time to endovascular treatment and outcome in acute ... · endovascular treatment (evt) has been...

July 17, 2018 Circulation. 2018;138:232–240. DOI: 10.1161/CIRCULATIONAHA.117.032600232

Key Words: endovascular procedures ◼ ischemic stroke ◼ thrombectomy ◼ treatment time

Sources of Funding, see page 239

Editorial, see p 241

BACKGROUND: Randomized, clinical trials in selected acute ischemic stroke patients reported that for every hour delay of endovascular treatment (EVT), chances of functional independence diminish by up to 3.4%. These findings may not be fully generalizable to clinical practice because of strict in- and exclusion criteria in these trials. Therefore, we aim to assess the association of time to EVT with functional outcome in current, everyday clinical practice.

METHODS: The MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands) is an ongoing, prospective, observational study in all centers that perform EVT in The Netherlands. Data were analyzed from patients treated between March 2014 and June 2016. In the primary analysis we assessed the association of time from stroke onset to start of EVT and time from stroke onset to successful reperfusion with functional outcome (measured with the modified Rankin Scale), by means of ordinal logistic regression.

RESULTS: We analyzed 1488 patients with acute ischemic stroke who underwent EVT. An increased time to start of EVT was associated with worse functional outcome (adjusted common odds ratio, 0.83 per hour; 95% confidence interval, 0.77–0.89) and a 2.2% increase in mortality. Every hour increase from stroke onset to EVT start resulted in a 5.3% decreased probability of functional independence (modified Rankin Scale, 0–2). In the 742 patients with successful reperfusion, every hour increase from stroke onset to reperfusion was associated with a 7.7% decreased probability of functional independence.

CONCLUSIONS: Time to EVT for acute ischemic stroke in current clinical practice is strongly associated with functional outcome. Our data suggest that this association might be even stronger than previously suggested in reports on more selected patient populations from randomized, controlled trials. These findings emphasize that functional outcome of EVT patients can be greatly improved by shortening onset to treatment times.

© 2018 American Heart Association, Inc.

Maxim J.H.L. Mulder, MD, PhD

Ivo G.H. Jansen, MDRobert-Jan B. Goldhoorn,

MDEsmee Venema, MDVicky Chalos, MDKars C.J. Compagne, BsCBob Roozenbeek, MD,

PhDHester F. Lingsma, PhDWouter J. Schonewille,

MD, PhDIdo R. van den Wijngaard,

MD, PhDJelis Boiten, MD, PhDJan Albert Vos, MD, PhDYvo B.W.EM. Roos, MD,

PhDRobert J. van

Oostenbrugge, MD, PhDWim H. van Zwam, MD,

PhDCharles B.L.M. Majoie,

MD, PhDAad van der Lugt, MD,

PhDDiederik W.J. Dippel, MD,

PhDfor the MR CLEAN Registry

Investigators

ORIGINAL RESEARCH ARTICLE

Time to Endovascular Treatment and Outcome in Acute Ischemic StrokeMR CLEAN Registry Results

http://circ.ahajournals.org

Circulation

by guest on July 19, 2018http://circ.ahajournals.org/

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Mulder et al Time to Endovascular Stroke Treatment and Outcome

Circulation. 2018;138:232–240. DOI: 10.1161/CIRCULATIONAHA.117.032600 July 17, 2018 233


When it comes to acute ischemic stroke treat-ment, we have learned from randomized tri-als regarding intravenous alteplase treatment

that time is brain.1–3 Studies performed in clinical prac-tice have extended our knowledge regarding the asso-ciation of time with outcome and provide data that are better applicable to routine clinical practice.4–6

Endovascular treatment (EVT) has been proven highly effective in patients with acute ischemic stroke caused by proximal intracranial artery occlusion in the anterior circulation,7–12 and therefore this treatment be-came standard of care in 2015.13 Before these positive EVT trials, data from several other studies had already suggested that faster reperfusion is associated with better outcomes after EVT.14–17 Shorter time from stroke onset to EVT start has been suggested to be one of the important factors in the success of the positive trials.18

A meta-analysis of data from the first 5 positive tri-als showed that every hour delay in time from onset to start of EVT resulted in a 3.4% decreased probability of functional independence. For every hour delay in time from onset to successful reperfusion, there was a 5.2% decreased probability of functional independence.19 These findings may not be fully generalizable to clini-

cal practice because of strict in- and exclusion criteria. Specifically, most trials selected patients on additional imaging criteria, such as Alberta Stroke Program Early Computed Tomography Score (ASPECTS) thresholds, perfusion imaging, and collateral status.8–11

Our aim was to assess the association of time from stroke onset to EVT and to successful reperfusion with outcome in current clinical practice.

METHODSWe used data from the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands),20 an ongoing, prospective, observational study in all centers that perform EVT in The Netherlands. Registration started directly after the final randomization in March 2014, in the MR CLEAN trial. The central medical ethics committee of the Erasmus Medical Center Rotterdam, The Netherlands, evaluated the MR CLEAN Registry study protocol and granted permission to carry out the study as a registry (MEC-2014-235). The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.

CentersAll 16 intervention centers that participated in the MR CLEAN trial registered their EVT patients. All patients who underwent EVT for acute ischemic stroke in the anterior or posterior circulation in these centers have been registered in the MR CLEAN Registry.

PatientsFor the purpose of this analysis, we used the following inclu-sion criteria: groin puncture within 6.5 hours after stroke onset; age of 18 years and older; treatment in a MR CLEAN trial center; intracranial proximal arterial occlusion in the anterior circulation (intracranial carotid artery [ICA, ICA-T] or middle [M1/M2] or anterior [A1/A2] cerebral artery), dem-onstrated by computed tomography angiography, magnetic resonance angiography, or digital subtraction angiography. The analyzed data concerned patients who were treated with EVT between March 16, 2014, and June 15, 2016.

Clinical DefinitionsThe EVT definition is actual artery puncture in the angiogra-phy suite in acute ischemic stroke patients. The exact choice of endovascular treatment modality for each patient was left to the discretion of the local interventionists. Stroke onset was defined as the moment of witnessed symptom onset or the moment that the patient was last seen well if the actual onset was unwitnessed. ASPECTS was graded from 0 to 10, with 1 point subtracted from 10 for any evidence of early ischemic changes in each defined region on noncontrast com-puted tomography.21 We defined time to start of EVT as the time from stroke onset to arterial puncture. We defined time from onset to successful reperfusion as the time from stroke onset to successful reperfusion in patients in whom an actual

Clinical Perspective

What Is New?• Time to endovascular treatment for acute ischemic

stroke in current clinical practice is strongly associ-ated with functional outcome, and this association might be even stronger than previously suggested in reports on more selected patient populations from randomized, controlled trials.

• Every hour delay in time from stroke onset to endo-vascular treatment start results in a 5.3% decreased probability of functional independence and a 2.2% increase in mortality.

• Every hour delay from stroke onset to successful reperfusion results in a 7.7% decreased probability of functional independence.

What Are the Clinical Implications?• These findings emphasize that functional outcome

of patients who undergo endovascular treatment can be greatly improved by shortening onset to treatment times.

• Reducing delays in the delivery of endovascu-lar treatment should be a primary objective of all stroke centers that refer or treat patients with acute ischemic stroke.

• Given the clear association of time to treatment with functional outcome, this is an important fac-tor in comparing endovascular treatment studies and cohorts.


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thrombectomy attempt was performed. Patients were not analyzed for this time window when the extended thrombol-ysis in cerebral ischemia (eTICI) score was <2A at the end of the intervention, when no target occlusion was seen during intervention, or when the target occlusion was not reached. Successful reperfusion was defined as a score on the eTICI score scale ≥2B.22

Outcome MeasuresFor the present analysis, the primary outcome was the modi-fied Rankin Scale (mRS) score at 90 days. The mRS is a 7-point scale ranging from 0 (no symptoms) to 6 (death). A score of ≤2 points indicates functional independence.23 Secondary outcomes were excellent (mRS of 0–1), good (mRS of 0–2), and favorable (mRS of 0–3) functional outcome, mortality, eTICI, and occurrence of symptomatic intracranial hemor-rhage. The eTICI scores range from grade 0 (no reperfusion) to grade 3 (complete reperfusion).22 An independent core laboratory, blinded for clinical outcome, assessed all digital subtraction angiographies. Hemorrhages were evaluated by the complication committee and the imaging core laboratory according to the Heidelberg criteria.24

Statistical AnalysisBaseline characteristics of the study population are tabulated by three subgroups according to onset to treatment time (<150, 151–270, 271–390 minutes), for illustration only. The primary analysis assessed the association of time from stroke onset to EVT as a continuous variable (onset to EVT) and onset to successful reperfusion with functional outcome, by means of ordinal logistic regression. For all analyses, time to EVT odds ratios were expressed per hour increase in time. Secondary analyses assessed the associations of time to EVT with secondary outcomes. Finally, in an exploratory analy-sis the association of other time intervals with functional outcome were analyzed. Any mRS score of 0 to 5 assessed within 30 days of symptom onset was considered invalid and treated as missing. These values were therefore replaced by mRS scores derived from multiple imputation for regression analyses. For both primary and secondary analyses, unad-justed and adjusted regression analyses were performed. We adjusted for age, sex, National Institutes of Health Stroke Score at baseline, collateral score, and additionally for base-line ASPECTS in the analysis of symptomatic intracranial hem-orrhage. Selection of these variables for adjustments was based on evidence from previous studies. The association of

time to EVT with functional independence (mRS 0–2) was shown in adjusted margin plots. All statistical analyses were performed with STATA/SE software (version 14.1; StataCorp, Boulder, CO).

RESULTSOverall, 1488 patients were included in this analysis (Fig-ure 1). For all patients, an estimate of stroke onset time was available. In 1117 patients (75%) this concerned the actual time of stroke onset and for the other 371 patients (25%) the time last seen well. The time of groin puncture was available for all subjects (Figure IA in the online-only Data Supplement). In 1280 patients (86%) the target oc-clusion was actually reached and an attempt to remove the thrombus was made. When no attempt was made to remove the target occlusion this was because the tar-get occlusion was not accessible (80 patients [5%]) or no target occlusion was present (spontaneously dissolved or migrated distally) on digital subtraction angiography (119 patients [8%]) or the intervention was stopped for other reasons (9 patients [1%]). For 1272 of the 1280 (99%) patients in whom removal of the thrombus was attempted, the time of reperfusion or end of the proce-dure was available, and 1266 patients (98%) had a post-eTICI scored by the imaging core laboratory. For 1363 patients the mRS score was not imputed, so multiple im-putation for regression analysis was performed in all 125 remaining patients (8%).

Median age was 71 (interquartile range [IQR], 60–80), 794 patients (53%) were male, National Institutes of Health Stroke Score at baseline was 16 (IQR, 11–20), and in 1161 patients (78%) intravenous alteplase was administered before EVT (Table 1). Successful reperfu-sion was achieved in 743 (59% of the 1266 patients in whom thrombectomy was attempted and interven-tion images were available), and in 1 patient the time of reperfusion was missing (Figure IB in the online-only Data Supplement). At 90 days after stroke, 517 of 1363 patients (38%) were independent (mRS 0–2) and mor-tality occurred in 398 patients (29%). In total 86 (5.8%) of the 1488 patients had a symptomatic intracranial hemorrhage.

Figure 1. Flowchart of MR CLEAN Registry patients in the current analysis. EVT indicates endovascular treatment; and MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands.


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Exactly 809 patients (54%) were transferred from a primary stroke center (where patients were treated with intravenous alteplase if indicated) to the intervention center. Median time from stroke onset to emergency de-partment arrival at the intervention center was 134 min-utes (IQR, 60–189), and onset to start of EVT took 208 minutes (IQR, 160–265). Median time from emergency department of the intervention center to start of EVT was 67 minutes (IQR, 41–103). Total intervention dura-tion was 63 minutes median (IQR, 40–90) and was clear-ly shorter when successful reperfusion was achieved (57 versus 85 minutes, P<0.01). Median time from onset to successful reperfusion was 260 minutes (IQR, 209–314).

An increased time from stroke onset to start of EVT was associated with a shift toward poor functional outcome with an adjusted common odds ratio of 0.83 (95% confidence interval [CI], 0.77–0.90) for every hour (Figure 2A, Table 2, and Table I in the online-only Data Supplement). The probability of functional indepen-dence declined from 47.3% at 90 minutes to 21.0% at 390 minutes, resulting in a 5.3% decreased probability of functional independence per hour delay (Figure 3A). Time to start of EVT was also significantly associated with mortality, which increased by 2.2% per hour treatment delay (Figure II in the online-only Data Supplement). We found no association between later start of EVT and suc-cessful reperfusion during EVT, nor with symptomatic in-tracranial hemorrhage occurrence (Table 2).

The associations of time from onset to successful re-perfusion with functional outcome and complications were similar in the 742 patients with successful reperfu-sion and available onset to reperfusion time (Figure 2B, Table 3, and Table II in the online-only Data Supplement). In the ordinal analysis, the association was significant, with an adjusted common odds ratio of 0.79 (95% CI, 0.71–0.88). The probability of functional independence declined from 62.7% at 120 minutes to 24.4% at 420 minutes, resulting in a 7.7% decreased probability of functional independence per hour increase (Figure 3B).

Intravenous alteplase treatment, n (%)

239 (77) 696 (82) 229 (70)

General anesthesia, n (%)

63 (21) 225 (28) 92 (30)

ASPECTS indicates Alberta Stroke Program Early Computed Tomography Score; CTA, computed tomography angiography; DSA, digital subtraction angiography; EVT, endovascular treatment; ICA, intracranial carotid artery; ICA-T, intracranial carotid artery Tandem; IQR, interquartile range; MRA, Magnetic resonance angiography; NIHSS, National Institutes of Health Stroke Scale; and SBP, systolic blood pressure.

*In 9 patients the occlusion location was considered to be M2 at the moment the decision for EVT was made, but the imaging core laboratory observed an M3 occlusion. Six patients had a proximal occlusion in anterior cerebral artery (A1/A2). There were 12 patients who underwent EVT without a definitive occlusion on CTA according to the core laboratory

†Admission between 5pm and 8am, on weekends, or on a national holiday.

Table 1. Continued

Characteristic<150 min (n=310)

151–270 min (n=850)

271–390 min (n=328)

Table 1. Baseline Characteristics of All Patients According to Time From Onset to Start of EVT

Characteristic<150 min (n=310)

151–270 min (n=850)

271–390 min (n=328)

Age, median (IQR) 69 (60–76) 72 (60–80) 71 (57–81)

Men, n (%) 174 (56) 468 (55) 152 (46)

NIHSS, median (IQR) 16 (11–20) 16 (12–20) 16 (11–20)

Clinical localization: Left hemisphere, n (%)

128 (50) 374 (55) 136 (53)

SBP, mean mm Hg (SD) 146 (23) 150 (24) 151 (26)

Medical history

Diabetes mellitus, n (%)

45 (15) 151 (18) 60 (18)

Hypertension, n (%) 151 (49) 424 (50) 172 (52)

Atrial fibrillation, n (%) 58 (19) 189 (22) 80 (24)

Myocardial infarction, n (%)

51 (16) 132 (15) 45 (14)

Peripheral artery disease, n (%)

27 (9) 83 (10) 25 (8)

Ischemic stroke, n (%) 46 (15) 159 (19) 45 (14)

Prestroke modified Rankin Scale score, n (%)

0 216 (70) 566 (68) 210 (66)

1 39 (13) 104 (12) 46 (14)

2 23 (7) 65 (8) 22 (7)

>2 30 (10) 103 (12) 40 (12)

Medication and intoxications

Statin use, n (%) 109 (35) 237 (28) 87 (26)

Antiplatelet use, n (%) 105 (34) 283 (33) 107 (33)

Current smoking, n (%) 77 (25) 189 (22) 72 (22)

Imaging

Level of occlusion on noninvasive vessel imaging, n (%)

ICA 15 (5) 47 (6) 16 (5)

ICA-T 67 (22) 180 (23) 61 (20)

M1 171 (57) 474 (59) 175 (58)

M2 42 (14) 85 (11) 48 (16)

Other* 1 (0) 2 (1) 1 (1)

ASPECTS subgroups

0–4, n (%) 8 (3) 54 (7) 31 (10)

5–7, n (%) 56 (19) 202 (25) 83 (27)

8–10, n (%) 238 (79) 552 (68) 199 (64)

Collaterals

Grade 0, n (%) 17 (6) 59 (7) 21 (7)

Grade 1, n (%) 88 (30) 268 (34) 105 (35)

Grade 2, n (%) 111 (38) 320 (40) 104 (34)

Grade 3, n (%) 75 (26) 144 (18) 69 (23)

Workflow

Transfers from primary stroke center, n (%)

48 (15) 552 (65) 210 (64)

Off hours, n (%)† 177 (57) 554 (65) 230 (70)

(Continued )


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We also considered the effect of time to reperfu-sion on functional independence for varying defini-tions of reperfusion. We found no time association between time and good outcome in in the eTICI 0 and 1 groups. The strongest association with outcome was found in the eTICI 2C and eTICI3 groups (Table III in the online-only Data Supplement). Despite in-evitable inaccuracies in assessment of onset time we found strong associations with functional outcome. Moreover, other, perhaps more exact time intervals showed similar and significant associations with out-come (Table IV in the online-only Data Supplement). Additional analysis of the association of time using only witnessed stroke onset, leaving out the patients with unwitnessed onset, shows a similar association of time with outcome: adjusted common odds ratio 0.79 (95% CI, 0.71–0.87).

DISCUSSIONIn this study we assessed the association of time with outcome of acute ischemic stroke patients treated with EVT in current clinical practice. Every hour delay from stroke onset to start of EVT resulted in a 5.3% decreased probability of functional independence (mRS

0–2). Every hour that successful reperfusion was de-layed resulted in a 7.7% decreased probability of func-tional independence.

Only 2 studies have described outcome of patients who underwent EVT in the current clinical setting, where EVT is standard of care. The first study did not

Figure 2. Distribution of modified Rankin Scale (mRS) score by 3 time intervals for stroke onset to endovascular treatment start (A), and stroke onset to successful reperfusion (B). eTICI indicates extended thrombolysis in cerebral ischemia; and EVT, endovascular treatment.

Table 2. Association of Time From Onset to Start of EVT With Outcomes and Complications

Outcome Unadjusted Adjusted

mRS at 90 d 0.82 (0.76–0.89) 0.83 (0.77–0.89)

mRS 0–1 at 90 d 0.80 (0.71–0.90) 0.80 (0.71–0.90)

mRS 0–2 at 90 d 0.79 (0.72–0.87) 0.78 (0.70–0.86)

mRS 0–3 at 90 d 0.82 (0.75–0.90) 0.81 (0.73–0.90)

Mortality at 90 d 1.16 (1.05–1.27) 1.16 (1.04–1.29)

Reperfusion during intervention (eTICI score 2B-3)

0.94 (0.87–1.02) 0.94 (0.87–1.02)

Symptomatic intracranial hemorrhage 1.03 (0.86–1.23) 1.01 (0.84–1.21)

eTICI indicates extended thrombolysis in cerebral ischemia; EVT, endovascular treatment; and mRS, modified Rankin Scale.

All analyses were done with continuous time in minutes. Odds ratios per hour of later onset to endovascular treatment are shown, with 95% confidence intervals. Adjustments for age, sex, baseline National Institutes of Health Stroke Scale, and collateral status and additionally for baseline Alberta Stroke Program Early Computed Tomography Score in the analysis of symptomatic intracranial hemorrhage.


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study the effect of time to EVT on functional out-come.25 The second was a large multicenter study in 984 patients treated with 1 type of thrombectomy device (Solitaire or Mindframe), which might not ad-equately represent EVT in the setting of routine clini-cal practice.26

When comparing the association of EVT times with functional outcome to the HERMES meta-analysis (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) of previous randomized EVT trials, our results suggest that the association might be even stronger in routine clini-cal practice. Every hour that EVT was started later resulted in less functional independence at 90 days (5.3% versus 3.4% per hour decline; estimates based on odds ratios in Table 2). Also, for every hour that successful reperfusion was achieved later, there was a larger decline of functional independence in our data than in the HERMES dataset (7.7% versus 5.2%).19 The HERMES data included randomized,

controlled trials only, but the association of time to EVT outcome could only be estimated in the arms of the randomized, controlled trials treated with EVT. From the perspective of our research question the designs of HERMES and the MR CLEAN Registry are similar and differences in patient selection seem the most likely explanation for the stronger time asso-ciation with outcome that we observed in the MR CLEAN Registry.12 Furthermore, no standard selec-tion on additional imaging was performed and there were no collateral or ASPECTS thresholds. Therefore, the data of the MR CLEAN Registry represents in our view the closest estimation of the true time associa-tion with functional outcome in EVT, although pa-tient and time selection in our data cannot be com-pletely excluded.

Our results confirm the following statement in the HERMES meta-analysis regarding time to EVT (statisti-cal analysis plan): “since imaging selection (ASPECTS thresholds, perfusion imaging, and collateral imaging) was used to some degree in many of the enrolled pa-tients, time effects observed in this pooled population are likely less than those that would occur in a popu-lation in which no imaging-selection whatsoever was used.”19 In the DEFUSE 2 trial (Diffusion Weighted Im-aging Evaluation for Understanding Stroke Evolution Study-3), for example, the association between endo-vascular reperfusion and improved functional outcomes was not time dependent in patients with a perfusion–diffusion mismatch.27 This emphasizes that the effect of time to treatment on outcome is diminished in a population in which strict patient selection for EVT has been applied. Additional imaging selection results in a patient population that may be more tolerant to delays in onset to reperfusion. As such, additional imaging se-lection may play an important role in selecting EVT pa-tients who arrive outside the 6-hour time window or af-

Figure 3. Probability of functional independence (modified Rankin Scale [mRS] score 0–2) with margins plot, including 95% confidence intervals. For this analyses time was used as a continuous variable and age, sex, baseline National Institutes of Health Stroke Score, and collaterals score were used for adjustments. A, Time from stroke onset to start of endovascular treatment (EVT). There was a 5.3% decreased probability of functional independence per hour delay. B, Time from stroke onset to successful reperfusion. There was a 7.7% decreased probability of functional independence per hour delay.

Table 3. Association of Time From Onset to Successful Reperfusion (eTICI ≥ 2B; n=742) With Outcomes and Complications

Outcome Unadjusted Adjusted

mRS at 90 d 0·77 (0·69-0·86) 0·79 (0·71-0·88)

mRS 0–1 at 90 d 0·82 (0·71-0·94) 0·84 (0·72-0.98)

mRS 0–2 at 90 d 0·75 (0·66-0·85) 0·74 (0·64-0·85)

mRS 0–3 at 90 d 0·76 (0·68-0·86) 0·74 (0·64-0·85)

Mortality at 90 d 1·26 (1·09-1·46) 1·27 (1·07-1·50)

Symptomatic intracranial hemorrhage

1·16 (0·91-1·49) 1·18 (0·91-1·51)

eTICI indicates extended thrombolysis in cerebral ischemia; and mRS, modified Rankin Scale.

All analyses were done with time as a continuous variable, in minutes. Odds ratios are shown with the accompanying 95% confidence intervals. Adjustments for age, sex, baseline National Institutes of Health Stroke Scale, and collateral status and additionally for baseline Alberta Stroke Program Early Computed Tomography Score in the analysis of symptomatic intracranial hemorrhage.


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ter unwitnessed stroke onset. Strict selection of patients with evidence of salvageable tissue on brain imaging is an approach that could personalize the time window for individual patients and potentially widen the time window for the overall population of stroke patients, as recently shown by the DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) and DEFUSE 3 trials.28,29

Patients who were treated faster had more favorable characteristics in our study: younger age, less atrial fibrilla-tion, lower prestroke mRS, higher ASPECTS, and less likely to receive general anesthesia. Therefore, it can be hypoth-esized that the association of faster EVT with better func-tional outcome is caused by favorable patient prognostic factors. However, as shown in Tables 2 and 3, adjusting for the most important prognostic factors in EVT resulted in very similar associations of EVT times with outcome. Even when extra factors are added (general anesthesia, prestroke mRS, ASPECTS, atrial fibrillation) the association with functional outcome remains almost identical: adjust-ed common odds ratio=0.84 (95% CI, 0.78–0.91), thus the observed confounding is negligible in our data. There-fore, we consider it likely that the effect of unobserved confounding will also be of little importance.

We found a significant association between longer time to treatment and increased mortality, in contrast to HERMES. That our study shows a significant differ-ence could be well explained by the larger sample size and the older patient population. EVT workflow in the MR CLEAN Registry was clearly better than during the MR CLEAN trial. The time interval from onset to start of EVT was decreased by 52 minutes, and the time interval from onset to reperfusion was decreased by 80 minutes on average.30 This improvement was achieved despite the increased number of patients who were transferred from a primary stroke center (55% versus 44% during the MR CLEAN trial). A factor that contributed to the re-duced treatment delays was that no randomization was necessary (with the concurring informed consent proce-dure), which resulted in faster computed tomography-angiography to groin times, after initiation of treatment with intravenous alteplase. Faster onset to EVT times will greatly improve treatment benefit, and it may result in more patients being candidates for EVT.31 These findings emphasize that functional outcome of patients who un-dergo EVT can be greatly improved by shortening onset to treatment times. Therefore, reducing delays in the de-livery of EVT should be a primary objective of all stroke centers that refer or treat patients with acute ischemic stroke.32 At last, given the clear association of time to treatment with functional outcome, this is an important factor in comparing EVT studies and cohorts.

This study has several limitations. Generalizability of our results may be limited because these data originate only from Dutch intervention centers. However, our

broad entry criteria will enhance the generalizability of our results and conclusions. Secondly, it is unknown which possible candidates with large vessel occlusion were not brought to the angiography suite, so a selec-tion of possible EVT candidates cannot be excluded. However, this is one of the few studies in which patients with poor ASPECTS and collateral status were included and treated, which suggests that patients with a poor prognosis were not systematically excluded from EVT. Moreover, inherent to any registry study, nonregistration of treated patients might be an issue. Because registra-tion of treatment was a prerequisite for reimbursement, we think that underregistration is minimal. Finally, these data were gathered in routine clinical practice. Regis-tries in general are prone to missing and incorrect val-ues. However, all data were verified by our study coor-dinators, with particular focus on all entered treatment times. This resulted in a near complete and verified data-set available for this analysis (100% of stroke onset and start of EVT times and 99% of reperfusion times). Fur-thermore, no central outcome adjudication was avail-able for our study, so we relied on local investigators for reporting the functional outcome at 90 days, possibly introducing optimism bias. Optimistic reports from local investigators could have resulted in a larger proportion of patients achieving functional independence. Howev-er, outcome assessment was by stroke or research nurs-es who were not involved in treatment of patients, and was performed according to standard questionnaires.

To conclude, in current clinical practice, every hour delay from acute ischemic stroke onset to start of EVT results in a >5% decreased probability of functional in-dependence (mRS 0–2). Every hour delay of successful reperfusion results in an almost 8% decreased probabil-ity of functional independence. This association might even be stronger than previously suggested in reports on more selected patient populations from random-ized, controlled trials. Our data further emphasize that functional outcome of EVT patients can be greatly im-proved by reducing treatment delays.

ARTICLE INFORMATIONReceived November 16, 2017; accepted March 5, 2018.

The online-only Data Supplement, podcast, and transcript are available as an online-only Data Supplement at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.117.032600/-/DC1.

CorrespondenceMaxim J.H.L. Mulder, MD, PhD, Department of Neurology & Radiology, Erasmus University Medical Center, Room EE-2240 PO 2040, 3000CA Rotterdam, The Netherlands. E-mail [email protected]

AffiliationsErasmus MC, University Medical Center, Rotterdam, The Netherlands (M.J.H.L.M., E.V., V.C., K.C.J.C., B.R., H.F.L., A.v.d.L., D.W.J.D.). Academic Medi-cal Center, Amsterdam, The Netherlands (I.G.H.J., Y.B.W.E.M.R., C.B.L.M.M.). Maastricht University Medical Center and Cardiovascular Research Institute


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Maastricht (CARIM), Maastricht, The Netherlands (R.-J.B.G., R.J.v.O., W.H.v.Z.). Sint Antonius Hospital, Nieuwegein, The Netherlands (W.J.S., J.A.V.). Haa-glanden Medical Center, The Hague, The Netherlands (I.R.v.d.W., J.B.). Leiden University Medical Center, Leiden, The Netherlands (I.R.v.d.W.).

Sources of FundingThe MR CLEAN Registry was partly funded by Toegepast Wetenschappelijk Instituut voor Neuromodulatie (TWIN) Foundation, Erasmus Medical Center University, Maastricht University Medical Center, and Academic Medical Center Amsterdam.

DisclosuresDr Majoie reports grants from Toegepast Wetenschappelijk Instituut voor Neu-romodulatie foundation, during the conduct of the study; grants from Cardio-vasculair Onderzoek Nederland/Dutch Heart Foundation, grants from Stryker, outside the submitted work (paid to institution). Dr van Zwam reports personal fees from Codman, personal fees from Stryker, outside the submitted work. Dr van der Lugt reports consulting fees from Stryker, outside the submitted work. Dr Dippel reports grants from the Dutch Heart Foundation, AngioCare, Medtronic/Covidien/EV3®, MEDAC Gmbh/LAMEPRO, Penumbra Inc, Top Medical/Concentric, and Stryker, during conduct of the study; consultation fees from Stryker, Bracco Imaging, and Servier, received by the Erasmus University Medical Center, outside the submitted work.

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for the MR CLEAN Registry InvestigatorsDippel

W.J.Oostenbrugge, Wim H. van Zwam, Charles B.L.M. Majoie, Aad van der Lugt and Diederik R. van den Wijngaard, Jelis Boiten, Jan Albert Vos, Yvo B.W.EM. Roos, Robert J. van

Chalos, Kars C.J. Compagne, Bob Roozenbeek, Hester F. Lingsma, Wouter J. Schonewille, Ido Maxim J.H.L. Mulder, Ivo G.H. Jansen, Robert-Jan B. Goldhoorn, Esmee Venema, Vicky

Registry ResultsTime to Endovascular Treatment and Outcome in Acute Ischemic Stroke: MR CLEAN

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SUPPLEMENTAL MATERIAL.

Supplemental tables

Supplemental Table 1. Distribution of outcomes and complications according to onset to

start of EVT.

<150

(n=310)

151-270

(n=850)

271-390

(n=328)

mRS at 90 days – median (IQR)\

2 (1-5) 3 (2-6) 4 (2-6)

mRS 0-1 at 90 days – n. (%)* 84 (29) 137 (18) 37 (13)

mRS 0-2 at 90 days – n. (%)* 150 (51) 284 (37) 83 (28)

mRS 0-3 at 90 days – n. (%)* 191 (64) 388 (50) 131 (45)

Mortality at 90 days – n. (%)* 66 (22) 237 (31) 95 (32)

Reperfusion during intervention (eTICI ≥2B) –

n./total n. (%)

152/269

(57)

451/719

(63)

139/278

(50)

Symptomatic intracranial hemorrhage – n (%) 15 (5) 53 (6) 18 (5)

* Of non-imputed outcome data only (n=1363)

Supplemental Table 2. Distribution of outcomes and complications according to onset to

reperfusion, for patients with successful reperfusion (eTICI≥2B).

<180

(n=92)

181-300

(n=426)

>300

(n=224)

mRS at 90 days – median (IQR)* 2 (1-3) 3 (2-5) 3 (2-6)

mRS 0-1 at 90 days – n. (%)* 28 (32) 85 (22) 34 (17)

mRS 0-2 at 90 days – n. (%)* 59 (68) 189 (49) 67 (34)

mRS 0-3 at 90 days – n. (%)* 69 (79) 239 (63) 102 (52)

Mortality at 90 days – n. (%)* 14 (16) 86 (23) 56 (29)

Symptomatic intracranial hemorrhage – n. (%) 1 (1) 28 (7) 10 (4)

* Of non-imputed outcome data only (n=1363)

Supplemental table 3. Association of one hour later time to treatment with good functional

outcome (modified Rankin Scale score 0-2) at 90 days per eTICI score.

Patients

(n)

EVT start Reperfusion or

end of procedure

eTICI = 0 183 0.93 (0.66-1.32) 0.80 (0.58-1.10)

eTICI = 1 48 0.99 (0.49-2.03) 0.53 (0·22-1·29)

eTICI = 2A 292 0.81 (0.65-1.01) 0.68 (0.55-0.84)

eTICI = 2B 239 0.80 (0.62-1.03) 0.82 (0.65-1.03)

eTICI = 2C 125 0.66 (0.46-0.97) 0.67 (0.46-0.97)

eTICI = 3 379 0.73 (0.59-0·91) 0·74 (0.60-0.92)

All analyses were done with continuous times in minutes om patients were actual EVT was performed. Odds

ratios are shown with the accompanying 95% confidence intervals. Adjustments for: age, sex, baseline NIHSS

and collateral score.

Supplemental Table 4. Association of one hour later time to treatment with functional

outcome (modified Rankin Scale score) at 90 days for different time windows.

Median (IQR) Unadjusted Adjusted

Onset to Emergency department 134 (60-189) 0·88 (0·82-0·95) 0·92 (0·85-0·98)

Onset to CT angiography 93 (68-138) 0·93 (0·87-0·99) 0·93 (0·87-0·99)

Onset to reperfusion/last contrast bolus 267 (217-331) 0.75 (0.70-0.80) 0.75 (0.69-0.80)

First emergency department to CT angiography* 28 (20-43) 0·70 (0·53-0·93) 0·73 (0·55-0·97)

Emergency department to start of EVT 63 (42-91) 0·95 (0·84-1·07) 0·85 (0·75-0·97)

Emergency department to successful reperfusion 130 (95-174) 0.91(0.86-0.97) 0.91 (0.86-0.97)

CT angiography to start of EVT 63 (42-91) 0·90 (0·83-0·97) 0·89 (0·82-0·98)

Duration of procedure 63 (40-90) 0·51 (0·43-0·60) 0·48 (0·40-0·59)

*of first hospital

All times are from the intervention Centre, except for emergency department to CT angiography (first

hospital). All analyses were done with continuous times in minutes. Odds ratios are shown with the

accompanying 95% confidence intervals. Adjustments for: age, sex, baseline NIHSS and collateral

score.

Supplemental figures

Figure S1. Distribution of duration from onset to start of EVT (A) and from onset to

successful reperfusion (B). Percentiles (10th,

25th

, 50th

, 75th

and 90th

) are indicated with red

vertical lines.

A

B

A

B

A B

Figure S2. Probability of mortality (non-imputed) with margins plot using time as continuous

variable, with 95% confidence intervals. The analysis is adjusted for age, sex, baseline NIHSS

and collaterals score. There was a 2.2% increase of mortality per hour delay.

Appendix

Executive committee

Diederik W.J. Dippel1;Aad van der Lugt2;Charles B.L.M. Majoie3;Yvo B.W.E.M.

Roos4;Robert J. van Oostenbrugge5;Wim H. van Zwam6;Jelis Boiten14;Jan Albert Vos8

Study coordinators

Ivo G.H. Jansen3;Maxim J.H.L. Mulder

1,2;Robert- Jan B. Goldhoorn

5,6

Local principal investigators

Wouter J. Schonewille7;Jan Albert Vos

8;Charles B.L.M. Majoie

3;Jonathan Coutinho

4;Marieke

J.H. Wermer9;Marianne A.A. van Walderveen

10;Julie Staals

5;Wim H. van Zwam

6;Jeannette

Hofmeijer11

;Jasper Martens12

;Geert J. Lycklama à Nijeholt13

;Jelis Boiten14

;Bob

Roozenbeek1;Bart J. Emmer

2;Sebastiaan F. de Bruijn

15;Lukas C. van Dijk

16;H. Bart van der

Worp17

;Rob H. Lo18

;Ewoud J. van Dijk19

;Jeroen Boogaarts20

;Paul L.M. de Kort21

;Jo

Peluso26

;Jan S.P. van den Berg22

;Boudewijn A.A.M. van Hasselt23

;Leo A.M. Aerden24

;René

J. Dallinga25

;Maarten Uyttenboogaart28

;Omid Eshghi29

;Tobien H.C.M.L. Schreuder30

;Roel

J.J. Heijboer31

;Koos Keizer32

;Lonneke Yo33

;Heleen M. den Hertog34

;Emiel J.C. Sturm35

Imaging assessment committee

Charles B.L.M. Majoie3(chair);Wim H. van Zwam

6;Aad van der Lugt

2;Geert J. Lycklama à

Nijeholt13

;Marianne A.A. van Walderveen10

;Marieke E.S. Sprengers3;Sjoerd F.M.

Jenniskens27

;René van den Berg3;Albert J. Yoo

37;Ludo F.M. Beenen

3;Stefan Roosendaal

3;Bas

van der Kallen13

;Ido van den Wijngaard13

;Ad van Es2;Bart Emmer

2,3;Jasper Martens

12;

Lonneke Yo33

;Jan Albert Vos8; Joost Bot

36, Pieter-Jan van Doormaal

2.

Writing committee

Diederik W.J. Dippel1(chair);Aad van der Lugt

2;Charles B.L.M. Majoie

3;Yvo B.W.E.M.

Roos4;Robert J. van Oostenbrugge

5;Wim H. van Zwam

6;Geert J. Lycklama à Nijeholt

13;Jelis

Boiten14

;Jan Albert Vos8;Wouter J. Schonewille

7;Jeannette Hofmeijer

11;Jasper M.

Martens12

;H. Bart van der Worp17

;Rob H. Lo18

Adverse event committee

Robert J. van Oostenbrugge5(chair);Jeannette Hofmeijer

11;H. Zwenneke Flach

23

Trial methodologist

Hester F. Lingsma38

Research nurses / local trial coordinators

Naziha el Ghannouti1;Martin Sterrenberg

1;Corina Puppels

7;Wilma Pellikaan

7;Rita

Sprengers3;Marjan Elfrink

11;Joke de Meris

14;Tamara Vermeulen

14;Annet Geerlings

19;Gina

van Vemde22

;Tiny Simons30

;Cathelijn van Rijswijk21

;Gert Messchendorp28

;Hester

Bongenaar32

;Karin Bodde24

;Sandra Kleijn34

;Jasmijn Lodico34

; Hanneke Droste34

; Maureen

Wollaert5;Daisy Ramakers

5;Ernas Bos

9;Yvonne Drabbe

15;Marjan Elfrink

11;Berber

Zweedijk17

; Mostafa Khalilzada15

.

PhD / Medical students:

Esmee Venema38

; Vicky Chalos1,2,38

;Kars C.J. Compagne2; Ralph R. Geuskens

3; Tim van

Straaten19

; Saliha Ergezen1; Roger R.M. Harmsma

1; Daan Muijres

1; Anouk de Jong

1; Wouter

Hinsenveld7;Olvert A. Berkhemer

1,3,6;Anna M.M. Boers

3,39; J. Huguet

3;P.F.C. Groot

3;Marieke

A. Mens3;Katinka R. van Kranendonk

3;Kilian M. Treurniet

3;Manon Kappelhof

3;Manon L.

Tolhuijsen3;Heitor Alves

3.

List of affiliations

Department of Neurology1, Radiology

2, Public Health

38, Erasmus MC University Medical

Center;

Department of Radiology3, Neurology

4, Biomedical Engineering & Physics

39, Academic

Medical Center, Amsterdam;


6, Maastricht University Medical Center and

Cardiovascular Research Institute Maastricht (CARIM);


8, Sint Antonius Hospital, Nieuwegein;


10, Leiden University Medical Center;

Department of Neurology11

, Radiology12

, Rijnstate Hospital, Arnhem;

Department of Radiology13

, Neurology14

, Haaglanden Medical Center, the Hague;


, Radiology16

, HAGA Hospital, the Hague;

Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus17

, Radiology18

,

University Medical Center Utrecht;


, Neurosurgery20

, Radiology27

, Radboud University Medical

Center, Nijmegen;


, Radiology26

, Sint Elisabeth Hospital, Tilburg;


, Radiology23

, Isala Klinieken, Zwolle;


, Radiology25

, Reinier de Graaf Gasthuis, Delft;


, Radiology29

, University Medical Center Groningen;


, Radiology31

, Atrium Medical Center, Heerlen;


, Radiology33

, Catharina Hospital, Eindhoven;


, Radiology35

, Medical Spectrum Twente, Enschede;


, VUMC, Amsterdam;


, Texas Stroke Institute, Texas, United States of America;

Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

In this day and age of endovascular treatment for acute ischemic stroke, does time to treatment really matter? Well, we will be discussing results of the MR CLEAN Registry from real-world clinical practice, coming right up after these summaries.

The first original paper this week describes the first mouse model of progerin-induced atherosclerosis acceleration. Progerin is an aberrant protein that accumulates with age, causes a rare genetic disease known as Hutchinson-Gilford Progeria Syndrome. Patients with Progeria Syndrome have ubiquitous progerin expression and exhibit accelerated aging and atherosclerosis, dying in their early teens mainly from myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part due to the lack of appropriate animal models. First author Dr Hamczyk, corresponding author Dr Andrews, and colleagues from CNIC in Madrid performed an elegant series of experiments and generated not only the first mouse model of progerin-induced acceleration of atherosclerosis, but also provided the first direct evidence that progerin expression restricted to vascular smooth muscle cells but not to macrophages was sufficient to induce premature atherosclerosis and death. Progerin-induced loss of vascular smooth muscle cells caused atherosclerotic plaque destabilization that led to myocardial infarction. Ubiquitous and vascular smooth muscle cell specific progerin expression increased LDL retention in aortic media, likely accelerating atherosclerosis.

The next original paper implicates dysregulation of mitochondrial dynamics as a therapeutic target in human and experimental pulmonary arterial hypertension. Now, mitotic fission is increased in pulmonary arterial hypertension. The fission mediator, dynamin-related protein 1, or Drp1, must complex with adaptor proteins to cause fission. In the current paper from co-first authors Dr Chen and Dasgupta, corresponding author Dr Archer from Queens University in Ontario Canada, and colleagues, the authors examined the role of two recently discovered but poorly understood Drp1 adaptor proteins known as mitochondrial dynamics protein of 49 and 51 kilodalton. They found pathological elevation of these mitochondrial dynamic proteins in pulmonary artery smooth muscle cells and endothelial cells in both human and experimental pulmonary arterial hypertension that accelerated mitotic fission and supported rapid cell proliferation. Mitochondrial dynamics protein's expression was epigenetically upregulated by a decreased expression of microRNA-34a-3p. Circulatory microRNA-34a-3p expression was decreased in both patients with pulmonary arterial hypertension and preclinical models, silencing the mitochondrial dynamics proteins or augmenting microRNA-34a-3p regressed experimental pulmonary arterial hypertension, thus, proving to be potential new therapeutic targets for pulmonary arterial hypertension.

Dyslipidemia guidelines currently recommend that non-HDL cholesterol and apolipoprotein B, or apoB, are secondary targets to the primary target of LDL cholesterol. However, how frequently does non-HDL cholesterol guideline targets change management, and what is the utility of apoB targets after meeting LDL and non-HDL targets?

Well, answers are provided in the next paper from first author Dr Sathiyakumar, corresponding author Dr Martin, and colleagues from Johns Hopkins University School of Medicine. These authors analyzed more than 2,500 adults in the US National Health and Nutrition Examination Survey, as well as more than 126,000 patients from the Very Large Database of Lipids Study with apoB. They identified all individuals as well as those with high-risk clinical features, including coronary disease, diabetes, and metabolic syndrome who met the very high and high-risk guidelines targets of LDL cholesterol of less than 70 and less than 100 mg/dL, respectively, and this was measured using either the Friedewald estimation or a novel, more accurate method. They found that after using the more accurate method of estimating LDL cholesterol, guidelines suggested non-HDL targets could alter management in only 1 to 2% of individuals, including those with coronary disease and other high risk clinical features.

However, using the Friedewald estimated LDL cholesterol gave a much higher percentage. Among all individuals with both LDL cholesterol less than 100 and non-HDL cholesterol less than 130 mg/dL, only 0-0.4% had an apoB above or equal to 100 mg/dL. Thus, the utility of current non-HDL targets appears to be contingent on the accuracy of LDL cholesterol estimation. When using a novel, more accurate estimation method to assess LDL cholesterol, the non-HDL cholesterol is infrequently above current guidelines' suggested targets after the LDL target is met. Current guidelines suggest that apoB targets also provide only modest utility after cholesterol targets are met. These findings were robust to high-risk clinical features, sex, fasting status, and presence of lipid-lowering therapies.

The final paper tells us that HIV infection increases the risk of developing peripheral artery disease. Dr Beckman from Vanderbilt University Medical Center and colleagues studied almost 92,000 participants in the Veterans Aging Cohort Study from 2003-2014 over a median follow-up of nine years. They excluded participants with known prior peripheral artery disease or prevalent cardiovascular disease. They found that infection with HIV was associated with a 19% increased risk of incident peripheral artery disease beyond that explained by traditional atherosclerotic risk factors. Once peripheral artery disease had developed, HIV infection increased the risk of mortality compared to uninfected patients. Whereas for those with sustained CD4 cell counts above 500, there was no excess risk of incident peripheral artery disease events compared to uninfected people. Furthermore, worsening HIV infection as measured by CD4 cell count and HIV viral load was associated with increased incident peripheral artery disease and mortality. In summary, HIV infection increased the risk of developing peripheral artery disease and mortality. The findings also suggest that aggressive antiretroviral therapy to reduce viral load and increase CD4 cell

counts may reduce the risk of developing peripheral artery disease. Furthermore, clinicians should solicit clinical complaints and physical signs consistent with peripheral artery disease to facilitate the diagnosis of peripheral artery disease in patients with HIV and ensure the addition of guideline-based anti-atherosclerotic therapies in these patients.

Well, that wraps it up for our summaries. Now for our feature discussion.

When it comes to acute ischemic stroke treatment, we've learned from trials of intravenous thrombolytics that time is brain. But what about the situation with endovascular treatment of strokes? Also, what's the situation like in the real world? Well, today's featured paper really provides precious data telling us about time-to-endovascular treatment and outcomes in acute ischemic stroke. I am so delighted to have with us the first and corresponding author of the MR CLEAN Registry, Dr Maxim Mulder from Erasmus University Medical Center, as well as our editorialist, Dr Micheal Hill, from University of Calgary, and our associate editor, Dr Graeme Hankey, from University of Western Australia, all here to discuss this hugely important topic.

Maxim, could we start with you? So, MR CLEAN Registry means there was a MR CLEAN trial. Could you tell us a little bit more about your paper?

Dr Maxim Mulder: Sure, well to start with, I think it's important to make sure all the people know the difference between the MR CLEAN trial and the registry since of course the trial was to show whether the intra-arterial treatment is effective when it comes to acute ischemic stroke treatments and then, of course, for people treated within six hours. When the MR CLEAN trial finished we continued in the Netherlands with all the participating centers from the trial to gather all the data from everybody who is treating in the whole country with the intra-arterial treatment, but they're not anymore in the light of the trial but in the clinical practice. We've had a lot of trials, but we don't have a lot of clinical practice date yet of the intra-arterial treatment, so that's where it all started.

So, what we found is we consider our data, so with the least possible selections or the only selection was basically to treat within six and a half hours and have patients that had a proven large vessel occlusion that were treated in the Netherlands and of course as we also know from when intravenous therapy was introduced that what happens in clinical trials doesn't necessarily happen when a new treatment is introduced into clinical practice. There are less strict criteria for patients to get treated, and you know everybody, of course, there is a lot of debate about which patients should be treated. In clinical trials it is very strictly coordinated, but in clinical practice there's a lot more room to have an interpretation and also treat a different population. So, we also see that our population is somewhat older and has more comorbidities than in all the trials. Also what we found, of course, our most important finding was that when compared to all the trials or the large trials combined together in the Emberson analysis about time that when we look at the influence or the association of

time with functional outcome of intra-arterial treatment that this association is clearly stronger than we found in the previous, the trial data.

So, I think that's a very important finding. Also, for everybody who's now treating this patient in clinical practice.

Dr Carolyn Lam: Exactly. I mean this is really stunning results. If I could paraphrase from your paper, every hour delay in time from stroke onset to the start of endovascular treatment resulted in a 5.3% decreased probability of functional independence and a 2.2% increase in mortality. This is stunning. Thank you, thank you for publishing these results with us in Circulation. I would like to ask Michael, I love the point you made in the editorial that time of stroke onset is really quite a difficult thing to determine. Could you tell us your thoughts about that, Michael?

Dr Micheal Hill: I mean, it's something like 15-20% of the time stroke is unwitnessed, either because stroke occurs in sleep and the patient is discovered with their stroke symptoms on awakening. Or the patient is simply alone and has their stroke unwitnessed by any bystander. Even in so-called witness stroke, there are probably significant errors in determining the exact time of stroke onset because it's an emergency, and everybody's flustered and time anchors are not necessarily well known. And, so, I think it's an important point that the actual measurement of time is challenging, yet it's still an easier clinical tool for us to use in gauging the extent or evolution of stroke. That's the most important thing to point out here is that this population effect that Max has observed in the MR CLEAN registry is certainly concordant with clinical trial data.

I certainly think it's correct, and, as you pointed out in your comments, dramatic, but a really important issue is that for the individual patient, there's quite a lot of variance in the evolution of stroke. So, whereas, on a population basis, it's absolutely true that the average time from estimated time of stroke onset to treatment initiation is absolutely critical; in some patients, the individual might be still a good candidate for treatment even in late time windows, and some patients, even after a couple hours, the damage is already extensive, and they may not be good candidates for treatment. It still requires individual decision making, and it still leaves a lot of room for clinical judgment largely based on imaging.

Dr Carolyn Lam: True, and I think you've really succinctly put that solid take-home message in the title really, which is acute ischemic stroke biology really demands fast treatment. I think that's the one thing that we'd really like clinicians to come away with. You agree?

Dr Micheal Hill: Absolutely. Especially, I think, the advantage of looking at whole populations and large, I mean this is a large registry, the MR CLEAN registry, and the group should be congratulated because it's clearly the biggest registry in the world right now of available data, and it's only getting larger week by week as they carry on with their work. You know the whole Netherlands group, the MR

CLEAN group, are a fantastic group, but absolutely right, on a population basis, we absolutely have to get our systems in place so that on average we're treating patients incredibly fast. On an individual basis, the clinicians and the teams treating an individual patient still need to make judgments about that patient's eligibility for treatment. It's easy when the times are fast, so if you're an hour and a half from onset, nearly everybody's gonna be a good candidate for treatment, but as time elapses you need to make judgements on the basis of imaging.

Dr Carolyn Lam: Well put. You know, Graeme, you're over there in Australia. What are your take-home messages about how generalizable these findings are to places outside perhaps of the Netherlands?

Dr Graeme Hankey: I think you're asking about the external validity. I think the internal validity is certainly there. As Michael said, this is the largest registry that we have that's been published data on this before. It's certainly novel, and we're very confident that the results are valid, although this is an observational study and not a randomized trial. The association between time and outcome seems to be independent of the major patient factors that may influence time to endovascular therapy. For example, younger people who are less frail and they're alert and they're mobile can get to treatment earlier. So, you might say, well of course they're gonna have a better outcome. But these factors were adjusted for. And, of course, there are procedural factors that could influence the association between time and outcome, but we're very confident in the results and the novelty of them in supporting and building on the randomized trial data.

We're also very confident in the registry and the nature of the population. The results are likely to be generalizable beyond the Netherlands population where this was conducted in routine clinical practice, certainly across Caucasian populations that are similar and with similar stroke interventional and assessment protocols, and I would hope to see this sort of study validated externally in other populations. But, also, as Michael said, I think this study not just highlights the importance of time as a factor and its implications for systems of care and recognizing people with disabling stroke and ensuring they’re assisted urgently to the appropriate imaging but also to acknowledge that time isn't the only factor. And as Michael has alluded to, our brain tissue has different collateral circulations and different probable genetic factors and metabolic factors. So, someone with a stroke at one hour, it might be all over for them. Whereas, another person with a stroke at 24 hours ago, they might have salvageable tissue.

So, although, generally time is an important prognosticator as we've learned here, there are probably other factors that need to be considered and accounted for. But this certainly takes us a step forward, and, in answer to your question, I think we have confidence in its generalizability.

Dr Carolyn Lam: Thank you Graeme. Maxim, in line with that, are there any next steps you plan?

Dr Maxim Mulder: In light of the most recent trials, the DAWN and DEFUSE 3 trial about 6 to 25-hour, 24-hour window, I think that both of the trials are very exciting, and they shine a new light into a new set of patients that are still able to offer a great benefit intra-arterial treatment. In my opinion, the most important thing, especially in those two trials, those are highly selective patients, especially selected on all the extra imaging parameters, and I guess that there's a whole larger population that could still benefit in this time window and that's also one of the things we're currently studying in one of our new trials in the Netherlands in the MR CLEAN-LATE trial, and that is randomizing patients who are having a large vascular occlusion 6 to 24 hours, and the only extra criteria they should meet is they should have at least a little bit of collateral circulation on the ischemic brain side.

Dr Carolyn Lam: Michael and Graeme, what do you think are the priorities for next steps in research.

Dr Micheal Hill: I guess overall in the field, I don't think there's any doubt that faster treatment is better. What we need to do across the world is make sure that everybody's receiving it on a system-wide basis. Right? I think there needs to be a lot of more careful work done on getting systems of care in place to make sure that patients are getting the treatment they can get. We have very many weaknesses. Some are related to lack of accreditation. Some are related to the resources required to get people treated quickly. Some are related to continuing resistance in some specialties to even giving intravenous thrombolytic drugs. So, I think faster treatment in general for acute stroke is a theme; it's not just limited to endovascular treatment. It's treatment for patients for intravenous thrombolysis. It's also actually true for TIA and minor stroke. We've had recent data on fast antiplatelet therapy, so, it's not an emergency in the same way in terms of minutes, but it's still a general theme of acute stroke care.

We need to be like the Ferraris and the Formula One, right? And get ourselves moving. That's a big challenge for people. Right? It's a big stress on systems. But, I think there are other examples in medicine. We've seen this evolution in acute coronary care, and we've seen the evolution in acute trauma care. In many ways, the next things that need to really continue to happen are publications like this and getting the message out that people need to start changing their mind. The biggest thing that I find when I talk to people or talk at meetings or talk to administrators is that they say, "Well, we can't do this many CTs that fast. We can't respond that fast." And the answer is actually that you can't change the biology of the disease, so if you decide you wanna treat stroke patients, you better figure out how to change your systems. It's a question of will here rather than trying to bend the disease to the system.

Dr Carolyn Lam: Wonderfully put. Can't change the biology so we better change the systems. How about you, Graeme? Any last words?

Dr Graeme Hankey: Just to concur with Michael’s comments there and Max's underlying theme that time is very important. And as Michael alludes to, it's not just acute ischemic

stroke due to large vascular disease, it's also acute intracerebral hemorrhage. We're learning now really if we're gonna have an effect in the bleeding brain probably we have to do that within the first three hours and maybe not be waiting so late. And as Michael alludes to, someone with a minor ischemic stroke who's had a hot volcano gone off in their neck, as you know, ruptured atherosclerotic plaque, it's like those volcanoes in Hawaii, they're gonna keep going off again. And the risk is 5% in the next two days and 10% in the next week. So, a TIA and a mild ischemic stroke, it is a medical emergency to find the cause and to get it treated, and that's why the synopsis of this message from Max's study is that people, if they do avail themselves of acute assessment early, even if they don't have a large vessel occlusion causing an ischemic stroke, they may actually have their intracerebral hemorrhage treated quickly or, more evidence based at the moment, their TIA or mild ischemic stroke have the cause ascertained and treated emergently and reduce that early risk of recurrence should they survive.

Dr Carolyn Lam: Excellent points. Thank you so much, gentlemen. This has been an amazing podcast.

Thank you so much for joining us today. Don't forget to tune in again next week, listeners.

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