analysis. If a patient with an ICA occlusion showed an additional MCA occlusion, the patient was placed into the larger, that is, into the ICA occlusion subgroup. After CTA or MRA, digital subtraction angiography (DSA) was performed in 28 (31.8%) patients if they were considered eligible for endovascular therapy. All images were reviewed retrospectively by a stroke neuroradiologist and neurologist, blinded to the clinical findings.
Thrombolysis in our Stroke Centre is performed according to international and institutional guidelines. In patients with minor or rapidly improving symptoms, treatment decision for or against thrombolysis is mainly based on multimodal imaging findings (ie, mismatch and its extension, the presence and site of a large vessel occlusion, the thrombus length), the patients’ age and the patients’ history, but also on clinical signs and the severity and relevance of deficits. Moreover, time from symptom onset to admission plays an important role in decision-making, as intravenous thrombolysis is performed up to 4.5 h, intra-arterial pharmacological thrombolysis up to 6 h and mechanical endovascular recanalisation usually up to 8 h after symptom onset of anterior circulation strokes.15–17 The procedure for endovascular therapy was: passing the thrombus with the microwire, thrombaspiration (8-Fr Guider SoftTip, Vasco+ 35 catheter Balt; Montmorency, France), application of angioplasty balloon catheters (Gateway; Boston Scientiﬁc Target), retrievable stents (Solitaire FR; ev3 Neurovascular, Irvine, California, USA) and permanent extracranial stent (Akkulink, Cristalloideale, Precise 7) placements.18 All patients or their families consented to thrombolysis.
Statistical analysis was performed using SPSS 20 (SPSS Inc, Chicago, Illinois, USA). Categorical variables were compared with χ2 test and continuous variables with Mann-Whitney test. To check for significant difference in the two groups of non-thrombolysed (non-TPs) and thrombolysed (TPs), the following parameters were compared: age, gender, vascular risk factors (diabetes mellitus, arterial hypertension, current smoking, hypercholesterolaemia, coronary artery disease, atrial fibrillation, previous stroke, cervical artery dissection, family history of stroke), stroke aetiology according to TOAST criteria, time to hospital admission, decreasing and/or fluctuating symptoms before admission, baseline NIHSS score (median (range)), location of vessel occlusion (ICA and M1 occlusion), MR mismatch, initial recanalisation according to Thrombolysis In Myocardial Infarction (TIMI) criteria 2–3 (in DSA), initial reperfusion according to Thrombolysis In Cerebral Infarction (TICI) criteria 2b-3 (in DSA), recanalisation TIMI 2–3 after 24 h (MRA/CTA), NIHSS score after 24 h, at discharge, after 3 months, modified Rankin score (mRS) dichotomised into excellent (mRS 0–1 vs mRS 2–6) and favourable outcome (mRS 0–2 vs mRS 3–6), survival at 3 months and symptomatic (sICH) and asymptomatic (aICH) haemorrhages (Prolyse in Acute Cerebral Thromboembolism (PROACT) II criteria).16 In PROACT II, sICH was defined as ICH causing neurological deterioration, specified to consist of either a 4-point increase in the NIHSS score or a 1-point deterioration in the level of consciousness. Forward stepwise logistic regression analysis including age, NIHSS score on admission, time from symptom onset to admission, mismatch on MR, atrial fibrillation, diabetes mellitus, current smoking, arterial hypertension, hypercholesterolaemia, history of stroke, sICH was used to determine the predictors of clinical outcome and survival. The parameters of the final models were estimated with bootstrapping (10 000 samples). A p value of <0.05 was considered significant.
The study protocol was approved by our institutional review board.
Eighty-eight patients (1.7%) had an occlusion of the internal carotid or of the main stem of the MCA with baseline NIHSS scores ≤5, 47 (53.4%) treated without thrombolysis and 41 (46.6%) were thrombolysed (intravenously, endovascularly or both).
Baseline characteristics and treatment details are listed in table 1.
Median time from symptom onset to hospital admission was 258 min in non-thrombolysed patients (non-TPs) compared with 101 min in the thrombolysed group (TPs; p<0.001). Baseline NIHSS score in non-TPs was 3 versus 4 in the thrombolysed group (p<0.001). Compared with TPs, non-TPs more often had an ICA occlusion (74.5% vs 29.3%) than an MCA occlusion (25.5% vs 70.7%; p<0.001). In patients with MRI, a perfusion–diffusion mismatch was more often observed in TPs than in non-TPs (100% vs 77.1%; p=0.005).
Fifteen of 41 (36.6%) of TPs were treated with intravenous rt-PA, 19/41 (46.3%) with endovascular therapy and 7/41 (17.1%) with bridging therapy (intravenous rt-PA followed by endovascular therapy).
TIMI 2–3 recanalisation was observed more often on 24 h follow-up MRA or CTA in TPs than in non-TPs (78.9% vs 10.5%; p<0.001; table 2).
In non-TPs, median NIHSS score did not decrease from baseline to 24 h (increment 0, range 25), to discharge (increment 0, range 43) and to 3 months (increment 0, range 43) in contrast to TPs. Worsening of the NIHSS score within the first 24 h occurred in 10/44 (22.7%), in 15/45 (33.3%) until hospital discharge and in 17/41 (41.4%) until the 3-month follow-up (table 2, figure 1). In the subgroup of non-TPs with NIHSS score ≤4 on admission, worsening occurred in 8/40 (20%) within the first 24 h, in 12/41 (29.3%) until hospital discharge and in 14/37 (37.8%) until the 3-month follow-up.
In TPs median NIHSS score decreased and was significantly better than in non-TPs. Median reduction of the NIHSS score from baseline to 24 h was 2 (range 36), to hospital discharge 2.5 (range 43) and to 3 months 3 (range 43; p<0.001 each). Worsening of the NIHSS score within 24 h occurred in 4/39 (10.3%), in 5/40 (12.5%) until hospital discharge and in 6/40 (15%) until the 3-month follow-up (table 2, figure 1).
TPs tended to have better outcomes at 3 months than non-TPs (mRS 0–2: 85% vs 66.7%; p=0.050; mRS 0–1: 62.5% vs 44.4%; p=0.096) but comparable survival rates (92.5% vs 93.3%; p=0.881; table 2, figure 2). In multivariable regression analysis (table 3), arterial hypertension (p=0.007, OR 0.187, 95% CI 0.049–0.716) and treatment type (TPs vs Non-TPs; p=0.030, OR 3.103, 95% CI 1.021 to 9.428) were predictors of favourable outcome (mRS 0–2). Age was the only predictor of excellent outcome (mRS 0–1; p=0.010, OR 0.958, 95% CI 0.926 to 0.992). Thrombolysis was not a predictor of survival at 3 months (p=0.606) but symptomatic intracerebral haemorrhage (p=0.003 by Fisher's exact test, risk estimate 0.600, 95% CI 0.293 to 1.227).
Symptomatic intracerebral haemorrhage occurred in two of the TPs (4.9%) and in none of the non-TPs.
The results of separate analyses for ICA and MCA occlusions are listed in tables 4 and 5.
The main findings of this study are that 41% of non-TPs with mild neurological deficits and large vessel occlusion deteriorated within 3 months compared with only 15% of TPs (p<0.001). In addition, TPs had a low rate of sICH (4.9%). These data suggest that thrombolysis seems to be safe in these patients.
Patients with mild or rapidly improving symptoms are commonly not considered for thrombolysis. Although more than 50% of patients with stroke have a NIHSS score ≤5,19 they have been rarely selected for randomised thrombolysis trials. However, observational studies have shown that up to 34% of these patients deteriorate during their hospital stay.1 ,6–9 Current guidelines recommend excluding patients with low NIHSS scores or rapidly improving symptoms from thrombolysis due to an uncertain risk–benefit ratio,20 although several studies have shown that thrombolysis with rt-PA may be safely performed in such patients.13 ,21–26 Additional studies have shown that the size of the penumbra and the location of vessel occlusion are independent predictors of outcome. Large vessel occlusion is a strong predictor for neurological deterioration.9–11 ,27 This raises the question whether patients with large vessel occlusions and mild neurological deficits could benefit from thrombolysis or other recanalisation therapy.
In this study we identified 88 patients with NIHSS scores ≤5 and ICA or central MCA occlusions. Forty-one of 88 patients were thrombolysed (TPs). A remarkable number of non-TPs, who represent the natural course of the disease, deteriorated within the 3 months following their stroke: 22.7% within 24 h, 33.3% during their hospital stay and 41.4% within 3 months. Excellent outcome (mRS 0–1) was only observed in 44.4%, favourable outcome (mRS 0–2) in 66.7% and 6.7% died. Considering the initial mild symptoms in these patients, our results reflect a surprisingly bad outcome of non-TPs.
In contrast, the course in TPs was more favourable: neurological deterioration was observed in 10.3% within 24 h, in 12.5% during the hospital stay and in 15% within 3 months, and this despite a higher median baseline NIHSS score in TPs. The effect of thrombolytic therapy was also reflected in higher recanalisation rates and that thrombolytic therapy turned out as an independent predictor of favourable outcome. Mortality was not significantly different in both groups.
Thrombolysis in this patient group seems to be safe: only two patients suffered a symptomatic intracerebral haemorrhage (4.9%), and also previous studies on rt-PA treatment in patients with mild or rapidly improving symptoms showed low haemorrhage rates.21–26
In subgroup analysis, the effect of thrombolysis was statistically more pronounced in patients with MCA occlusions than in patients with ICA occlusions. This might be explained by better collateralisation in more proximal occlusions but might represent a chance finding because of the low numbers of patients in each group.
Our study has several limitations. It is a retrospective analysis and the decision for or against thrombolytic treatment was made on an individual basis. The time window from symptom onset to hospital admission in non-TPs was longer than in TPs and probably the main reason against thrombolysis. Additional baseline characteristics such as cardioembolic stroke aetiology, location of vessel occlusions and MR mismatch differed in the two groups. Existence of mismatch and its extension was used as a decision for or against thrombolysis as well as patient's age and previous history, the severity, type and relevance of deficits.
Moreover, we did not perform subgroup analyses between the different thrombolysis treatment methods mainly due to too small subgroups. Furthermore, time to follow-up was limited to 3 months and we did not analyse long-term effects at 1 year or even later. Owing to all the limitations of our study the results can be used only to generate the hypothesis that recanalisation of large vessel occlusions in patients with low NIHSS score improves the outcome at 3 months. Whether the hypothesis turns out to be true needs to be tested in a prospective randomised trial.
The authors thank Pietro Ballinari, PhD, for statistical advice. The authors thank the ESO for the awarded poster prize at ESC 2013 London for preliminary analysis of this project.
MRH, SJ, MA and UF contributed equally to this study.
Contributors MRH, SJ and UF were involved in study concept and design. MRH, SJ, CZ, PM, AW, MLM CO, ME-K, HPM, GS, JG, MA and UF were involved in acquisition of data. MRH, SJ, UF and HPM were involved in analysis and interpretation of data. MRH, SJ, UF and HPM were involved in drafting of the manuscript. MRH, SJ, CZ, PM, AW, MLM, CO, ME-K, HPM, GS, JG, MA and UF were involved in critical revision of the manuscript for important intellectual content. MRH and SJ were involved in statistical analysis. HPM, GS, JG, MA and UF were involved in study supervision.
Competing interests None.
Ethics approval The study protocol was approved by our institutional review board.
Provenance and peer review Not commissioned; externally peer reviewed.