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Owing to the fear of an increased bleeding risk, thrombolytic therapy is withheld from many patients with acute stroke >80 years of age.
To analyse the risk for symptomatic intracranial haemorrhage (sICH), morbidity and mortality after thrombolytic therapy in octogenarians focusing, in particular, on whether patients selected using magnetic resonance imaging (MRI) had a better risk:benefit ratio.
The prospectively collected single‐centre data of all patients treated with systemic thrombolytic therapy for acute ischaemic stroke since 1998 (n=468) were reviewed, and patients 80 years (n=90) were compared with those aged <80 years (n=378). In addition, the group of octogenarians was analysed with respect to initial imaging modality.
The overall rate of sICH in the octogenarians was 6.9%, compared with 5.3% in younger patients (p=0.61). In older patients selected by computed tomography, the rate of sICH was 9.4%; no patient selected by MRI had sICH (p=0.10). Mortality in the octogenarians selected by computed tomography was 29.7% after 3 months as compared with 26.9% in the patients selected by MRI (p=1.0). 20.3% of the octogenarians selected by computed tomography and 15.4% of those selected by MRI had a favourable outcome (modified Rankin scale 1) after 3 months (p=0.77).
Compared with younger patients, octogenarians do not have an increased risk of sICH. The use of MRI to select octogenarians for thrombolytic therapy seemed to decrease the risk of sICH, but did not influence the overall outcome after 3 months.
The incidence of stroke increases steeply with age. In a population‐based survey, incidence of a first‐ever stroke was around 0.8 per 1000 population per year in people aged <75 years as compared with 14 per 1000 population per year in those aged 75–84 years and 29 per 1000 population per year in those aged >85 years.1 With respect to changes in the population's age structure in the industrialised world, the number of acute vascular events in elderly people will almost double in the course of the next 25 years.1 Furthermore, age is an independent predictor for poor outcome after ischaemic stroke. Older patients, especially those aged >80 years, have a higher in‐hospital mortality risk and a favourable functional outcome is less likely.2 Intravenous thrombolysis with recombinant tissue‐type plasminogen activator (rt‐PA) is the only approved therapy for patients with acute ischaemic stroke. However, the European and Australian rt‐PA stroke trials excluded patients >80 years of age.3,4,5 Older patients were only allowed to be enrolled in the National Institute of Neurological Disorders and Stroke (NINDS) rt‐PA stroke study, but a mean age of 69 years in this trial shows that few patients >80 years of age were actually included.6 Owing to the lack of knowledge about the safety and efficacy of thrombolysis in this age group from randomised trials, the European Medicines Evaluation Agency (EMEA) recommends that rt‐PA not be used in patients with ischaemic stroke aged >80 years.7
In the past few years, it has become increasingly popular to select patients for thrombolytic therapy using multiparametric magnetic resonance imaging (MRI) techniques. Our objective was to analyse the morbidity, mortality and risk for symptomatic intracranial haemorrhage (sICH) after thrombolytic therapy in octogenarians, focusing in particular on whether the risk:benefit ratio was higher in patients selected by MRI.
Since 1998, data from all patients with stroke treated with thrombolytic therapy in our institution have been prospectively collected and entered into a local database. These include age, sex, time of symptom onset (or time when last seen well), time of starting treatment, National Institution of Health Stroke Scale Score (NIHSSS; before treatment, at day 1 and at day 7), concomitant drugs and disease, imaging data, baseline glucose level, assumed stroke origin according to Trial of ORG 10172 in Acute Stroke Treatment criteria8 and modified Rankin Scale (mRS) at day 90. At our institution an algorithm is used whereby, within 3 h of symptom onset, patients are selected for thrombolysis on the basis of either computed tomography or MRI. MRI is used when >3 h have passed since onset or if the time of onset is unclear. On the basis of the MRI results, patients are treated with rt‐PA when they show a perfusion imaging/diffusion‐weighted imaging (DWI) mismatch and the DWI lesion is not larger than half of the middle cerebral artery territory.9 No age limit is applied.
To detect post‐therapeutic complications, all patients underwent computed tomography or MRI within 24–36 h after thrombolysis. Neuroimaging was analysed by an experienced neuroradiologist. Following the NINDS criteria, sICH was defined as a computed tomography‐documented haemorrhage within 36 h after treatment leading to a deterioration in the patient's clinical condition.10 Whether bleeding was symptomatic or not was rated by the treating doctor and reassessed by one of the authors of this manuscript (SK, MK or PR). The mRS was used to assess outcome at 90 days after stroke either by conducting a semistructured interview by telephone or in person. Favourable clinical outcome was defined as a score of 0 or 1.
Further details of the overall cohort were published recently.11 For this retrospective analysis, patients were divided into two groups: (1) patients aged <80 years and (2) patients aged 80 years. Both groups were subdivided following the imaging modality (computed tomography or MRI) used for treatment decision.
Qualitative variables are expressed as numbers and percentages, and continuous variables as median and interquartile range (IQR). χ2 test, Fisher's exact test or Kruskal–Wallis test was used to analyse group differences. Statistical analyses were performed using STATVIEW V.5.0.1.
To compare our results, references were identified by PubMed searches from 1995 to 2006 using the terms “thrombolytic therapy”, “thrombolysis”, “stroke” and “age”. Trials were selected for a Peto odds ratio (OR) meta‐analysis if they met the following criteria: compared younger with older patients, with age 80 years as cut‐off; had an equivalent definition of sICH; reported numbers or rates for outcome 3 months after treatment and used the mRS as outcome measure. For this analysis, StatsDirect V.2.5.6 (StatsDirect, Altrincham, Cheshire, UK) was used.
Between April 1998 and May 2006, we treated 468 patients, aged 17–95 years, who had had an acute hemispheric ischaemic stroke, with intravenous thrombolysis (table 11).). Of these, 378 (81%) patients were <80 years (median 69 years) and 90 (19%) were at least 80 years old, with a median age of 83 years (table 11).). A total of 157 (42%) of the patients aged <80 years and 26 (29%) of the octogenarians were treated on the basis of MRI findings. Owing to the non‐randomised selection of the imaging modality, patients in the computed tomography‐selected group of octogenarians were more often women than those in the other groups (χ2 test: p<0.001). The median NIHSSS was 12 in the patients aged <80 years selected by computed tomography, and 13 in the other three groups (Kruskal–Wallis test: p=0.105). Owing to the algorithm for selection of imaging modality, median time to treatment was longer in patients selected by MRI (median 175 min, IQR 120–270 min) than in those selected by computed tomography (median 130 min, IQR 105–160 min; Kruskal–Wallis test: p<0.001). There was a significant difference between younger and older patients regarding baseline blood glucose level (p=0.021), but no difference regarding stroke aetiology was found (p=0.155; table 11).
sICH occurred in 20/378 (5.3%) patients <80 years and in 6/90 (6.7%) octogenarians. These rates can be transferred to an OR of 1.28 with a 95% confidence interval (95% CI) of 0.50 to 3.28 (p=0.61). In the octogenarians selected by computed tomography, the sICH rate was 6/64 (9.4%) as compared with 0% in patients selected by MRI. The two‐sided p value for comparison of the two imaging modalities in the octogenarians using a Fisher's exact test was 0.1. Similar results were found in younger patients; the risk of sICH was 7.2% if screened on the basis of computed tomography and 2.5% if treated on the basis of MRI (OR 2.99; 95% CI 0.98 to 9.11; p=0.06). In all, 48 (12.7%) of the younger patients were dead after 3 months, as were 26 (28.9%) of the octogenarians (p<0.001). After 3 months, mortality in the octogenarians was almost identical between patients selected by computed tomography (29.7%) and MRI (26.9%; p=1.0). Twelve of the octogenarians had died within 7 days after treatment (nine in the computed tomography group and three in the MRI group). All six patients aged 80 years, who had sICH died within 7 days. The three other deaths in the computed tomography group were related to a mass effect of a large hemispheric infarction. All three in‐hospital deaths in the MRI group had non‐neurological cause (two myocardial infarctions and one sepsis). Favourable clinical outcome was observed in 158 (41.8%) of the younger patients, as compared with 17 (18.9%) in the octogenarians. In all, 13 (20.3%) octogenarians selected by computed tomography and 4 (15.4%) selected by MRI had a favourable clinical outcome after 3 months (p=0.77; table 11).
For the meta‐analysis, besides our data, eight studies were identified,12,13,14,15,16,17,18,19 but not all trials reported all information. The rate of sICH in patients aged >80 years in these trials was 6.1%, which was not significantly higher than that in younger patients (OR 1.27; 95% CI 0.85 to 1.91; p=0.239). Six of these trials provided data about the 3‐month mortality, which was significantly higher in older patients (OR 3.18; 95% CI 2.48 to 4.09; p<0.0001).12,14,15,16,18,19 Five studies had evaluated the clinical outcome after 3 months using the mRS.12,14,16,18,19 Favourable outcome (mRS 1) was significantly less frequent in the older patients (OR 0.52; 95% CI 0.42 to 0.64; p<0.0001; fig 11).). For none of these end points was a significant heterogeneity detected between the trials.
Age is an independent risk factor for poor outcome in patients with stroke. In a European survey of 1358 patients with stroke aged 80 years, a 3‐month mortality of 44.6% was reported.20 In the more recent study of Kammersgaard et al,2 the in‐hospital mortality of patients aged >85 years was 35.6%; >90% of these patients died or were confined to a nursing home after 5 years.2 Thrombolysis in acute ischaemic stroke is an effective treatment when performed in well‐selected patients.6,21 However, many centres withhold thrombolytic therapy from older patients, who currently fall outside licensing restrictions in Europe on the basis of age alone. Therefore, few studies have ever focused on thrombolytic treatment for stroke in older patients.12,13,14,15,16,17,18,19,22 Our data on the octogenarians are comparable to these studies (sICH 6.7% in our patients v 6.1% in the meta‐analysis; 3‐month mortality 28.9% in our patients v 32.3% in the meta‐analysis; and favourable clinical outcome after 3 months in 18.9% of our patients v 25.9% in the meta‐analysis). Another population‐based study by Simon et al22 in patients aged 80 years reported similar results: a 9.7% sICH rate, 32.8% mortality and 19.7% favourable outcome. This trial was not included in the meta‐analysis, because it does not contain a cohort of patients aged <80 years.
Undisputedly, sICH is a severe complication, with a high in‐hospital mortality of up to 75%.23 In our series, all octogenarians with sICH died within 7 days. A better selection of patients for thrombolytic therapy to decrease the risk of bleeding may therefore increase the chance of a good clinical outcome. Multiparametric MRI is a possible tool that can be used for the appropriate selection of candidates for thrombolytic therapy. DWI shows ischaemic brain tissue in the early stroke phase more precisely than computed tomography.24 Perfusion imaging can be used to define tissue at risk of infarction, which is characterised by a perfusion imaging/DWI mismatch. In a multicentre trial using this concept, the rate of sICH was 3% in patients with rt‐PA selected by MRI.25 This was comparable to that in the placebo group (2.1%; p=0.39) and lower than in the rt‐PA group (8.45; p=0.01) of the pooled analysis of the large randomised computed tomography‐based rt‐PA trials.21 Our results confirm the possibility that MRI selection may reduce the risk of thrombolytic therapy even in elderly patients. In none of our octogenarians selected by MRI has a sICH occurred. However, this did not lead to a decrease in the in‐hospital or 3‐month mortality. Furthermore, clinical outcome did not improve if patients were screened with MRI. This effect is probably not caused by the longer time window of the patients in the MRI‐screened group. In several previous studies, the numbers of patients with favourable clinical outcome did not differ between those treated within 3 h and those treated after 3 h if patients with stroke were selected by MRI.25,26,27 A possible explanation for our observation might be the higher number of women in the group of octogenarians selected using cranial computed tomography (68% v 40%). In a pooled analysis of European Cooperative Acute Stroke Study II, (Alteplase Thrombolysis for Acute Non‐interventional Therapy in Ischaemic Stroke A and B), and NINDS, women benefited considerably more than men in a time window up to 6 h, and the usual sex difference in outcome favouring men was not observed in the thrombolytic therapy group.28 On the basis of our observation, there seemed to be no reason to screen octogenarians in an earlier time window using MRI. The main goal of treatment in an early time window is to be fast (“time is brain”). If only safety but not outcome is improved by using the more time‐consuming MRI, this should not be performed within the first 3 h after symptom onset. In our institution computed tomography‐perfusion is not used systematically as a tool for treatment decision before thrombolytic therapy. Therefore, we cannot provide any data of whether this would also be a method to increase the safety of thrombolytic therapy in elderly people.
There are several limitations to this study. Firstly, it is a single‐centre study. As in many others, older patients are under‐represented in our trial. For example, in 2005, 243 of 857 (28.4%) patients admitted to our emergency room with an acute ischaemic stroke with persisting symptoms were at least 80 years old. However, of the patients treated with thrombolytic therapy, only 18.7% were of this age. The decision of whether to use computed tomography or MRI for screening was not randomised, but the main difference between the groups is a longer time window for patients screened by MRI. It is unlikely that patients with less comorbidity were more often screened with MRI, which could also explain the observation of a smaller bleeding risk, because the median of the initial NIHSSS was 13 in both subgroups of octogenarians. Nevertheless, we cannot exclude all possibility of doubt that the decision for the imaging modality was biased. Information about screening failures was not collected systematically, and therefore cannot be presented. Owing to the lack of a control group, the efficacy of thrombolysis in older patients cannot be analysed in our study and this major question still remains to be answered.
Our study confirms that thrombolytic therapy can be performed in elderly patients and in extended time windows without increased risk, especially if the patients are screened with multiparametric MRI. However, this has not reduced mortality or increased favourable outcome. Further randomised trials should not exclude patients only because of their age, which is being done in the ongoing international stroke trial‐3.29
DWI - diffusion‐weighted imaging
EMEA - European Medicines Evaluation Agency
IQR - interquartile range
mRS - modified Rankin Scale
MRI - magnetic resonance imaging
NIHSSS - National Institution of Health Stroke Scale Score
NINDS - National Institute of Neurological Disorders and Stroke
rt‐PA - recombinant tissue‐type plasminogen activator
sICH - symptomatic intracranial haemorrhage
Funding: PAR, WH and PDS received lecture fees and funding from Boehringer Ingelheim.
Competing interests: None declared.