Background There has been a growing interest in improving systems of care for the endovascular treatment of acute ischemic stroke. We analyzed data from previous registries and studies to determine if there has been an improvement in times to reperfusion with increasing experience.
Methods We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), MERCI Registry and Thrombectomy Revascularization of Large Vessel Occlusions (TREVO), and TREVO 2 trials and assessed times from last known normal to puncture, from hospital arrival to puncture, and procedure duration by year to determine if there has been a reduction in times. Demographic, radiographic, and clinical information were also assessed in a multivariate regression analysis to determine the predictors of good outcomes defined as a modified Rankin Scale score of 0–2 at 3 months.
Results 1248 patients of mean age 68±14 years and median NIH Stroke Scale score 18 were analyzed from 2001 to 2011. Procedure times showed a significant improvement while last known normal to puncture times remained static. In multivariate logistic regression analysis, longer last known normal to puncture time and longer procedure duration were associated with a decreased chance of a good outcome (OR 0.84, 95% CI 0.76 to 0.92, p=0.0004 and OR 0.75, 95% CI 0.61 to 0.91, p=0.0040, respectively).
Conclusions Despite a reduction in procedure times, there has not been a corresponding improvement in overall last known normal to puncture times over a 10-year period. The current study shows that there are many opportunities to create more efficient endovascular stroke systems of care in trials.
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There has been a rapid evolution of technology to remove a thrombus from the cerebral circulation during the acute phase of ischemic stroke. Such advances have allowed operators to achieve reperfusion more efficiently and effectively in the hope of improving neurological recovery. Unfortunately, despite improving reperfusion rates, there has not been a dramatic improvement in neurological outcomes at 90 days.1 The reasons for this discordance are probably manifold. One potential reason is suboptimal systems of care that produce delays to arrival in the interventional suite.2 ,3 Parameters such as onset to reperfusion or door to puncture times4 ,5 have been shown to correlate with neurological outcome. It has been estimated that pre-procedure times account for roughly 75% of the time spent from the ictus of symptom onset or last known normal to reperfusion.3 As experience with endovascular reperfusion therapy for ischemic stroke has grown, it is not clear whether the systems of care are concomitantly improving. We therefore analyzed the combined datasets from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial,6 MERCI registry,7 Thrombectomy REvascularization of Large Vessel Occlusions (TREVO),8 and TREVO 29 studies in order to assess whether there has been evidence of improvement in the systems of care for endovascular stroke treatment over the past decade.
We analyzed pooled data from the MERCI, MERCI Registry, TREVO, and TREVO 2 trials encompassing the years from 2001 to 2011. Demographic, clinical, procedural, and outcome data were analyzed, including time from last known normal to groin puncture, time from emergency room arrival to groin puncture, procedure length, use of intra-arterial lytic therapy, angiographic characteristics, and symptomatic intracranial hemorrhage. We selected all patients who had time from last known normal to arterial puncture within 9 h. The details of the data collection methodology have been previously reported.6–9
All statistical analyses were performed using SAS software (V.9.4). We summarized data with standard descriptive statistics (ie, mean and SD for continuous variables, median and IQR for non-normal or ordinal data, and percentages for categorical variables) and analyzed annual changes in three time interval variables (ie, time from last known normal to groin puncture, time from emergency room arrival to groin puncture, and procedure length). We tested the trend over years by fitting with a linear regression model. Logistic regression was used to model good clinical outcome at 90 days, defined as modified Rankin Scale (mRS) score of ≤2. In univariate analysis, pre-specified clinical and procedural variables of interest were correlated with good functional outcome as a binary outcome measure. A significant association was considered at a p value of <0.05. All covariates with p<0.15 were then entered into a multivariable logistic regression model to assess the effects of clinical and procedural variables on functional outcome. Level of significance was established at a two-tailed p value of <0.05 in the final model.
A total of 1248 patients of mean age 67.8±14.4 years and NIH Stroke Scale (NIHSS) score 18±6 from 2001 to 2012 were analyzed. The mean time from last known normal to arterial puncture was 4.6±1.7 h and from emergency room arrival to arterial puncture was 2.7±1.3 h. Table 1 summarizes the clinical characteristics of the entire cohort. As shown, the overall good outcome rate was 29.9% and the Thrombolysis In Cerebral Infarction (TICI) 2b/3 rate was 57.7% with a mean procedure length of 1.8±0.9 h.
Table 2 and figure 1 summarize the annualized time parameters of last known normal to arterial puncture, emergency room arrival to arterial puncture, and procedure duration. As seen in the table 2, there was a steady decline in mean procedure times between 2003 and 2011 from 2.2 h to 1.5 h (p<0.0001). There was also a significant decline in hospital arrival to puncture times between 2008–2010 and 2011 (p<0.001). The time from hospital arrival to procedure was stagnant prior to the drop in 2011. Additionally, time from last known normal to arterial puncture did not change over the decade.
Table 3 summarizes the univariate analysis of predictors of a good clinical outcome at day 90. Younger age, lower baseline NIHSS, successful reperfusion, and absence of diabetes mellitus led to favorable outcomes. As anticipated, the use of a Trevo device over the Merci device was also associated with a favorable outcome. Longer time from symptom onset to arterial puncture and longer procedure length were associated with poor outcomes.
Table 4 shows the multivariate analysis of independent predictors of good clinical outcome. Patients who had longer procedure lengths (OR 0.75, 95% CI 0.61 to 0.91, p=0.0040) and longer time from symptom onset to arterial puncture (OR 0.84, 95% CI 0.76 to 0.92, p=0.0004) were noted to have poor neurologic recovery after endovascular reperfusion therapy.
Several clinical trials have recently shown the benefit of endovascular reperfusion therapy compared with medical therapy in patients with large vessel occlusive disease.10–12 There has been increased recognition of the importance of door to needle times for intravenous tissue plasminogen activator, with a focus on reducing these times and increasing delivery rates in order to improve clinical outcomes.13 Similarly, the American Heart Association has proposed an ‘arrival to treatment’ time of <2 h for patients undergoing endovascular stroke therapy.14 The current study shows that the majority of highly experienced centers participating in clinical trials and registries do not achieve this metric. Moreover, despite improving procedure and hospital arrival to puncture times (door to puncture), there does not appear to be a concordant improvement in the last known normal to puncture times which is strongly correlated with neurological outcomes at 90 days. It interesting to note that in the last quarter of 2010 there was a last known normal to treatment time of <180 min with a good outcome rate of nearly 60%. Although there may be alternative explanations for this high rate of good outcome, the time component is likely to be contributory.
Endovascular reperfusion therapies have continued to evolve over the past decade. New devices have been introduced with the promise of improving reperfusion rates in an expeditious manner. These efforts, along with increasing operator experience, appear to be making an impact. Our results show a decrease of roughly 40 min or 30% between 2003 and 2011, and other studies have reported similar reductions in procedure times.15–17 Yet neurological outcomes have not improved in a similar fashion. This is probably due to the fact that the procedure length accounts for a relatively small proportion of the time interval from symptom onset to successful reperfusion. It is estimated that almost 75% of the occlusion time precedes the start of intra-arterial treatment in the care of the patient and, as we have shown, pre-procedure times have not changed in the last decade.3 This stresses the importance of process improvement for the workflow leading up to the interventional suite. It is important to note that patients treated beyond 9 h were excluded from this analysis and the reason for the lack of improvement cannot be attributed to selecting patients with later onset strokes only.
In thinking about process improvement, it is helpful to break down the pre-procedure time interval around the time of patient arrival at the treating facility. The problems related to pre-arrival delay are distinct from those accounting for in-hospital delays to the interventional suite. With respect to in-hospital delays, there have been few efforts to systematically improve door to puncture times for intra-arterial therapy. This is in contrast to the major initiatives that seek to reduce door to needle times in the delivery of intravenous tissue plasminogen activator for eligible patients. The Target Stroke Initiative is working towards a goal door to needle time of <60 min.18 The aim of this initiative is for 50% of patients to be treated within this time frame.
The recent analysis of the Interventional Management of Stroke III study showed the mean time from symptom onset to reperfusion was 325 min.15 Roughly 45% of the delay (146 min) is attributed to the time from arrival at the emergency room to groin puncture (door to puncture).16 This is similar to our finding in the current analysis of 162±78 min for the overall cohort. It is interesting to note that there was a significant improvement in the door to puncture time in 2011 to 120±66 min, similar to that reported in a recent registry from patients enrolled in 2012 where the median door to puncture time was 112 min.5 This improvement may reflect the recent emphasis on the speed of intra-arterial treatment delivery, although this finding needs to be verified in other datasets.
A frequently cited delay that occurs within the hospital is the time spent obtaining advanced modality imaging at the treatment facility.2 ,19 The addition of imaging such as MRI and CT perfusion may lead to delays in the pre-endovascular treatment of the patient and may be more prevalent than in the earlier period of this study. Unfortunately, we do not have access to the timings and rates of advanced modality imaging in this cohort. More data are needed to determine whether the additional information obtained from this imaging is worth the time spent in acquiring and interpreting it.
With respect to pre-arrival delay, valuable time is lost when patients are transferred from a non-interventional to an interventional center. In a recent analysis, transferred patients had a last known normal to puncture time of 301 min compared with 177 min for non-transferred patients and a 90-day good neurological outcome rate of 29% versus 51%, respectively.3 The low rate of favorable outcomes associated with patient transfer raises questions about the effectiveness of the current inter-facility transfer paradigm. A more encompassing variable metric that would encapsulate the entire spectrum of the patient's care would be the time from first medical contact to reperfusion. This would be a more comprehensive and comparable metric that would integrate the pre-hospital and inter-facility transfer timelines. The current model in the USA of taking a patient to a primary stroke center for delivery of intravenous tissue plasminogen activator prior to transportation to an endovascular-ready center may be challenged in the face of recent clinical data showing a strong efficacy of endovascular reperfusion treatments. It will be important to develop a pre-hospital triage scale to enable emergency medical service providers to distinguish between patients with a possible large stroke syndrome where direct transportation to an endovascular-ready center is best for the patient. This trial was performed in patients with ST segment elevation myocardial infarction (STEMI) in the PRAGUE-220 and DANAMI-221 trials where it was shown that percutaneous coronary intervention (PCI) for STEMI was more effective than stopping for thrombolysis prior to PCI. Although an ECG for the brain does not exist in the field, clinical tools such as the Los Angeles Motor Scale22 may be sensitive enough to triage patients without having to incur time delays by stopping at a primary stroke center first.
There are several limitations to the current analysis. The MERCI registry is a site adjudicated registry for outcomes and thus there may be biases inherent to the retrospective nature of the registry. Second, several time points were not available for analysis, thus limiting our ability to report on specific bottlenecks that may be causing the delays. Third, the types of imaging employed and pre-treatment core infarcts prior to treatment are not accounted for in regression analysis. Last, there is variability in practice patterns that may exist leading to the variances noted in this analysis.23 The SDs are quite large, probably because of the heterogeneity that exists among treatment sites. Standardization of time metrics and targets similar to that achieved with the Target Stroke Initiative may allow for a reporting standard for the treating center.
Despite the limitations, the study confirms the importance of times to treatment and their impact on neurological recovery after endovascular stroke therapy. The time from last known normal to reperfusion has not changed over the decade studied despite an improvement in the procedure times and door to puncture times. There are several opportunities to work towards a standard time metric that encapsulates first medical contact to reperfusion as a meaningful standard across studies.
Contributors RG, C-HJS: writing of manuscript, data interpretation. BX, SG: data analysis and statistics. AJY, BPM: critical revision of manuscript.
Competing interests RG: Scientific advisory board for Stryker Neurovascular, Covidien, and Rapid Medical; Associate Editor of Journal of Neuroimaging, Journal of NeuroInterventional Surgery, and Interventional Neurology; Royalties from UpToDate; Steering Committee for the DAWN Trial sponsored by Stryker Neurovascular and THERAPY trial sponsored by Penumbra; Grant research funding for ReCCLAIM II from the Wellstar Health Foundation. BX: Funding for statistical support through Stryker Neurovascular. SG: Employee of Stryker Neurovascular. AJY: Research funding from the National Institutes of Health, Penumbra, and Remedy Pharmaceuticals.
Ethics approval Institutional Review Board for each institution in the trials analyzed.
Provenance and peer review Not commissioned; externally peer reviewed.
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