Author: Sarah Gorey
Trinity College Dublin, Ireland
Time is brain. Our number one priority in treating stroke patients is getting the right therapy to the right patients as quickly as possible. However, achieving this goal is not always straightforward.
One uncertainty is whether it is beneficial for patients with suspected large vessel occlusion (LVO) stroke to bypass a local primary stroke centre (PSC) and be brought directly to a mechanical thrombectomy (MT) capable comprehensive stroke centre (CSC). Two trials RACECAT1, based in Catalonia and TRIAGE-STROKE2, based in Denmark, have sought to address this question.
RACECAT was a cluster randomised trial set in predominantly non-urban regions in Catalonia. EMS personnel used the RACE Scale3 to predict LVO (score 5-9 suggesting LVO present). The unit of ‘clustering’ was temporal, i.e. 12 hour time slots, stratified by territory and day of the week. Patients were either brought to the nearest stroke centre, and if LVO confirmed transfer to MT capable centre or were transported directly to the MT capable centre. The primary outcome was disability at 90 days assessed by mRS.
1401 patients were randomised in RACECAT, however 7475 adults total were screened for inclusion. Most excluded did not meet eligibility criteria. LVO was detected in approximately two-thirds of the patients. Median time from onset to arrival at first hospital was 88 minutes (IQR 61-145) for PSC arm and 142 minutes (IQR 100-231) in CSC arm. Door-to-needle time for those receiving tPA was similar in both arms: 33 minutes (25-48) in PSC and 30 minutes (22-40) in CSC, but time from symptom onset to tPA was 34 minutes faster in the PSC arm. (PSC 120 minutes (IQR 89-168) versus CSC 155 minutes (IQR 120-195). Median stroke onset to groin puncture times was 270 minutes (215-347) in the PSC and 214 minutes (172-330) in the CSC arm (56 minutes quicker in CSC arm.)
RACECAT was halted at the second interim analysis due to futility. There was no significant difference in mRS at 90 days between the two transport strategies, with a median mRS of 3 in both arms at 90 days. Safety outcomes and 90 day mortality were the same between both arms. However, in a further secondary analysis the RACECAT4 authors reported that for patients with a final diagnosis of intracranial haemorrhage, (ICH) (302 patients in total, representing 21.6% of the total number randomised in RACECAT) transportation to a CSC was associated with worse functional outcome at 90 days, with higher rates of medical complications (22.6% in CSC arm compared with 5.6% in PSC arm) and specifically a higher rate of pneumonia in the CSC arm: 35.8% (versus 17.6% in PSC). Mortality at 90 days was numerically higher in the CSC arm for those with ICH (48.9% CSC versus 37.6% PSC) although this was not statistically significant.
A second RCT examining transport strategy in suspected LVO stroke was published in Stroke this month. TRIAGE-STROKE2 was a multicentre RCT in Central and Northern Denmark which ran from 2018-2022. However, it was terminated at 4 years due to lack of funding and also hindered by lack of recruitment at all participating centres as well as withdrawal of two CSC from the trial due to increased burden of accepting bypassed patients directly. As such, TRIAGE-STROKE is underpowered to answer its primary outcome which was mRS at day 90.
In TRIAGE-STROKE the PASS5 score was used by EMS to predict LVO. The inclusion criteria was stricter than RACECAT and patients in TRIAGE-STROKE also had to be eligible for IVT as well as likely EVT, and to be able to arrive at the CSC and PSC within 4 hours of onset of stroke. The target sample size was 600 participants, but only 186 were screened and 171 were randomised. Of these, 104 were confirmed to have ischaemic stroke, with 51 haemorrhages and 16 mimics. LVO was confirmed in 71 (68.3%). Time from stroke onset to arrival at first hospital was 81 minutes (IQR 64-116) for PSC and 177 minutes (IQR 95-158) in CSC. Symptom onset to tPA was 30 minutes faster in the PSC arm: PSC 114 minutes (IQR 90-157) versus 144 minutes (IQR 122-171) in CSC arm. Stroke onset to groin puncture was 35 minutes faster in the CSC arm: 187 minutes (IQR 158-245) CSC arm versus 222 minutes (IQR 196-297) in PSC.
Due to lack of power, TRIAGE-STROKE was unable to demonstrate a functional benefit at 90 days. Despite low power, the OR of mRS shift for all 171 patients randomised was neutral OR 1.01 (0.60-1.71) For the haemorrhage subgroup (n=51) the OR was 0.94 (0.34-2.63) somewhat replicating the signal of harm for those with ICH if bypassed directly to a CSC, although due to wide confidence intervals, we cannot draw firm conclusions.
Overall, from these two trials there is certainly not an overwhelming signal that a bypass approach is better for patients with suspected LVO. We certainly need to take heed of the signal of potential harm and increased complications for patients with ICH – especially considering ICH will often present similarly to LVO and will ‘screen positive for LVO’ on whatever pre-hospital clinical tool is used. The number-needed to harm (for a patient with ICH to have mRS of 5 or 6 at 90 days) in RACECAT ICH secondary analysis was 9. It would not be fair to streamline stroke workflow to benefit only ischaemic strokes to the determent of those with haemorrhagic strokes. Additionally, consider the increased burden on CSCs if all potential LVO strokes (including ICH and mimics) were admitted directly. Questions surrounding repatriation of stroke patients and mimics to their local hospital would need to be addressed.
Another take home point is to underscore the value of early Stroke Unit care and the importance of proactively managing medical complications, especially in haemorrhagic stroke. We must also consider that the potential beneficial effect of getting to EVT quicker may have been neutralised by the PSC arms getting to IVT quicker. The complex screening process, EMS training and coordinated workflows required to ensure these trials were performed must be commended, however these complex workflows may not translate into other countries or areas. Overall, I think we should focus on ensuring that our existing stroke pathways run smoothly and efficiently. For those delivering ‘drip-and-ship’ stroke care, these trials are reassuring that the stroke care we are delivering is as good as that at the CSC and we should be motivated to renew our efforts to keep door-to-needle and door-in-door-out times as brisk as possible.
- Pérez de la Ossa N, Abilleira S, Jovin TG, et al. Effect of Direct Transportation to Thrombectomy-Capable Center vs Local Stroke Center on Neurological Outcomes in Patients With Suspected Large-Vessel Occlusion Stroke in Nonurban Areas: The RACECAT Randomized Clinical Trial. JAMA 2022; 327(18): 1782-94.
- Behrndtz A, Blauenfeldt RA, Johnsen SP, et al. Transport Strategy in Patients With Suspected Acute Large Vessel Occlusion Stroke: TRIAGE-STROKE, a Randomized Clinical Trial. Stroke 2023; 54(11): 2714-23.
- Ossa NPdl, Carrera D, Gorchs M, et al. Design and Validation of a Prehospital Stroke Scale to Predict Large Arterial Occlusion. Stroke 2014; 45(1): 87-91.
- Ramos-Pachón A, Rodríguez-Luna D, Martí-Fàbregas J, et al. Effect of Bypassing the Closest Stroke Center in Patients with Intracerebral Hemorrhage: A Secondary Analysis of the RACECAT Randomized Clinical Trial. JAMA Neurology 2023; 80(10): 1028-36.
- Hastrup S, Damgaard D, Johnsen SP, Andersen G. Prehospital Acute Stroke Severity Scale to Predict Large Artery Occlusion: Design and Comparison With Other Scales. Stroke 2016; 47(7): 1772-6.
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