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. 2024 Jun 3;81(7):752–761. doi: 10.1001/jamaneurol.2024.1562

Time From Hospital Arrival Until Endovascular Thrombectomy and Patient-Reported Outcomes in Acute Ischemic Stroke

Raed A Joundi 1,2,✉, Eric E Smith 3,4,5, Aravind Ganesh 3,4,5, Raul G Nogueira 6, Ryan A McTaggart 7, Andrew M Demchuk 3,5,8, Alexandre Y Poppe 9, Jeremy L Rempel 10, Thalia S Field 11, Dar Dowlatshahi 12, Jim Sahlas 13, Richard Swartz 14, Ruchir Shah 15, Eric Sauvageau 16, Volker Puetz 17,18, Frank L Silver 19, Bruce Campbell 20, René Chapot 21, Michael Tymianski 22, Mayank Goyal 3,8, Michael D Hill 3,4,5,8,23, for the ESCAPE-NA1 Investigators
PMCID: PMC11148789  PMID: 38829660

This cohort study investigates the association between treatment time to endovascular thrombectomy for large vessel occlusion stroke and patient-reported quality of life.

Key Points

Question

Is faster treatment with endovascular thrombectomy in large vessel occlusion stroke associated with improved patient-reported quality of life?

Findings

In this secondary analysis of 1043 patients from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, faster time from hospital arrival to endovascular thrombectomy was associated with improved self-reported mobility, usual activities, self-care, pain or discomfort, anxiety or depression, and overall quality of life.

Meaning

Results of this cohort study suggest that faster treatment with endovascular thrombectomy was associated with a substantial improvement in outcomes from the perspective of the patient.

Abstract

Importance

The time-benefit association of endovascular thrombectomy (EVT) in ischemic stroke with patient-reported outcomes is unknown.

Objective

To assess the time-dependent association of EVT with self-reported quality of life in patients with acute ischemic stroke.

Design, Setting, and Participants

Data were used from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, which tested the effect of nerinetide on functional outcomes in patients with large vessel occlusion undergoing EVT and enrolled patients from March 1, 2017, to August 12, 2019. The ESCAPE-NA1 trial was an international randomized clinical trial that recruited patients from 7 countries. Patients with EuroQol 5-dimension 5-level (EQ-5D-5L) index values at 90 days and survivors with complete domain scores were included in the current study. Data were analyzed from July to September 2023.

Exposure

Hospital arrival to arterial puncture time and other time metrics.

Main Outcomes and Measures

EQ-5D-5L index scores were calculated at 90 days using country-specific value sets. The association between time from hospital arrival to EVT arterial-access (door-to-puncture) and EQ-5D-5L index score, quality-adjusted life years, and visual analog scale (EQ-VAS) were evaluated using quantile regression, adjusting for age, sex, stroke severity, stroke imaging, wake-up stroke, alteplase, and nerinetide treatment and accounting for clustering by site. Using logistic regression, the association between door-to-puncture time and reporting no or slight symptoms (compared with moderate, severe, or extreme problems) was determined in each domain (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) or across all domains. Time from stroke onset was also evaluated, and missing data were imputed in sensitivity analyses.

Results

Among 1105 patients in the ESCAPE-NA1 trial, there were 1043 patients with EQ-5D-5L index values at 90 days, among whom 147 had died and were given a score of 0, and 1039 patients (mean [SD] age, 69.0 [13.7] years; 527 male [50.7%]) in the final analysis as 4 did not receive EVT. There were 896 survivors with complete domain scores at 90 days. There was a strong association between door-to-puncture time and EQ-5D-5L index score (increase of 0.03; 95% CI, 0.02-0.04 per 15 minutes of earlier treatment), quality-adjusted life years (increase of 0.29; 95% CI, 0.08-0.49 per 15 minutes of earlier treatment), and EQ-VAS (increase of 1.65; 95% CI, 0.56-2.72 per 15 minutes of earlier treatment). Each 15 minutes of faster door-to-puncture time was associated with higher probability of no or slight problems in each of 5 domains and all domains concurrently (range from 1.86%; 95% CI, 1.14-2.58 for pain or discomfort to 3.55%; 95% CI, 2.06-5.04 for all domains concurrently). Door-to-puncture time less than 60 minutes was associated higher odds of no or slight problems in each domain, ranging from odds ratios of 1.49 (95% CI, 1.13-1.95) for pain or discomfort to 2.59 (95% CI, 1.83-3.68) for mobility, with numbers needed to treat ranging from 7 to 17. Results were similar after multiple imputation of missing data and attenuated when evaluating time from stroke onset.

Conclusions and Relevance

Results suggest that faster door-to-puncture EVT time was strongly associated with better health-related quality of life across all domains. These results support the beneficial impact of door-to-treatment speed on patient-reported outcomes and should encourage efforts to improve patient-centered care in acute stroke by optimizing in-hospital processes and workflows.

Introduction

Endovascular thrombectomy (EVT) is a highly effective therapy in acute ischemic stroke with large vessel occlusion (LVO).1 EVT results in higher odds of functional independence at 90 days as measured by the modified Rankin Scale (mRS) and is associated with better health-related quality of life.1,2 However the effect of EVT is highly time dependent, whereby faster treatment from stroke onset improves reperfusion and clinical outcomes.3,4,5,6 Thus far, the time-dependent impact of EVT has been demonstrated with the mRS, a clinician-reported scale.4,6 The mRS is a commonly used, flexible, global outcome rating scale that broadly captures disability. Although patient symptoms are often elicited to determine the mRS score, information can also be obtained from caregivers and family, the medical record, and the physician’s clinical impression, which may introduce bias and assumptions. The mRS is also heavily focused on mobility, and although it is likely that other factors indirectly affect scores, it does not directly assess other important domains such as pain or emotional health. Given the multidimensional debilitating impact of LVO stroke, effective acute stroke management should be measured not only on improving physical functioning but also on ameliorating patients’ health status across multiple domains.2,7

Developing a comprehensive evaluation of patient-centered outcomes in the context of EVT treatment time—a powerful driver of outcome in LVO stroke—would enrich our understanding of the impact of treatment speed on patients’ lives. It is fundamentally important to consider the patient’s perspective when implementing interventions or systems changes. Demonstration of such an association between time to treatment and patient-reported quality of life would provide further impetus for quality improvement initiatives for stroke workflow using patient-reported outcome measures.

We sought to determine whether time to treatment with EVT was associated with improvement in patient-reported health-related quality of life in a large sample of patients receiving EVT for proximal occlusion in the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial.

Methods

This study was a secondary analysis of the ESCAPE-NA1 trial,8 a multicenter, double-blind, randomized clinical trial that investigated the safety and efficacy of intravenous nerinetide in patients with acute ischemic stroke due to large vessel occlusion who were undergoing EVT.9 The ESCAPE-NA1 trial enrolled patients with acute ischemic stroke due to occlusion of the internal carotid artery (ICA) and/or M1 segment of the middle cerebral artery (MCA). Patients were required to be previously functionally independent (Barthel Index score >90), have an Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS) of 5 or greater, and moderate to good collateral circulation. Noncontrast CT and multiphase CT angiography were completed on all patients at the endovascular center. Patients were enrolled up to 12 hours from last known well, and all patients underwent EVT. The ESCAPE-NA1 study was approved by the ethics board at each site and by the responsible regulatory authorities. Signed informed consent was obtained from the patients, their legally authorized representative, or, if required by applicable national laws or regulations for obtaining consent, from the investigator after consultation with an independent physician who was not otherwise participating in the trial. The full study protocol accompanies the main trial publication.9 The current study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

All participants had standard assessment of demographics, medical history, laboratory values, and stroke severity using the National Institutes of Health Stroke Scale (NIHSS) at baseline. Participants self-identified with the following racial groups: American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, and other (ie, race cannot be determined, does not fit the current categories, was not reported by the patient, or local regulations do not allow reporting). Due to small participant numbers in some groups, this analysis reports data on Asian, White, and all other racial groups combined. Clinic follow-up was obtained in-person at 30 and 90 days from randomization, or video or telephone conference when in-person follow-up was not possible. In-person follow-up was done in 95% of patients, and the remainder had virtual follow-up. The EuroQol 5-dimension 5-level (EQ-5D-5L) score was collected at 30 and 90 days by trained personnel unaware of group assignment. The EQ-5D-5L questionnaire is a standardized measure of health-related quality of life developed in 2009 and has better performance compared with the EuroQol 5-dimension 3-level scale.10 The descriptive system includes 5 dimensions: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression, and each dimension has 5 ordered categorical levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ-5D-5L also contains a visual analog scale (EQ-VAS) and a vertical scale or “thermometer” that takes values between 0 (worst imaginable health) and 100 (best imaginable health) on which patients provide a global subjective assessment of their health. Coordinators were instructed that the EQ-5D-5L questionnaire had to be completed by the participant. Therefore, if the patient was unable to respond themselves, then no proxy response was collected.

Statistical Analyses

Country-specific value sets have been developed for the EQ-5D-5L questionnaire, which reflect the preference of representative samples of the public. The scoring algorithms use responses to each of the 5 levels to generate a single number that represents a unique health state ranging from under 0 (state worse than dead), through 0 (equivalent to dead), to 1 (perfect health), and define a total of 3125 health states. In order to reflect local preferences and perceptions of health, we used published value sets for each of the participating countries (Canada, US, Korea, Ireland, Sweden, and Germany) to calculate EQ-5D-5L index score at 90 days.11,12,13,14,15,16 At the time of analysis, there were no published value sets for Australia; therefore, the Canadian value set was used instead. We assigned those who died by 90 days a value of 0 on the EQ-5D-5L scale by convention as preference-based measures are anchored at full health (1) and dead (0).

For 90-day survivors who had missing EQ-5D-5L data, we carried forward responses from 30-day follow-up if they were available. This was done to prioritize the patient’s last self-reported status over an imputed response. The intraclass correlation coefficient was high (0.83, 95% CI, 0.81-0.86) between 30- and 90-day EQ-5D-5L among those with recorded 30- and 90-day values. We used proportions to describe the number of participants at each descriptive level, and medians and histograms for the EQ-5D-5L index score. For descriptive analyses, we stratified by EVT hospital arrival to arterial-access time (door-to-puncture time) of less than 60 minutes compared with 60 minutes or longer. We chose this cutoff point due to recommendations of door-to-puncture time of less than 60 minutes17 and because this value was the median in our dataset. Due to the skewed distribution of the EQ-5D-5L and nonnormality of residuals with multiple linear regression, we modeled the association of time to treatment with median EQ-5D-5L score using quantile regression.

In a meta-analysis from the Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke (HERMES) trials collaboration, the impact of time to treatment on healthy life-years lost was greatest when analyzing door-to-puncture time in both early and late presenters. In contrast, the effect of time-to-treatment from stroke onset was weak overall and nonsignificant in late presenters, likely due to a systematic bias toward the null when including more patients with wake-up stroke (ie, stroke on awakening) or unwitnessed-onset strokes and less fast progressors.6 For this reason, we focused our main analysis on hospital arrival-to-arterial-puncture time (door-to-puncture time), in addition to the fact that door-to-puncture time can be more directly modified. We did secondary analysis on time from stroke onset (onset-to-puncture time). We determined the association between continuous door-to-puncture time (up to the 99th percentile of data at 200 minutes) and EQ-5D-5L index score, adjusting for age, sex, wake-up stroke, NIHSS score, ASPECTS score, site of occlusion, receipt of nerinitide, and receipt of alteplase, specifying that SEs allow for intragroup correlation to account for clustering by site. There was no evidence of intraclass correlation (P < .05 for all models).18 As the ESCAPE-NA1 trial showed no overall difference between treatment groups and the focus of this secondary analysis was not on nerinitide, we included both nerinitide and placebo groups in this study and adjusted for treatment arm. We assessed for modification by age, sex, NIHSS score, nerinitide, alteplase treatment, affected hemisphere, and wake-up stroke. In sensitivity analyses, we (1) used multiple imputation for missing EQ-5D-5L data at 90 days, (2) additionally adjusted for self-declared race and diabetes due to observed differences at baseline, and (3) evaluated the impact of stroke onset-to-arterial puncture time and other time metrics (onset-to-reperfusion, door-to-reperfusion, CT-to-puncture, and CT-to-reperfusion time). We also multiplied the EQ-5D-5L index score by published age-, sex-, and mRS-specific life expectancies19 to obtained quality-adjusted life-years (QALYs) and performed the same analysis. We performed the same assessment for the EQ-VAS.

To establish the association of treatment time with individual self-reported domains, we used logistic regression to model and plot the predicted probability of achieving level 1 or 2 (no problems or slight problems) compared with moderate to extreme problems in each domain among survivors at 90 days, by continuous door-to-puncture time and adjusted for the same variables. We also evaluated and plotted the probability of achieving no or slight problems on all domains concurrently. To quantify the impact of time with odds ratios (ORs) we evaluated the association of door-to-puncture time less than 60 minutes, compared with 60 minutes or longer, on reporting no or slight problems in each domain. From the absolute probabilities of no or slight problems in each time category, we calculated absolute risk reduction (ARR) and numbers needed to treat (NNT).

We did a sensitivity analysis using multiple imputation for missing data. EQ-5D-5L data were likely missing due to many known and unknown reasons. We observed that age, stroke on awakening, severe aphasia at baseline (score 2-3 on item 9 of the NIHSS score), and 90-day mRS score were associated with missing 90-day EQ-5D-5L responses; 69% of those with missing data were mRS 4 or 5 at 90 days compared with 12% who were not missing. We used multiple imputation with chained equations20 using ordinal regression to replace missing EQ-5D-5L domain scores. We created 20 imputed datasets as this ensured that the least replicable SE in the output would change by less than 5% if data were imputed again.21 Variables in the model were those included in the main models previously described, in addition to severe aphasia and 90-day mRS score. Visual inspection of the replaced values was done to ensure face validity. New variables for no or slight problems and the EQ-5D-5L index score were generated from the imputed values. Then, the models were repeated on the imputed data, adjusting coefficients and SEs of the estimates for the variability between imputations according to Rubin rules.22 Statistical analysis of study data was performed using Stata software, version 17.0 (StataCorp). A 2-sided P value <.05 was considered statistically significant. Data were analyzed from July to September 2023.

Results

In total, 1105 patients were enrolled in the ESCAPE-NA1 trial between March 2017 and August 2019. There were 1043 patients with EQ-5D-5L index values at 90 days, among whom 147 (13.3%) had died and were given a score of 0, and 1039 patients (mean [SD] age, 69.0 [13.7] years; 512 female [49.3%]; 527 male [50.7%]) in the final analysis as 4 did not receive EVT. Participants self-identified with the following race and ethnicity groups: 95 Asian (9.1%), 841 White (80.9%), and 103 other (9.9%). Among 90-day survivors, 91 had missing EQ-5D-5L data, and 30 of these had responses at the 30-day point that were brought forward (29 for anxiety or depression), leaving 897 domain responses (896 for anxiety or depression) in the main analysis. There were 896 survivors with complete domain scores (eFigure 1 in Supplement 1). Median (IQR) door-to-puncture time was 59 (42-84) minutes, and 529 of 1039 patients (50.9%) received EVT within 60 minutes. Median (IQR) NIHSS score was 17 (12-21), and median (IQR) ASPECTS score was 8 (7-9) (eTable 1 in Supplement 1). The following factors were associated with missing EQ-5D-5L score at 90 days: older age, wake-up stroke, severe aphasia at baseline, and higher 90-day mRS score (eTable 2 in Supplement 1).

Baseline characteristics of included patients stratified by door-to-puncture time of 60 minutes are shown in eTable 1 in Supplement 1. Compared with those with a door-to-puncture time of 60 minutes or longer, those with door-to-puncture time less than 60 minutes were more likely to be White (465 of 529 [87.9%] vs 376 of 510 [73.7%]), less likely to have type 2 diabetes (82 of 529 [15.5%] vs 112 of 510 [22.0%]), more likely to have ICA occlusion (116 of 529 [21.9%] vs 79 of 510 [15.5%]), and less likely to have stroke on awakening (71 of 529 [13.4%] vs 92 of 510 [18.0%]). Rates of treatment with alteplase and nerinetide were similar between the 2 groups. Median (IQR) EQ-5D-5L index score was 0.86 (0.65-0.94) in those with door-to-puncture times less than 60 minutes and 0.78 (0.28-0.91; P < .001) in those with door-to-puncture times of 60 minutes or longer. The distribution of EQ-5D-5L values is shown in Figure 1. Patients had higher EQ-5D-5L values when receiving EVT within 60 minutes compared with those receiving EVT 60 minutes or longer from hospital arrival and a lower number who were assigned a score of 0 due to having died.

Figure 1. Distribution of EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index Scores For Patient Door-to-Puncture Times.

Figure 1.

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Patients with times <60 minutes had substantially higher index scores. The large number of zeroes is due to patients who died by 90 days. Bins are in 0.02 increments.

There was a significant association between door-to-puncture time and adjusted median EQ-5D-5L index score (increase of 0.03; 95% CI, 0.02-0.04 per 15 minutes of earlier treatment) (Figure 2A and eTable 3 in Supplement 1). There was a similar association for QALYs (increase of 0.29; 95% CI, 0.08-0.49 per 15 minutes of earlier treatment) (Figure 2B) and for the EQ-VAS (increase of 1.65; 95% CI, 0.56-2.72 per 15 minutes of earlier treatment) (Figure 2C; eTable 3 in Supplement 1). Results were essentially identical when adjusting for race and diabetes, and there was no significant modification of the time effect by age, sex, NIHSS score, nerinitide, alteplase treatment, or affected hemisphere.

Figure 2. Association Between Continuous Door-to-Puncture Times and EuroQol 5-Dimension 5-Level (EQ-5D-5L), Quality-Adjusted Life-Years (QALYs), and EQ–Visual Analog Scale (VAS).

Figure 2.

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Faster door-to-puncture treatment time was associated with higher predicted EQ-5D-5L index score for all patients (A), and with higher QALYs (B) and EQ-VAS (C). Shaded areas represent 95% CIs. Predicted probabilities obtained from quantile regression models, adjusted for age, sex, wake-up stroke, National Institutes of Health Stroke Scale, Alberta Stroke Program Early Computed Tomography Score, site of occlusion, receipt of nerinitide, and receipt of alteplase.

There was a clear shift toward the favorable levels of each domain when door-to-puncture time was less than 60 minutes (Figure 3A-E). There was also a favorable shift for total number of domains with no or slight impairment (Figure 3F). Faster door-to-puncture time was associated with higher predicted probability of no or slight problems in each of the 5 domains with an increase in probability per 15 minutes of earlier treatment (mobility: 2.80%; 95% CI, 1.72-3.88; self-care: 2.20%; 95% CI, 1.32-3.08; usual activities: 2.58%; 95% CI, 1.50-3.66; pain or discomfort: 1.86%; 95% CI, 1.14-2.58; anxiety or depression: 2.67%; 95% CI, 1.36-3.99; all domains concurrently: 3.55%; 95% CI, 2.06-5.04) (Figure 4A-E and eTable 3 in Supplement 1). There was greater probability of reporting no or slight problems in all domains concurrently with earlier door-to-puncture time (3.6%; 95% CI, 2.1-5.0 increase per 15 minutes of earlier treatment) (Figure 4F and eTable 3 in Supplement 1).

Figure 3. Percentage of Patients in Each Domain Level Stratified By Door-to-Puncture Time.

Figure 3.

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A, Mobility. B, Self-care. C, Usual activities. D, Pain or discomfort. E, Anxiety or depression. F, No or slight problems across all 5 domains. Domain levels are as follows: 1 = no problems, 2 = slight problems, 3 = moderate problems, 4 = severe problems, and 5 = extreme problems. When door-to-puncture was less than 60 minutes, there was a higher percentage of patients with no or slight problems in each domain and in all domains concurrently.

Figure 4. Association Between Continuous Door-to-Puncture Time and Predicted Probability of Reporting No or Slight Problems .

Figure 4.

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A, Mobility. B, Self-care. C, Usual activities. D, Pain or discomfort. E. Anxiety or depression. F, All domains concurrently. Shaded areas represent 95% CIs. Predicted probabilities obtained from logistic regression models, adjusted for age, sex, wake-up stroke, National Institutes of Health Stroke Scale, Alberta Stroke Program Early Computed Tomography Score, site of occlusion, receipt of nerinitide, and receipt of alteplase.

There was a stronger association of hospital-based, including door-to-puncture (0.03 higher EQ-5D-5L index score per 15 minutes of earlier treatment; 95% CI, 0.02-0.04) or door-to-reperfusion (0.02; 95% CI, 0.01-0.03), CT-to-puncture (0.03; 95% CI, 0.02-0.04) or CT-to-reperfusion (0.02; 95% CI, 0.01-0.03), compared with prehospital-based onset-to-puncture (0.003; 95% CI, 0.001-0.005) and onset-to-reperfusion (0.003; 95% CI, 0.001-0.005) (eTable 3 and eFigure 2 in Supplement 1) with EQ-5D-5L index score, but all were significant. Associations of onset-to-puncture time with EQ-5D-5L domains were only significant for mobility (0.26% per 15 minutes of earlier treatment; 95% CI, 0.005-0.51). When stratifying by wake-up stroke, the association with EQ-5D-5L index score was significant only for non–wake-up stroke (0.003; 95% CI, 0.0004-0.006); however, the interaction by wake-up stroke was not significant (eTable 3 and eFigure 3 in Supplement 1).

Treatment with EVT within 60 minutes of arrival to hospital, compared with 60 minutes or longer, was associated with higher odds of reporting no or slight problems in mobility (adjusted OR [aOR], 2.59; 95% CI, 1.83-3.68), self-care (aOR, 2.42; 95% CI, 1.68-3.48), usual activity (aOR, 2.0; 95% CI, 1.54-2.59), pain or discomfort (aOR, 1.49; 95% CI, 1.13-1.95), and anxiety or depression (aOR, 2.12; 95% CI, 1.57-2.86), or all domains concurrently (aOR, 1.84; 95% CI, 1.43-2.37). Treatment within 60 minutes resulted in an estimated improvement in the absolute probability of no of slight problems ranging from 6.1% for pain or discomfort (NNT of 17) to 14.3% for mobility (NNT of 7) (Table). Results were similar, although attenuated, when evaluating the association with achieving the best category of no problems (Table).

Table. Odds Ratios (ORs) and Percentages for No or Slight Problems, Absolute Risk Reduction (ARR), and Number Needed To Treat (NTT) in Each Domain According to Door-to-Puncture Time.

Domain OR (95% CI) Percent (EVT ≥60 min) Percent (EVT <60 min) ARR P value (ARR) NNTa
Main analysis
Mobility 2.59 (1.83-3.68) 71.8 (68.4-75.2) 86.1 (82.7-89.5) 14.3 <.001 7
Self-care 2.42 (1.68-3.48) 78.5 (76.0-81.0) 89.2 (86.6-91.8) 10.7 <.001 10
Usual activities 2.00 (1.54-2.59) 64.9 (60.8-69.0) 77.9 (74.5-81.2) 13.0 <.001 8
Pain/discomfort 1.49 (1.13-1.95) 77.2 (73.9-80.5) 83.3 (80.0-86.7) 6.1 .003 17
Anxiety/depression 2.12 (1.57-2.86) 75.0 (70.7-79.2) 86.3 (83.9-88.7) 11.3 <.001 9
All domains 1.84 (1.43-2.37) 49.2 (44.9-53.6) 63.5 (58.7-68.3) 14.3 <.001 7
Imputed
Mobility 2.28 (1.67-3.12) 69.8 (66.3-73.3) 83.0 (79.5-86.6) 13.2 <.001 8
Self-care 2.05 (1.45-2.91) 76.6 (73.7-79.5) 86.1 (83.1-89.2) 9.5 <.001 11
Usual activities 1.86 (1.44-2.40) 62.9 (59.1-66.8) 74.8 (71.3-78.2) 11.9 <.001 9
Pain/discomfort 1.42 (1.09-1.85) 76.1 (72.5-79.7) 81.5 (78.0-85.0) 5.4 .009 19
Anxiety/depression 1.99 (1.49-2.66) 73.5 (69.1-77.9) 84.5 (81.8-87.1) 11.0 <.001 10
All domains 1.78 (1.41-2.24) 46.9 (42.7-51.1) 60.3 (55.7-64.9) 13.4 <.001 8
Achieved no problems
Mobility 1.93 (1.45-2.60) 49.9 (44.2-55.6) 64.8 (59.1-70.5) 14.9 <.001 7
Self-care 1.74 (1.32-2.31) 65.0 (61.1-68.9) 75.6 (71.5-79.7) 10.6 <.001 10
Usual activities 1.47 (1.09-2.00) 45.7 (38.6-52.8) 54.9 (50.1-59.7) 9.2 .01 11
Pain/discomfort 1.48 (1.13-1.94) 49.6 (44.9-54.4) 59.0 (53.8-64.3) 9.4 .004 11
Anxiety/depression 1.24 (0.91-1.69) 50.0 (44.5-55.4) 55.2 (49.6-60.7) 5.2 .18 20
All domains 1.47 (1.01-2.12) 19.4 (14.7-24.2) 25.9 (20.8-31.0) 6.5 .04 16
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Abbreviation: EVT, endovascular thrombectomy.

a

NNT is rounded up to nearest whole number.

Multiple imputation of EQ-5D-5L at 90 days accounted for all remaining missing data (62 for anxiety or depression, 61 for other domains) after bringing forward available 30-day values, resulting in 958 domain responses and 1105 index scores. The nature of the associations and the effect estimates were very similar to those the main analyses (Table and eTable 3 and eFigure 4 in Supplement 1).

Discussion

We found a strong and consistent association between speed of treatment with EVT from hospital arrival and patient-reported health-related quality of life at 90 days after acute ischemic stroke. Patients with faster treatment had greater overall index score on the EQ-5D-5L scale as well as substantial benefit in each of the 5 domains reflecting a powerful and broad impact of EVT treatment speed across important aspects of self-rated health.

Our findings are highly consistent with and extend prior findings on the association between treatment times and outcomes after acute stroke. The HERMES trials collaboration and large observational studies demonstrated significant associations between faster time to treatment with EVT and outcomes, including independence and disability-adjusted life years, discharge home, and mortality, which are important but not directly patient-reported outcomes.4,5,6 These findings have emphasized that programs and systems to shorten treatment times to EVT are critical. Although optimizing prehospital processes are important, we chose to focus on time from EVT hospital arrival to reflect the component of acute stroke workflow, which is under direct control of typical stroke teams, and due to the known dilution of onset-to-treatment time effects due to unwitnessed onset strokes and slow progressors.6 This was suggested in our results with a steeper slope for door-to-puncture compared with onset-to-puncture times, and for non–wake-up vs wake-up stroke, although the interaction by wake-up stroke was not significant. In our study, one-half of patients had door-to-puncture times of less than 60 minutes, compared with less than 10% in large samples from routine care in the US.4,23 Although it is difficult to compare between clinical trial and routine clinical care populations, these large differences imply that substantial improvements can be made to treatment times in clinical practice. Many potential opportunities for improvement exist, including prenotification tools, automated LVO detection tools, preprepared EVT kits, availability of around the clock neurointerventional team, and transfer directly from brain imaging suite to the angiography suite.24,25

The number of individuals experiencing stroke is expected to increase substantially in the next 2 decades.26,27 Stroke survivors are at high risk of disability and poor quality of life, and significant impairments persist even in follow-up after EVT for large vessel occlusion.28 Receiving EVT improves quality of life compared with not receiving EVT.2,29,30 Previously shown improvements in mRS with speed of treatment raised the potential of benefit to patient-reported outcomes, as information on the mRS is partly gathered from self-report and broadly reflects their health status. However, information gathered for the mRS score is interpreted by raters or clinicians and does not explicitly represent important health domains such as pain or anxiety and depression. Even when caregivers report outcomes on behalf of the patients, investigators tend to help with such reporting. In addition, the EQ-5D-5L questionnaire is anchored in region-specific preferences and individual perceptions on various health states and their impact on quality of life. Use of patient-reported outcome measures to grade health-related quality of life has been increasingly used in recent acute stroke clinicals trials for thrombolysis and thrombectomy.31,32,33,34,35 Our study results suggest a clear association of time-to-treatment benefit of EVT with patient-reported outcomes by showing improvements in both overall and domain-specific quality of life with faster EVT treatment from hospital arrival. Treatment under 60 minutes was strongly associated with favorable outcomes, with NNT to achieve no or slight problems ranging from 7 (mobility or usual activities) to 17 (pain and discomfort). However, every 15 minutes of earlier treatment provided measurable benefit. The minimally clinically importance difference for EQ-5D-5L in an international population has been estimated at 0.03 to 0.05,36 which was achieved with 15 minutes of faster door-to-puncture time and surpassed with 30 minutes of faster treatment time.

An additional important finding was the improvement in pain or discomfort and anxiety or depression with faster treatment. Chronic poststroke pain, anxiety, and depression are common and underrecognized after stroke but can be resistant to modification by hyperacute and chronic stroke treatments and are associated with significant disability.2,37,38,39 Our finding of improvements in these nonmotor domains extends the benefit of hyperacute treatments to areas of impairment that were not previously targeted by hyperacute treatments and suggests further research to understand the mechanisms. We also found improvement in the EQ-VAS, which reflects the patient’s global subjective health experience. Our results show that speed of treatment with EVT from hospital arrival was associated with improvement across the spectrum of patient-reported outcomes and provide useful knowledge for clinicians, administrators, policy makers, and patients and their caregivers.

Limitations

There were some limitations to the study. First, there were some missing data for EQ-5D-5L at 90 days, but this was minimized after considering deaths and carrying forward some observations from the 30-day assessment, followed by multiple imputation in a sensitivity analysis. The amount of missing data was relatively low considering the population with moderate to severe stroke and that we did not allow proxy responses, and comparing with rates of missing patient-reported or proxy-reported outcome data in the thrombectomy arm of prior clinical trials.2,29,40 Although proxy responses can be helpful to increase response rate and reduce missing data, they have only poor to fair agreement with patient responses, with lowest agreement for domains of pain or discomfort and anxiety or depression and for more severely affected patients.41,42 Not including proxy responses ensured that our data directly reflected the patient’s experience. Questionnaires were administered in-person often with family members present, and we did not document the proportion or degree to which family members may have influenced the responses in people with severe disability. Second, the trial was not powered to detect differences in outcome by time to treatment. However, the sample was large, and the results across all analyses were consistent and robust. Third, although the trial was randomized and baseline differences between groups were very similar, there remains the possibility of residual confounding by socioeconomic status, social support, and additional factors and clinical decision-making, which may be related to both speed of treatment and quality of life at 90 days. Lastly, our results are in the context of a clinical trial, and despite a large sample size from 7 countries and full range of outcomes, there could be limitations in generalizability to more heterogeneous populations in routine clinical practice.

Conclusions

In this cohort study, for patients with acute ischemic stroke and LVO, faster time between hospital arrival to endovascular treatment was strongly associated with improvement in patient-reported health-quality of life across multiple domains. These findings should encourage further efforts to shorten door-to-EVT times worldwide in patients with acute stroke to improve quality of life. Clinical trials in stroke should consider including self-reported patient outcomes to explore the impact of therapies across patient-centered domains.

Supplement 1.

eTable 1. Baseline Characteristics of Patients With EQ-5D-5L Data Stratified by Door-to-Puncture Time

eTable 2. Association Between Baseline Characteristics and 90-Day mRS With Missing 90-Day EQ-5D Score

eTable 3. Effect Estimates per 15 Minutes of Earlier Treatment With Endovascular Thrombectomy

eFigure 1. Patient Flowchart

eFigure 2. Association Between Continuous Onset-to-Puncture Times and EQ-5D-5L

eFigure 3. Association Between Continuous Door-to-Puncture Times and EQ-5D-5L, Stratified by Wake-Up Stroke

eFigure 4. Association Between Continuous Door-to-Puncture Times and EQ-5D-5L, With All Missing Values Replaced Using Multiple Imputation

jamaneurol-e241562-s001.pdf (1.1MB, pdf)
Supplement 2.

Nonauthor Collaborators. ESCAPE-NA1 Investigators

jamaneurol-e241562-s002.pdf (161.7KB, pdf)
Supplement 3.

Data Sharing Statement.

jamaneurol-e241562-s003.pdf (13.1KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Baseline Characteristics of Patients With EQ-5D-5L Data Stratified by Door-to-Puncture Time

eTable 2. Association Between Baseline Characteristics and 90-Day mRS With Missing 90-Day EQ-5D Score

eTable 3. Effect Estimates per 15 Minutes of Earlier Treatment With Endovascular Thrombectomy

eFigure 1. Patient Flowchart

eFigure 2. Association Between Continuous Onset-to-Puncture Times and EQ-5D-5L

eFigure 3. Association Between Continuous Door-to-Puncture Times and EQ-5D-5L, Stratified by Wake-Up Stroke

eFigure 4. Association Between Continuous Door-to-Puncture Times and EQ-5D-5L, With All Missing Values Replaced Using Multiple Imputation

jamaneurol-e241562-s001.pdf (1.1MB, pdf)
Supplement 2.

Nonauthor Collaborators. ESCAPE-NA1 Investigators

jamaneurol-e241562-s002.pdf (161.7KB, pdf)
Supplement 3.

Data Sharing Statement.

jamaneurol-e241562-s003.pdf (13.1KB, pdf)

Articles from JAMA Neurology are provided here courtesy of American Medical Association

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