The impact of intravenous thrombolysis on outcome of patients with acute ischemic stroke after 90 years old

Stroke care in older people is becoming a public health problem given the increased ageing of the population [1]. Indeed, the incidence of stroke increases with age and about 30 % of stroke patients are older than 80 years old [2]. It is widely admitted that oldest patients have a worse post-stroke functional outcome and a higher rate of death [3, 4]. Mortality at three months increases by 72 % whereas probability of good outcome decreases by 25 % every ten years [5].

The benefit of intravenous thrombolysis (IV-tPA) in ischemic stroke (IS) patients has been widely demonstrated [6, 7] but most of the studies excluded patients older than 80, therefore potentially limiting thrombolysis in this population. Several observational studies found that, compared to younger patients, tPA infusion to patients older than 80 y.o. was associated with higher functional dependency [3, 4, 8, 9]. While no significant increase of hemorrhagic transformation was observed in these older patients, this worse functional outcome seemed to be related to a worse pre-stroke functional status, a higher clinical severity at baseline, and more frequent post-stroke complications during the acute (pneumonia, heart failure). Despite the less favorable outcome of older patients, recent studies have suggested that IV-tPA could improve the functional prognosis of patients aged between 80 and 90 y.o. [10, 11]. However, old age remains a limitation for using IV-tPA for many physicians [12, 13]. That is even more true in the subgroup of very old patients, those aged over 90 y.o., for whom available data are scarce. In this population, few studies [4, 10] failed to identify a benefit of IV-tPA on functional outcome or mortality at three months. None of these studies have evaluated the potential benefit of IV-tPA depending on the neuroradiological imaging pattern at baseline. While still a matter of debate, some studies have suggested that a perfusion mismatch was associated with a better post-stroke functional prognosis among patients receiving IV-tPA [14]. The aim of our study was to evaluate the influence of IV-tPA on the three months functional outcome in a population of patients aged over 90 y.o., considering their perfusion-imaging profile.

The main result of this study is the absence of significant difference on functional outcome at three months between patients older than 90 y.o. receiving and not receiving IV-tPA for an acute IS. In line with previous studies, this result suggests poor outcome in this very elderly population treated with IV-tPA for acute IS [4, 10]. However, a recent sub-group analysis of the Third International Stroke Trial (IST-3) reported a good outcome in 111 patients > 90 y.o. treated with alteplase versus 98 control patients, and this good outcome was not significantly different from the other groups [23]. Our different results might be explained by the lack of power of our study.

Interestingly, our results were observed despite a favorable neuroimaging pattern on CTP imaging with the presence of a MTT-CBV mismatch in all available perfusion maps of the patients receiving IV-tPA and presence of a high ASPECT score [24, 25]. The impact of CTP imaging profile in patients receiving IV-tPA is not clearly established in the literature. This result suggests that even with the presence of a favorable perfusion profile, the response to thrombolysis in terms of efficacy and safety in the sub-population of very old patients was not improved. A worse collateral supply in older compared to younger patients could partly explain this result. Indeed, the long term exposure to vascular risk factors could have reduced the permeability of collateral vessels [26].

Patients included in the present study had relatively high NIHSS at baseline, which, in combination with the old age could have increased the risk of poor prognosis. This result is in accordance with previous reports which suggested that a positive SPAN-100 (patient age + NIHSS at baseline ≥ 100) could predict no significant benefit of thrombolysis [27]. Unfortunately, the use of CTP parameters did not seem to modify this cut-off.

Swallowing disorders and delirium were significantly more frequent in the thrombolysed group. Swallowing disorders appeared to be related to stroke severity, and delirium to a side-effect of IV-tPA combined with the effect of age. Delirium could also have been favored by the cognitive frailty of these very elderly patients. In addition, the decubitus often imposed in the acute phase given the presence of a proximal intracranial occlusion probably increased these disorders. The trend to more frequent pulmonary infections in the thrombolysed group might have been the consequence of swallowing disorders in addition of agitation and altered awareness, with the risk of getting in a vicious circle. These factors might have contributed to impair the functional prognosis, increase mortality and interfere with the potential benefit of thrombolysis.

The high rate of hemorrhagic transformation observed in our population receiving IV-tPA (53 %) is in accordance with the rate predicted by the SPAN-100 [27]. Hemorrhagic transformation and symptomatic intracranial hemorrhage might also partly explain the absence of IV-tPA benefit in the present study as we showed that symptomatic intracranial hemorrhage tended to be associated with the mRS at three months and death in the first 7 days. However, in IST-3, symptomatic intracranial hemorrhage did not affect clearly the outcome at six months [23], and while thrombolysis was found to be associated with hemorrhagic transformation in bivariate analysis, it did not remain significant in multivariate analysis. Conversely, intracranial occlusion and stroke severity at 24 h were independent predictors of hemorrhagic transformation. The association between intracranial occlusion and hemorrhagic transformation has already been described [28] and might be related to the larger infarct size observed in this condition.

The results of this study should be interpreted cautiously due to several limitations. First, the retrospective design and the small sample size limits the power of statistical analysis. But the characteristics of our population are in line with previous studies and support the validity of our sample. Second, IV-tPA was administered until 4.5 h while some recommendations limit the use of this treatment to 3 h post-stroke onset in patients older than 80 y.o. [21]. However, treatment was initiated early in our sample (mean 168 ± SD 48 min) which might have limited the influence of the delay. Third, CTP imaging was not performed in non-thrombolysed patients, which did not allow direct comparisons between groups. Finally, the absence of evaluation of recanalization and/or reperfusion and final infarct size also limits the interpretation of results.

IV-tPA administered early after IS onset in our sample of patients aged over 90 y.o. did not influence the functional prognosis whereas most of them had a favorable neuroimaging pattern. Moreover, hemorrhagic transformation and post-stroke complications were more frequent in thrombolysed patients, and symptomatic intracranial hemorrhage tended to worsen the functional outcome at three months and increase the rate of death in the first 7 days.

While the identification of additional predictors could be useful to improve the selection of patients suitable for IV-tPA, other revascularization techniques such as mechanical thrombectomy might be considered in this frail population in order to reduce hemorrhagic transformation, early clinical worsening, the vicious circle of post-stroke complications and extended duration of hospitalization. Further studies are needed to confirm those results.