Predictors of futile recanalization in nonagenarians treated with mechanical thrombectomy: a multi-center observational study

Mechanical thrombectomy (MT) currently represents the standard of care of acute ischemic stroke due to large vessel occlusion (LVO) regardless of the age of the patient [1]. A recent analysis of data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke (MR CLEAN) including 2807 patients with a median age ranging from 71 to 75 years reported the association between clinical outcome and the thrombolysis in cerebral infarction (TICI) classification scores [2]. Functional independence at 90 days from the index event was achieved in 42.8% of TICI 2B, 49.3% of TICI 2C, and 51.9% of TICI 3 patients. Although major clinical trials have demonstrated the benefit of MT for the general population, the degree of benefit is less clear in very elderly patients aged 90 years or older as this subgroup was often excluded or under-represented in past trials [3‐6]. Indeed, although previous observational studies have shown that a good functional outcome is achieved in a low rate of nonagenarians who underwent MT following an acute ischemic stroke, MT in nonagenarians is associated with a recanalization rate often comparable to younger patients [7‐12]. Therefore, there is still a significant proportion of patients aged ≥ 90 who do not achieve a good functional outcome at 90 days after MT despite successful recanalization, also known as futile recanalization.

Previous studies have investigated predictors of futile recanalization of MT in acute ischemic stroke caused by LVO in the anterior circulation for the general population [13, 14]. However, there is a lack of data specifically regarding patients aged 90 years or older and their predictors of futile recanalization after MT. Considering the overall aging population, it is expected that an increasing number of patients aged 90 years or older with LVO will meet the criteria for MT in the future. Therefore, it is of paramount importance to better understand the efficacy of MT in this age group and to define factors that might help to identify patients likely to benefit from the treatment. We conducted a multi-center observational retrospective study aiming to explore the rate and predictors of futile recanalization in patients aged 90 years or older with LVO undergoing MT.

Our cohort included 139 patients aged 90 years or older with acute ischemic stroke due to anterior circulation LVO consecutively treated with MT in four thrombectomy capable centers. One hundred seventeen of one hundred thirty-nine patients aged 90 years or older achieved successful recanalization after MT and were included in the analysis, of whom thirty-one (26.49%) experienced effective recanalization and eighty-six (73.51%) experienced futile recanalization (see flow chart Fig. 1).

The demographical and clinical data of the patients with effective and futile recanalization are presented in Table 1. Overall, the mean age was 92 years (IQR 90–93) and 64.9% were female (n = 76). The median ages in the two groups did not differ significantly. The two groups did not differ significantly for most of the variables taken into account except for the fact that patients with futile recanalization had a higher NIHSS on admission (p < 0.001).

Table 2 shows the comparison of the procedural features between patients with effective and futile recanalization patients aged 90 years or older. The two groups did not differ in terms of site of occlusion, CS, symptom onset to door time, door to needle time, symptom onset to groin puncture time, and rate of sICH. The median ASPECTS score at 24 h was significantly lower in patients with futile recanalization (p = 0.004). Patients with futile recanalization were less frequently treated with IVT (p = 0.048) and underwent the procedure more often with GA (p = 0.011). They also had a higher NIHSS at 24 h from MT (p < 0.001) and longer door to groin puncture delay (p = 0.002).

As shown in Table 3, after the multivariable logistic analysis, in patients aged 90 years or older with LVO treated with MT, the use of IVT was associated with reduced probability of futile recanalization (0.44, 95% CI 0.09–0.88, p = 0.039), while door to groin puncture delay (1.02, 95% 1.001–1.05, p = 0.026) was positively correlated with futile recanalization.

The main finding of our multi-center observational study is that the use of intravenous thrombolysis was associated with a reduced probability of futile recanalization in patients aged 90 years or older with LVO undergoing MT. Current guidelines recommend IVT with alteplase for patients over 80 years of age with acute ischemic stroke within the 4.5-h window [24]. However, data are relatively limited regarding the specific benefits and risks of IVT in nonagenarians, since many clinical trials of tPA did not include patients aged > 80 years, and tPA has strict selection criteria that exclude many of these patients from eligibility. Indeed, Arora et al. documented in their national quality registry that up to one-third of patients ≥ 90 years eligible for lytic therapy did not receive IVT [25]. This was primarily because of fear that advancing age is associated with poorer prognosis with greater risk for symptomatic intracerebral hemorrhage and in-hospital mortality. Moreover, nonagenarian patients have often already a higher burden of morbidity and premorbid baseline disability. It is noteworthy to mention that in our study, all the patients included in the analysis had a baseline mRS score ≤ 2 and this might be one of the reasons to explain our high rate of use of IVT with almost 70% of our nonagenarian patients treated with lytic therapy. Data on bridging thrombolysis in the elderly population remain sparse and equivocal, to date. Although thrombolytic agents, such as alteplase, may contribute to early recanalization, IVT could delay the MT, increase the risk of symptomatic intracerebral hemorrhage, or distal migration of thrombi, rendering them inaccessible to MT. Previous randomized controlled trials have addressed this question, and although some trials met liberal noninferiority end points, noninferiority of MT alone compared with MT with bridging thrombolysis could not be uniformly established [26‐29]. In the SKIP trial [26] and SWIFT-DIRECT trial [30], subgroup analyses showed that in patients older than 70 years old, MT with or without bridging IVT led to no differences in outcomes. Retrospective studies evaluated the safety and efficacy of IVT before MT in elderly patients [31‐33]. An analysis based on the data of the ANGEL-ACT registry documented that MT alone had similar efficacy to bridging MT in terms of 90-day functional outcomes in 482 patients ≥ 65 years [33]. In this present analysis, the authors found that the time from door to groin puncture was longer in the bridging group which could lead to the conclusion that bridging IVT might delay the time for endovascular treatment. Conversely, Barral et al. showed that bridging IVT was associated with better outcomes in 169 patients with anterior circulation LVO over 80 [31]. In our study, patients with effective recanalization after MT were more often treated with also IVT, and also had a shorter door to groin puncture time compared to patients with futile recanalization. Of note, in our analysis, we documented a strong trend to futile recanalization in patients with proximal occlusion rather than distal. However, while, on univariable analysis, the site of occlusion distal (M2) vs proximal (ICA, M1, ICA + M1) resulted to be significantly associated with decreased likelihood of futile reperfusion, this variable did not result to be significantly associated with reduced probability of futile reperfusion on multivariable analysis although we can appreciate a trend toward this direction. Moreover, in our analysis, door to groin puncture time delay is associated with increased risk of functional dependence at 90 days after the stroke. This finding may be explained by the synergistic action of intravenous thrombolysis and MT in targeting small vessel recanalization and improving distal microvascular perfusion. Future studies are still needed to fully elucidate the efficacy and safety of bridging thrombolysis in nonagenarians.

Another important finding of our study is that 73.51% of the nonagenarian patients experienced futile recanalization after MT and this is in line with previous studies. In the analysis of Drouard-de Rousiers et al., among 124 nonagenarians, treated with MT those with successful recanalization were 93, of whom 18 (19%) experienced effective recanalization while 75 (81%) experienced futile recanalization [34]. Meyer et al. described outcome and safety of a large cohort of patients ≥ 90 years undergoing MT [35]. In this study, the authors found that the frequency of good recanalization (TICI 2b or 3) was not significantly different in patients with good functional outcome compared to those with mRS ≥ 4 at 90 days after the event. Interestingly, in this study, successful recanalization was not a predictor of good outcome after MT. According to the authors, this could be explained by the fact that a significant proportion of patients worsened regardless the successful recanalization. Unfortunately, the authors did not provide data regarding the exact rate and predictors of futile recanalization in their patient sample. Singer et al. investigated the impact of patient age on the outcomes post-MT for anterior circulation LVO [36]. The authors found that the proportion of patients with futile recanalization increased from 29% (age group 18–53 year old) to 53% in patients within the age group 77–94 years old. Overall, the current literature clearly suggested that the effect of recanalization on 90-day outcome seems to be lower in patients ≥ 90 years. The aging process of the cerebral vessels, in terms of atherosclerosis, amyloid angiopathy, friability, small vessel disease [37] (including leukoaraiosis and brain atrophy) may be important factors to determine futile recanalization after MT [38, 39]. In addition, in older patients, the presence of poor collateral circulation, increased risk of hemorrhagic transformation and impaired cerebrovascular autoregulation, and large hypoperfusion volume could also lead to earlier tissue loss and therefore worse functional outcomes than younger patients [40, 41]. Therapeutic strategies targeting tissue recanalization and attenuation of futile recanalization in the clinical setting are needed.

Finally, our study confirmed the correlation between door to groin puncture delay and treatment outcomes. In-hospital delays include any portion of the neurointerventional activation process and, therefore, represent a significant opportunity to improve time to treatment. Interestingly, in our study, we did not observe any significant difference in terms of pre-hospital delay and door to needle time between patients with futile recanalization and effective recanalization. However, we showed that patients with futile recanalization experienced longer door to groin puncture time compared to those with effective recanalization. Based on our findings, we could not clarify the reasons for this significant treatment delay. Nevertheless, it is noteworthy to mention that patients with futile recanalization had a higher NIHSS score on admission and more often had GA as choice of sedation for the procedure. However, in our cohort, the median door to groin time (min) in patients with GA was not significantly higher compared to patients with LA, i.e., respectively, 118 (88.5–143.5) vs 111.5 (59.75–147) (p = 0.443). Therefore, it is possible to hypothesize that the increased stroke severity could have impacted on the hyperacute stroke management. Treatment delays not only limit candidacy for MT, but also worsen functional disability and reduce number of healthy life years after treatment [42, 43].

Our analysis had the following strengths: (1) large cohort of nonagenarian patients; (2) multi-center study. Nevertheless, our study has several limitations. First is the non-randomized design of the study that might have introduced bias. Even though we adjusted for this factor in the logistic regression analyses to determine their impact on the outcomes, this could represent a potential bias. Infarct volume was not available. Finally, our analysis included patients who had the initiation of the procedure within 6 h after the stroke onset.

Our study seems to suggest that MT with IVT is associated with reduced probability of futile recanalization in patients aged 90 years or older. Further studies are warranted to confirm the results and to evaluate the safety and efficacy of bridging thrombolysis in nonagenarians.