Shorter Door-to-Needle Times are Associated with Better Outcomes after Intravenous Thrombolytic Therapy and Endovascular Thrombectomy for Acute Ischemic Stroke

Shumei Man; Nicole Solomon; Brian Mac Grory; Brooke Alhanti; Ken Uchino; Jeffrey L Saver; Eric E Smith; Ying Xian; Deepak L Bhatt; Lee H Schwamm; Muhammad Shazam Hussain; Gregg C Fonarow

doi:10.1161/CIRCULATIONAHA.123.064053

. Author manuscript; available in PMC: 2024 Jul 4.

Published in final edited form as: Circulation. 2023 May 18;148(1):20–34. doi: 10.1161/CIRCULATIONAHA.123.064053

Shorter Door-to-Needle Times are Associated with Better Outcomes after Intravenous Thrombolytic Therapy and Endovascular Thrombectomy for Acute Ischemic Stroke

Shumei Man ¹, Nicole Solomon ², Brian Mac Grory ³, Brooke Alhanti ², Ken Uchino ¹, Jeffrey L Saver ⁴, Eric E Smith ⁵, Ying Xian ⁶, Deepak L Bhatt ⁷, Lee H Schwamm ⁸, Muhammad Shazam Hussain ¹, Gregg C Fonarow ⁹

PMCID: PMC10356148 NIHMSID: NIHMS1897658 PMID: 37199147

Abstract

Background:

Existing data and clinical trials could not determine whether faster intravenous thrombolytic therapy (IVT) translates into better long-term functional outcomes after acute ischemic stroke among those treated with endovascular thrombectomy (EVT). Patient-level national data can provide the required large population to study the associations between earlier IVT, versus later, with longitudinal functional outcomes and mortality in patients receiving IVT+EVT combined treatment.

Methods:

This cohort study included older US patients (aged ≥65 years) who received IVT within 4.5 hours or EVT within 7 hours after acute ischemic stroke using the linked 2015–2018 Get With The Guidelines–Stroke and Medicare database (38913 treated with IVT only and 3946 with IVT+EVT). Primary outcome was home-time, a patient prioritized functional outcome. Secondary outcomes included all-cause mortality in one year. Multivariate logistic regression and Cox proportional hazards models were used to evaluate the associations between door-to-needle times (DTN) and outcomes.

Results:

Among patients treated with IVT+EVT, after adjusting for patient and hospital factors including onset-to-EVT times, each 15-minute increase in DTN times for IVT was associated with significantly higher odds of zero home-time in a year (never discharged to home) (aOR, 1.12; 95% CI, 1.06–1.19), less home-time among those discharged to home (aOR, 0.93 per 1% of 365 days; 95% CI, 0.89–0.98), and higher all-cause mortality (aHR 1.07; 95% CI 1.02–1.11). These associations were also statistically significant among patients treated with IVT but at a modest degree (aOR, 1.04 for zero home-time, 0.96 per 1% home-time for those discharged to home, and aHR 1.03 for mortality). In the secondary analysis where IVT+EVT group were compared with 3704 patients treated with EVT only, shorter DTN times (≤60, 45, and 30 minutes) achieved incrementally more home-time in a year, and more mRS 0–2 at discharge (22.3%, 23.4%, and 25.0%, respectively), vs EVT only (16.4%, p<0.001 for each). The benefit dissipated with DTN>60 minutes.

Conclusions:

Among older stroke patients treated with either IVT only or IVT+EVT, shorter DNT times are associated with better long-term functional outcomes and lower mortality. These findings support further efforts to accelerate thrombolytic administration in all eligible patients, including EVT candidates.

Keywords: ischemic stroke, door-to-needle time, intravenous thrombolytic therapy, endovascular thrombectomy, outcome

Intravenous thrombolytic therapy (IVT) and endovascular thrombectomy (EVT) improve the outcomes of acute ischemic stroke but the benefits are time-dependent.^1–8 Therefore, door-to-needle (DTN) time has become a target of local and national quality initiatives because DTN time is under the complete control of the hospital care team.⁹ Studies have demonstrated that shorter DTN times are associated with better outcomes at discharge and lower one-year mortality and readmission.^3,4 However, it remains unclear whether shorter DTN times for IVT are associated with better long-term functional outcomes among patients also undergoing EVT treatment. In addition, for patients with large vessel occlusion, the benefits of IVT preceding EVT have been questioned, leading to delaying or skipping thrombolytic therapy for faster EVT access in some practice. Six previous randomized clinical trials exploring the effect of IVT preceding EVT showed mixed results.^10–15 Importantly, the trials were not powered sufficiently to study the time-dependent effect of IVT. In fact, the workflow of the trials may have delayed thrombolytic administration due to patient consent and randomization.¹²

In the present study, we used data from the large nationwide real-practice data Get With The Guidelines (GWTG)-Stroke to examine whether shorter DTN times were associated with better outcomes in 2 separate cohorts: patients treated with IVT only and patients treated with IVT+EVT combined therapy.^16,17 GWTG-Stroke provides access to a patient population an order of magnitude larger than any existing reperfusion therapy clinical trials.^4,8,16–18 It allows outcome analyses using reperfusion timeliness as a continuous variable, as well as patient stratification based on the timeliness of both IVT and EVT. By linking GWTG-Stroke data with Medicare data, we can calculate home-time, defined as the total number of days alive and out of a health care facility.^19,20 Home-time has been validated as a functional outcome and correlated with the 90-day modified Rankin Scale (mRS) among patients treated with IVT.^19,20 It was identified in patient surveys as an outcome that was the most relevant and meaningful to stroke survivors.^19,20 We hypothesized that longer DTN times would be associated with increased risk of poor outcomes in patients treated with EVT, knowing that EVT is a highly effective procedure for recanalization and IVT usually fails to recanalize the occluded artery before EVT.

Methods

Given that GWTG data were collected for clinical care and quality improvement, rather than primarily for research, data sharing agreements require an application process in order for other researchers to access the data. Researchers interested in utilizing GWTG data for research purposes, including for validation, can submit proposals at https://www.heart.org/en/professional/quality-improvement/quality-research-and-publications/national-level-program-data-research-opportunities. Additional information regarding the statistical analysis plan and analytic codes may also be available from Duke Clinical Research Institute on request.

Data Source and Study Population

This cohort study included U.S. Medicare beneficiaries (aged ≥65 years) treated for acute ischemic stroke with IVT within 4.5 hours or EVT within 7 hours from last known well at GWTG-Stroke participating hospitals from January 1, 2015 to December 31, 2018, with a 1-year follow-up through December 31, 2019. Patients aged<65 years at the time of the stroke admission were not included because the post-discharge data were not available in this population. A Study Flow Chart is provided in Supplemental Figure S1. Patients with DTN time >4.5 hours or missing, onset-to-arrival time >24 hours or missing, discharge destination missing, or left against medical advice were excluded. In-hospital strokes were excluded because these patients often have thrombolytic contraindications and different disease profiles from patients presenting directly to the emergency department.^21–23

Patient-level clinical data including reperfusion treatment timeliness were obtained from GWTG-Stroke. GWTG-Stroke is an ongoing data collection that was launched by the American Heart Association/American Stroke Association (AHA/ASA) to support continuous quality improvement.^16,17 Patient-level clinical data are collected by trained hospital personnel on consecutive patients with acute ischemic stroke and transient ischemic attack.^16,17 A previous audit has demonstrated above 90% accuracy of GWTG-Stroke for most variables and excellent (κ ≥0.75) reliability for time-related performance measures.¹⁷ Each participating hospital received either human research approval to enroll cases without individual patient consent under the common rule, or a waiver of authorization and exemption from subsequent review by their institutional review board. The Duke Clinical Research Institute serves as the data analysis center. The Institutional Review Board at Duke University Health approved this study.

Medicare is a national health insurance program in the United States and covers 98% of adults aged ≥65 years. To obtain longitudinal outcomes, GWTG-Stroke records were linked to Medicare claims files by matching on a series of indirect identifiers including admission date, discharge date, hospital identification, and patient’s date of birth and sex, as previously described and validated.²⁴

Outcomes

Pre-specified primary outcomes were home-time at 90 days and 1 year from the date of hospital admission. Home-time was zero days for patients who died during hospitalization.

Pre-specified secondary outcomes included all-cause mortality and all-cause readmission in 1 year follow-up, as well as mRS at discharge and 90 days among those treated with EVT. For patients who were treated with IVT only, mRS were not routinely collected in GWTG-Stroke during the study period. Time of death or readmission was counted starting from the date of hospital discharge.

Data Analysis

Primary analyses examined the associations of DTN times with outcomes in IVT only group and IVT+EVT group separately. Secondary analyses compared the outcomes in IVT+EVT group with different DTN times with the EVT only treatment group. DTN time was analyzed as a continuous variable, per 15-minute increments, and as AHA/ASA Target:Stroke initiative pre-defined targets (within 30, 45, and 60 minutes) vs longer than those targets.^3,9,25,26 For transferred patients, arrival time at the first hospital was defined as “door” time. Because a large proportion of patients had zero days of home-time, as shown on the histogram in Supplemental Figure S2, the associations between DTN time and home-time were analyzed using a two-stage logistic regression model²⁷: (1) a logistic regression analysis of the binary outcome home-time =0 (never discharged to home due to death or long-term facility stay) vs home-time >0 (those ever discharged to home), and (2) a logistic regression model with Generalized Estimating Equation (GEE) for patients with home-time >0 (those ever discharged to home) where the outcome was the proportion of follow-up days at home. The odds ratio of each 1% home-time increase was computed. A logit link was used to reflect the upper (90-day or 1-year) and lower (0 days) bounds on home-time. Robust, empirical variance estimates were used in the GEE model to account for potential clustering within sites and for data that may not follow an independent binomial distribution. Both models were adjusted for the covariates listed below. Restricted cubic splines with four knots were applied as appropriate to continuous variables. The associations of DTN times with mortality and readmission were analyzed using Cox proportional hazard models with robust sandwich covariance estimates to account for within hospital clustering. The proportional hazards assumption was assessed with Schoenfeld residuals. For readmission, a cause-specific hazard model was used to account for the competing risk of mortality.²⁸

The adjusted models controlled for potential confounders including (1) patient characteristics, including age, sex, race-ethnicity, insurance, comorbidities (atrial fibrillation/flutter, previous stroke and transient ischemic attack, history of coronary artery disease/myocardial infarction, heart failure, carotid stenosis, diabetes mellitus, peripheral artery disease, hypertension, dyslipidemia, renal insufficiency, and smoking), antiplatelet or anticoagulant therapy, admission systolic blood pressure, heart rate, glucose, and stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS); and (2) hospital characteristics, including geographic region, urban/rural, total bed number, annual ischemic stroke volume, teaching status, and stroke center certification. For EVT treatment, the models also adjusted for onset-to-EVT times (time from last known well to arterial puncture).

Missing data: Rates of missingness of key patient and hospital characteristics were low (Table S1). Patients missing socioeconomic variables or from sites with missing hospital characteristics were excluded from adjusted analyses. Covariates with ≥25% missingness were not used in the models. For remaining covariates with missing data, values were imputed using multiple imputation with 20 datasets. The missing rate of NIHSS was very low: 278 patients (0.7%) in IVT only cohort and 19 patients (0.5%) in the IVT+EVT cohort. Evidence of modest bias in NIHSS documentation was observed in older GWTG-Stroke data (before 2012), but this bias has lessened as the documentation of NIHSS has improved in recent years.²⁹ Therefore NIHSS was not imputed in the current analysis. The missing rates of mRS were high, especially at 90 days (Table S2). Therefore the analyses of mRS were limited to those with documented mRS.

All statistical analyses were performed using SAS Version 9.4 software (SAS Institute). All tests were 2-sided, with P<0.05 considered statistically significant.

Results:

Among the 503876 patients with matching records, 43989 received IVT only, 4603 received IVT+EVT, and 9125 received EVT only treatment (Figure S1). After excluding patients with incomplete records, in-hospital stroke, IVT initiated after 4.5 hours, EVT initiated after 7 hours of last known well, left against medical advice, and discharge status missing, the final analysis included 38913 patients treated with IVT only, 3946 with IVT+EVT, and 3704 with EVT only.

Shorter DTN Times were associated with more Home-Time and lower Mortality and Readmission in Patients Treated with IVT Only.

Patient and hospital characteristics for IVT only cohort are provided in Table S3. The outcomes by every 15-minute increment of DTN times are provided in Table 1. Using DTN ≤30 minutes as the reference, the increase of DTN times to 31–45, 46–60, 61–75, 76–90, and >90 minutes was associated with incremented odds of zero home-time in a year (never discharged to home due to death or long-term facility stay) [adjusted odds ratio (aOR), 0.95, 1.04, 1.15, 1.13, and 1.33, respectively) and with decrement of home-time among those ever discharged to home (home-time >0) (aOR per 1% of 365 days, 0.98, 0.92, 0.90, 0.87, and 0.85, respectively). These associations held true in 90-day home-time. The adjusted spline plots in Figure 1A and B delineate the relationship between home-time and DTN times as a continuous variable, which showed a turning point at DTN time of 90 minutes. Each 15-minute additional DTN time, up to 90 minutes, was associated with higher odds of zero home-time in one year (aOR, 1.04; 95% CI, 1.01–1.07), less home-time among those discharged to home (aOR per 1% of 365 days, 0.96; 95% CI, 0.94–0.98), higher all-cause mortality [adjusted hazard ratio (aHR), 1.03, 95% CI, 1.01–1.04], and higher readmission (aHR, 1.02, 95% CI, 1.01–1.03) (Table 1). This directionality dissipated after a DTN time of 90 minutes.

Table 1.

Home-Time in IVT Only Cohort with Every 15-Minute Increment of Door-to-Needle Times

Door-to-Needle Time	≤30 min	31–45 min	46–60 min	61–75 min	76–90 min	>90 min	Per 15-min increment^*

	Ref						DTN≤90 min	DTN>90 min

90-day Home-Time (HT)

Median [IQR]	71 [14–85]	71 [12–85]	71 [11–85]	69 [10–85]	70 [10–85]	70 [8–85]

HT=0, never discharged to home within 90 days after acute stroke
Unadjusted OR (95% CI)		0.99 (0.90, 1.10)	1.03 (0.93, 1.14)	1.07 (0.96, 1.20)	1.07 (0.94, 1.22)	1.20 (1.07, 1.34)	1.03 (1.01, 1.05)	1.01 (0.96, 1.06)
Adjusted OR (95% CI)		0.96 (0.87, 1.07)	1.03 (0.93, 1.15)	1.07 (0.95, 1.20)	1.10 (0.96, 1.26)	1.28 (1.13, 1.45)	1.03 (1.01, 1.06)	1.04 (0.99, 1.10)

HT>0, per 1% (of 90 days) increase of home-time among those ever discharged to home
Unadjusted OR (95% CI)		0.97 (0.91, 1.04)	0.97 (0.91, 1.03)	0.91 (0.85, 0.98)	0.95 (0.87, 1.03)	0.96 (0.89, 1.03)	0.98 (0.97, 0.99)	1.05 (1.02, 1.08)
Adjusted OR (95% CI)		0.98 (0.92, 1.04)	0.95 (0.89, 1.01 )	0.90 (0.84, 0.96)	0.91 (0.84, 0.99)	0.86 (0.80, 0.92)	0.97 (0.96, 0.98)	1.01 (0.98, 1.04)

1-year Home-Time

Median [IQR]	335 [119–359]	334 [82–359]	335 [113–359]	335 [84–359]	331 [65–358]	332 [60–358]

HT=0, never discharged to home in a year after acute stroke
Unadjusted OR (95% CI)		0.99 (0.88, 1.12)	1.05 (0.94, 1.18)	1.16 (1.02, 1.31)	1.11 (0.96, 1.29)	1.26 (1.11, 1.44)	1.04 (1.01, 1.06)	1.01 (0.96, 1.07)
Adjusted OR (95% CI)		0.95 (0.84, 1.08)	1.04 (0.92, 1.18)	1.15 (1.00, 1.32)	1.13 (0.96, 1.33)	1.33 (1.15, 1.53)	1.04 (1.01, 1.07)	1.05 (0.99, 1.12)

HT>0, per 1% (of 365 days) increase of home-time among those ever discharged to home
Unadjusted OR (95% CI)		0.97 (0.90, 1.04)	0.92 (0.85, 1.00)	0.90 (0.84, 0.98)	0.89 (0.81, 0.98)	0.93 (0.86, 1.01)	0.97 (0.95, 0.98)	1.09 (1.05, 1.13)
Adjusted OR (95% CI)		0.98 (0.91, 1.05)	0.92 (0.85, 0.99)	0.90 (0.83, 0.97)	0.87 (0.79, 0.97)	0.85 (0.78, 0.92)	0.96 (0.94, 0.98)	1.04 (1.00, 1.08)

1-year all-cause mortality
Unadjusted HR (95% CI)		0.98 (0.91, 1.07)	1.04 (0.95, 1.13)	1.07 (0.98, 1.17)	1.08 (0.97, 1.19)	1.06 (0.96, 1.16)	1.03 (1.01, 1.05)	0.93 (0.90, 0.97)
Adjusted HR (95% CI)		0.99 (0.92, 1.08)	1.08 (1.00, 1.17)	1.09 (1.00, 1.19)	1.12 (1.01, 1.25)	1.15 (1.05, 1.27)	1.03 (1.01, 1.04)	-

1-year all-cause readmission ^†
Unadjusted HR (95% CI)		1.01 (0.96, 1.07)	1.01 (0.96, 1.07)	1.04 (0.98, 1.11)	1.04 (0.96, 1.12)	1.08 (1.01, 1.15)	1.02 (1.00, 1.03)	0.99 (0.96, 1.02)
Adjusted HR (95% CI)		1.01 (0.96, 1.07)	1.03 (0.98, 1.10)	1.06 (0.99, 1.13)	1.08 (1.00, 1.17)	1.14 (1.06, 1.22)	1.02 (1.01, 1.03)	-

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Abbreviations: IVT, intravenous thrombolytic therapy; Ref: reference; DTN, door-to-needle time; IQR, interquartile range;OR, odds ratio; HR, hazard ratio; CI, confidence interval.

HT=0 refers to patients who either died or were unable to be discharged to home from acute hospital or post-acute care facility due to severe disability.

HT>0 refers to those ever discharged to home. Median home-time were calculated among patients with HT>0.

Covariates for the adjusted models: (1) patient characteristics: age, sex, race-ethnicity, insurance, comorbidities (atrial fibrillation/flutter, previous stroke and transient ischemic attack, history of coronary artery disease/myocardial infarction, heart failure, carotid stenosis, diabetes mellitus, peripheral artery disease, hypertension, dyslipidemia, renal insufficiency, and smoking), antiplatelet or anticoagulant, admission systolic blood pressure, heart rate, glucose, and stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS); and (2) hospital characteristics: geographic region, urban/rural, total bed number, annual ischemic stroke volume, teaching status, and stroke center certification.

Door-to-Needle time was modeled as continuous variable.

^†

Cause-specific model was used for readmission to account for competing risk of death.

- Data were not available because there were too few events to fit the adjusted model.

Figure 1. — Panel A and C were drawn from the adjusted model of zero home-time (patients who either died within 90 days of stroke admission or were unable to be discharged to home from acute hospital or post-acute care facility due to severe disability). Panel B and D were drawn from the adjusted model predicting proportion of days at home for those with home-time >0 (patients who were ever discharged to home within 90 days). The Y-axis represents proportion of 90 days. The grey zone represents 95% CI. In the IVT Only cohort, but not the IVT+EVT cohort, the association of home-time and DTN changed at door-to-needle (DTN) time of 90 minutes. Covariates for the adjusted models: (1) patient characteristics including age, sex, race-ethnicity, insurance, comorbidities (atrial fibrillation/flutter, previous stroke and transient ischemic attack, history of coronary artery disease/myocardial infarction, heart failure, carotid stenosis, diabetes mellitus, peripheral artery disease, hypertension, dyslipidemia, renal insufficiency, and smoking), antiplatelet or anticoagulant, admission systolic blood pressure, heart rate, glucose, and stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS); and (2) hospital characteristics including geographic region, urban/rural, total bed number, annual ischemic stroke volume, teaching status, and stroke center certification. For EVT treatment (Panel B and D), the models also adjusted for onset-to-EVT times. Abbreviations: IVT, intravenous thrombolytic therapy; and EVT, endovascular thrombectomy.

The outcomes by AHA/ASA recommended DTN targets of 30, 45, and 60 minutes are shown in Table 2. DTN >45 minutes, compared to DTN ≤45 minutes, was associated with higher odds of zero home-time in a year (aOR, 1.16; 95% CI, 1.08–1.26), less home-time (aOR, 0.90 per 1%; 95% CI, 0.86–0.94), higher all-cause mortality (aHR, 1.11; 95% CI, 1.06–1.16), and higher readmission (aHR, 1.05; 95% CI, 1.02–1.09). These associations were also evident with DTN >60 vs ≤60 minutes, as well as in the sensitivity analysis excluding DTN >90 minutes (Table S4).

Table 2.

Home-Time in IVT Only Cohort with Pre-specified Door-to-Needle Time Targets

Door-to-Needle Time	≤30 min (reference)	>30 min	≤45 min (reference)	>45 min	≤60 min (reference)	>60 min

90-day Home-Time (HT)

Median [IQR]	71 [14–85]	70 [10–85]	71 [13–85]	70 [10–85]	71 [12–85]	69 [9–85]

HT=0, never discharged to home within 90 days after acute stroke
Unadjusted OR (95% CI)		1.05 (0.96, 1.15)		1.08 (1.02, 1.15)		1.10 (1.04, 1.17)
Adjusted OR (95% CI)		1.04 (0.94, 1.14)		1.12 (1.05, 1.19)		1.13 (1.06, 1.21)

HT>0, per 1% (of 90 days) increase of home-time among those ever discharged to home
Unadjusted OR (95% CI)		0.96 (0.90, 1.01)		0.97 (0.93, 1.00)		0.96 (0.92, 0.99)
Adjusted OR (95% CI)		0.92 (0.87, 0.98)		0.93 (0.89, 0.96)		0.91 (0.88, 0.95)

1-year Home-Time

Median [IQR]	335 [119–359]	334 [82–359]	335 [116–359]	333 [69–358]	335 [102–359]	331 [57–358]

HT=0, never discharged to home within a year after acute stroke
Unadjusted OR (95% CI)		1.09 (0.98, 1.20)		1.13 (1.06, 1.21)		1.16 (1.08, 1.24)
Adjusted OR (95% CI)		1.06 (0.95, 1.19)		1.16 (1.08, 1.26)		1.20 (1.11, 1.29)

HT>0, per 1% (of 365 days) increase of home-time among those ever discharged to home
Unadjusted OR (95% CI)		0.93 (0.87, 1.00)		0.94 (0.90, 0.98)		0.95 (0.91, 0.99)
Adjusted OR (95% CI)		0.91 (0.85, 0.97)		0.90 (0.86, 0.94)		0.91 (0.87, 0.96)

1-year all-cause mortality
Unadjusted HR (95% CI)		1.04 (0.96, 1.12)		1.07 (1.02, 1.12)		1.07 (1.02, 1.12)
Adjusted HR (95% CI)		1.06 (0.99, 1.14)		1.11 (1.06, 1.16)		1.08 (1.03, 1.14)

1-year all-cause readmission ^*
Unadjusted HR (95% CI)		1.03 (0.98, 1.08)		1.03 (1.00, 1.06)		1.04 (1.01, 1.08)
Adjusted HR (95% CI)		1.04 (0.99, 1.10)		1.05 (1.02, 1.09)		1.07 (1.03, 1.11)

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Abbreviations: IVT, intravenous thrombolytic therapy; Ref: reference; DTN, door-to-needle time; IQR, interquartile range.

HT=0 refers to patients who either died or were unable to be discharged to home from acute hospital or post-acute care facility due to severe disability.

HT> 0 refers to those ever discharged to home. Median home-time were calculated among patients with HT>0.

Cause-specific model was used for readmission to account for competing risk of death.

Shorter DTN Times were associated with more Home-Time and lower Mortality in IVT+EVT Combined Therapy

The outcomes by every 15-minute increment of DTN times in patients treated with IVT+EVT combined therapy are shown in Table 3. The adjusted spline plots are provided in Figure 1C and D. Using DTN ≤30 minutes as the reference group, the increase of DTN time to 31–45, 46–60, and >60 minutes was associated with incremented odds of zero home-time in a year (aOR 1.20, 1.29, and 1.62, respectively), decrement in home-time among those discharged to home (median 284, 237, and 200 days, respectively vs 302 days in DTN ≤30 minutes; aOR per 1% of 365 days, 1.03, 0.88, and 0.72, respectively), and increment in mortality (aOR 0.99, 1.12, and 1.32, respectively). When DTN times were modeled as a continuous variable, each 15-minute increment of DTN time was associated with higher odds of zero home-time in a year (aOR, 1.12; 95% CI, 1.06–1.19), less home-time among those discharged to home (aOR, 0.93 per 1% of 365 days; 95% CI, 0.89–0.98), and higher all-cause mortality (aHR 1.07; 95% CI 1.02–1.11).

Table 3.

Outcomes in IVT+EVT Cohort with Every 15-Minute Increment of Door-to-Needle Times

Door-to-Needle Time	≤30min (reference)	31–45min	46–60min	>60min	Per 15-min Increment^*

90-day Home-Time (HT)

Median [Interquartile Range]	56 [1–81]	48 [0–77]	33 [0–74]	18 [0–69]

HT=0, never discharged to home within 90 days after acute stroke
Unadjusted OR (95% CI)		1.11 (0.92, 1.34)	1.32 (1.07, 1.61)	1.55 (1.25, 1.92)	1.12 (1.07, 1.17)
Adjusted OR (95% CI)		1.08 (0.88, 1.32)	1.19 (0.95, 1.50)	1.43 (1.11, 1.84)	1.10 (1.04, 1.16)

HT>0, per 1% (of 90 days) increase of home-time among those ever discharged to home
Unadjusted OR (95% CI)		0.91 (0.79, 1.04)	0.78 (0.67, 0.91)	0.71 (0.60, 0.83)	0.93 (0.90, 0.96)
Adjusted OR (95% CI)		1.00 (0.87, 1.14)	0.92 (0.79, 1.08)	0.79 (0.67, 0.94)	0.95 (0.92, 0.99)

1-year Home-Time

Median [Interquartile Range]	302 [8–352]	284 [4–349]	237 [2–344]	200 [0–340]

HT=0, never discharged to home within a year after acute stroke
Unadjusted OR (95% CI)		1.23 (1.00, 1.52)	1.43 (1.14, 1.80)	1.74 (1.37, 2.20)	1.13 (1.08, 1.19)
Adjusted OR (95% CI)		1.20 (0.95, 1.52)	1.29 (0.99, 1.67)	1.62 (1.22, 2.14)	1.12 (1.06, 1.19)

HT>0, per 1% (of 365 days) increase of home-time among those ever discharged to home
Unadjusted OR (95% CI)		0.96 (0.82, 1.13)	0.77 (0.64, 0.92)	0.68 (0.56, 0.83)	0.92 (0.88, 0.95)
Adjusted OR (95% CI)		1.03 (0.87, 1.22)	0.88 (0.72, 1.07)	0.72 (0.58, 0.90)	0.93 (0.89, 0.98)

1-year all-cause mortality
Unadjusted HR (95% CI)		1.01 (0.86, 1.20)	1.24 (1.04, 1.48)	1.34 (1.10, 1.63)	1.08 (1.04, 1.12)
Adjusted HR (95% CI)		0.99 (0.83, 1.20)	1.12 (0.92, 1.36)	1.32 (1.06, 1.65)	1.07 (1.02, 1.11)

1-year all-cause readmission ^†
Unadjusted HR (95% CI)		1.09 (0.95, 1.26)	1.16 (1.01, 1.33)	1.03 (0.89, 1.21)	1.02 (0.99, 1.06)
Adjusted HR (95% CI)		1.09 (0.94, 1.26)	1.05 (0.90, 1.23)	1.00 (0.83, 1.20)	1.01 (0.97, 1.05)

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Abbreviations: IVT, intravenous thrombolytic therapy; EVT, endovascular thrombectomy; Ref: reference; OR, odds ratio; HR, hazard ratio; CI, confidence interval.

HT=0 refers to patients who either died or were unable to be discharged to home from acute hospital or post-acute care facility due to severe disability.

HT> 0 refers to those ever discharged to home. Median home-time were calculated among patients with HT>0.

Covariates for the adjusted models: (1) patient characteristics: age, sex, race-ethnicity, insurance, comorbidities (atrial fibrillation/flutter, previous stroke and transient ischemic attack, history of coronary artery disease/myocardial infarction, heart failure, carotid stenosis, diabetes mellitus, peripheral artery disease, hypertension, dyslipidemia, renal insufficiency, and smoking), antiplatelet or anticoagulant, onset-to-EVT times, admission systolic blood pressure, heart rate, glucose, and stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS); and (2) hospital characteristics: geographic region, urban/rural, total bed number, annual ischemic stroke volume, teaching status, and stroke center certification.

Door-to-Needle time was modeled as continuous variable.

^†

Cause-specific model was used for readmission to account for competing risk of death.

DTN times within 30, 45, and 60 minutes in IVT+EVT combined treatment, compared to longer than those targets, were associated with longer home-time in 90 days and 1 year, and lower all-cause mortality in 1 year (Table 4). DTN >45 minutes, compared to DTN ≤45 minutes, had higher odds of zero home-time in 1 year (aOR, 1.26; 95% CI, 1.05–1.51), less home-time among those discharged home (aOR, 0.80 per 1%; 95% CI, 0.69–0.91), and higher mortality (aHR, 1.20; 95% CI, 1.03–1.38). Readmission risk did not differ. These associations held true in the sensitivity analysis excluding transferred patients (Table S5).

Table 4.

Outcomes in IVT+EVT Cohort with Pre-specified Door-to-Needle Time Targets

Door-to-Needle Time	≤30 min (reference)	>30 min	≤45 min (reference)	>45 min	≤60 min (reference)	>60min

90-day Home-Time (HT)

Median [IQR]	56 [1–81]	35 [0–75]	51 [0–79]	24 [0–72]	46 [0–77]	18 [0–69]

HT=0, never discharged to home within 90 days after acute stroke
Unadjusted OR (95% CI)		1.27 (1.08, 1.49)		1.33 (1.16, 1.54)		1.37 (1.15, 1.64)
Adjusted OR (95% CI)		1.17 (0.97, 1.41)		1.23 (1.04, 1.44)		1.30 (1.07, 1.60)

HT>0, per 1% (of 90 days) increase of home-time among those ever discharged to home
Unadjusted OR (95% CI)		0.82 (0.73, 0.92)		0.79 (0.71, 0.89)		0.79 (0.68, 0.91)
Adjusted OR (95% CI)		0.94 (0.84, 1.06)		0.87 (0.77, 0.98)		0.82 (0.70, 0.95)

1-year Home-Time

Median [IQR]	302 [8–352]	259 [2–345]	293 [5–351]	226 [0–342]	280 [4–349]	200 [0–340]

HT=0, never discharged to home within a year after acute stroke
Unadjusted OR (95% CI)		1.40 (1.16, 1.69)		1.38 (1.18, 1.62)		1.44 (1.19, 1.75)
Adjusted OR (95% CI)		1.29 (1.05, 1.60)		1.26 (1.05, 1.51)		1.37 (1.10, 1.71)

HT>0, per 1% (of 365 days) increase of home-time among those ever discharged to home
Unadjusted OR (95% CI)		0.83 (0.72, 0.96)		0.74 (0.66, 0.84)		0.74 (0.63, 0.88)
Adjusted OR (95% CI)		0.93 (0.79, 1.08)		0.80 (0.69, 0.91)		0.75 (0.62, 0.89)

1-year all-cause mortality
Unadjusted HR (95% CI)		1.15 (1.00, 1.33)		1.27 (1.12, 1.45)		1.25 (1.06, 1.48)
Adjusted HR (95% CI)		1.08 (0.92, 1.27)		1.20 (1.03, 1.38)		1.27 (1.06, 1.52)

1-year all-cause readmission ^*
Unadjusted HR (95% CI)		1.10 (0.97, 1.24)		1.05 (0.95, 1.16)		0.96 (0.84, 1.10)
Adjusted HR (95% CI)		1.06 (0.93, 1.21)		0.98 (0.87, 1.10)		0.95 (0.81, 1.11)

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Abbreviations: IVT, intravenous thrombolytic therapy; EVT, endovascular thrombectomy; Ref: reference; IQR, interquartile range; OR, odds ratio; HR, hazard ratio; CI, confidence interval.

HT=0 refers to patients who either died or were unable to be discharged to home from acute hospital or post-acute care facility due to severe disability.

HT>0 refers to those ever discharged to home. Median home-time were calculated among patients with HT>0.

The associations of DTN with home-time were estimated using a two-stage model, producing two odds ratios (ORs) for each DTN comparison. The ORs for “HT=0” indicated the ORs for having zero home-time in the longer DTN group compared with the shorter DTN group; values higher than one indicated that longer DTN was associated with higher odds of zero home days, an unfavorable outcome. The ORs for “home-time>0, 1% increase” indicated the ORs of a one percent (of 90 days or 365 days) increase in the proportion of home-time in the longer DTN group compared with the shorter DTN group among those who were discharged home; values lower than one indicated that longer DTN times were associated with lower odds of additional days spent at home, an unfavorable outcome. For example, DTN>45 minutes was associated with higher odds of zero home time and, among those discharged to home, lower odds of a higher proportion of time spent at home, indicating that outcomes were worse with longer treatment times. Covariates for the adjusted models: (1) patient characteristics: age, sex, race-ethnicity, insurance, comorbidities (atrial fibrillation/flutter, previous stroke and transient ischemic attack, history of coronary artery disease/myocardial infarction, heart failure, carotid stenosis, diabetes mellitus, peripheral artery disease, hypertension, dyslipidemia, renal insufficiency, and smoking), antiplatelet or anticoagulant, onset-to-EVT times, admission systolic blood pressure, heart rate, glucose, and stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS); and (2) hospital characteristics: geographic region, urban/rural, total bed number, annual ischemic stroke volume, teaching status, and stroke center certification.

Cause-specific model was used for readmission to account for competing risk of death.

IVT-to-EVT Times and Door-to-EVT times were also associated with Outcomes in IVT+EVT Combined Treatment

The associations of IVT-to-EVT times with outcomes are shown in Table 5 and the sensitivity analyses excluding transferred patients are provided in Table S6. The unadjusted analyses did not show significant associations between IVT-to-EVT times with outcomes within each pre-specified DTN time category. However, after adjusting for patient and hospital characteristics, as well as onset-to-arrival and DTN times, the associations became statistically significant for some outcomes. Each 30-minute increase of IVT-to-EVT times was associated with less home-time in 1 year among those who were discharged to home, but mortality did not differ. Similar directionality was observed when onset-to-needle times were within 3 hours (Table S7).

Table 5.

Association of IVT-to-EVT Times with Outcomes in IVT+EVT Cohort

	Home-Time, Days, Median [Interquartile rang]		Unadjusted OR/HR (95% CI)	Adjusted OR/HR (95% CI)	Unadjusted OR/HR (95% CI)	Adjusted OR/HR (95% CI)
	IVT-to-EVT ≤60 min	IVT-to-EVT >60 min	Ref: IVT-to-EVT ≤60 min		Per 30-min increment^*

Door-to-needle ≤30 min
90-day home-time=0			1.25 (0.94, 1.66)	1.56 (1.12, 2.19)	1.03 (0.92, 1.14)	1.11 (0.98, 1.26)
90-day home-time>0, per 1% increase	61 [1–83]	44 [0–79]	0.87 (0.70, 1.09)	0.77 (0.61, 0.97)	0.97 (0.90, 1.05)	0.91 (0.83, 1.00)
1-year home-time=0			1.09 (0.78, 1.52)	1.38 (0.94, 2.02)	1.04 (0.92, 1.17)	1.15 (0.99, 1.33)
1-year home-time>0, per 1% increase	306 [9–354]	298 [7–352]	1.01 (0.77, 1.34)	0.83 (0.62, 1.10)	1.03 (0.93, 1.14)	0.95 (0.85, 1.06)
1-year mortality			0.89 (0.68, 1.17)	-	0.98 (0.89, 1.09)	-
1-year readmission^†			1.05 (0.85, 1.28)	-	1.01 (0.95, 1.07)	-

Door-to-needle ≤45 min
90-day home-time =0			1.09 (0.91, 1.32)	1.22 (1.00, 1.51)	1.04 (0.98, 1.11)	1.09 (1.01, 1.17)
90-day home-time>0, per 1% increase	57 [0–81]	41 [0–77]	0.82 (0.72, 0.94)	0.76 (0.67, 0.87)	0.94 (0.90, 0.98)	0.91 (0.87, 0.96)
1-year home-time =0			1.00 (0.82, 1.23)	1.12 (0.89, 1.41)	1.00 (0.93, 1.08)	1.04 (0.96, 1.13)
1-year home-time> 0, per 1% increase	299 [5–351]	282 [5–350]	0.90 (0.77, 1.05)	0.78 (0.66, 0.93)	0.97 (0.92, 1.03)	0.93 (0.88, 0.99)
1-year mortality			1.04 (0.88, 1.23)	1.20 (1.00, 1.45)	1.00 (0.95, 1.06)	1.06 (0.99, 1.12)
1-year readmission^†			1.11 (0.98, 1.25)	1.20 (1.05, 1.38)	1.01 (0.98, 1.05)	1.02 (0.97, 1.07)

Door-to-needle ≤60 min
90-day home-time=0			1.13 (0.97, 1.32)	1.20 (1.01, 1.43)	1.05 (0.99, 1.10)	1.07 (1.01, 1.13)
90-day home-time>0, per 1% increase	54 [0–80]	34 [0–76]	0.80 (0.71, 0.90)	0.75 (0.67, 0.84)	0.93 (0.89, 0.97)	0.91 (0.87, 0.94)
1-year home-time=0			1.06 (0.89, 1.26)	1.14 (0.94, 1.39)	1.02 (0.97, 1.08)	1.05 (0.99, 1.12)
1-year home-time>0, per 1% increase	286 [4–350]	273 [4–348]	0.89 (0.78, 1.02)	0.81 (0.70, 0.94)	0.97 (0.93, 1.01)	0.94 (0.90, 0.99)
1-year mortality			1.07 (0.93, 1.23)	1.16 (1.00, 1.35)	1.01 (0.97, 1.06)	1.05 (1.00, 1.10)
1-year readmission^†			1.06 (0.96, 1.18)	1.13 (1.01, 1.27)	1.01 (0.98, 1.04)	1.01 (0.97, 1.05)

Door-to-needle >60 min
90-day home-time=0			1.34 (0.97, 1.84)	1.65 (1.12, 2.44)	1.14 (1.03, 1.27)	1.24 (1.09, 1.40)
90-day home-time>0, per 1% increase	24 [0–71]	10 [0–68]	0.92 (0.71, 1.20)	0.77 (0.59, 1.01)	0.98 (0.89, 1.07)	0.92 (0.84, 1.01)
1-year home-time=0			1.15 (0.82, 1.63)	0.72 (0.52, 1.00)	1.07 (0.96, 1.19)	1.17 (1.02, 1.34)
1-year home-time> 0, per 1% increase	215 [0–341]	194 [0–337]	1.00 (0.74, 1.36)	1.52 (0.99, 2.34)	0.99 (0.89, 1.10)	0.89 (0.79, 0.99)
1-year mortality			0.98 (0.74, 1.31)	-	0.99 (0.90, 1.08)	-
1-year readmission^†			1.06 (0.81, 1.39)	-	1.00 (0.93, 1.07)	-

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Data are expressed as Median [interquartile range], adjusted odds ratio (95% CI) for home-time, or adjusted hazard ratio (95% CI) for mortality and readmission.

Abbreviations: IVT, intravenous thrombolytic therapy; EVT, endovascular thrombectomy.

IVT-to-EVT time was defined as the time from IVT bolus to arterial puncture for EVT.

Home-time= 0 refers to patients who either died or were unable to be discharged home due to severe disability.

Home-time> 0 refers to those ever discharged home. Median home-time were calculated among patients with HT>0.

The associations of IVT-to-EVT times with home-time were estimated using a two-stage model, producing two adjusted odds ratios (ORs) for each comparison. The ORs for “home-time=0” indicated the ORs for having zero home-time in the longer IVT-to-EVT group compared with the shorter IVT-to-EVT group; values higher than one indicated that longer IVT-to-EVT was associated with higher odds of zero home days, an unfavorable outcome. The ORs for “home-time>0, per 1% increase” indicated the ORs of a one percent (of 90 days or 365 days) increase in the proportion of time at home in the longer IVT-to-EVT group compared with the shorter IVT-to-EVT group among those who were discharged to home; values lower than one indicated that longer IVT-to-EVT was associated with lower odds of additional days spent at home, an unfavorable outcome.

Covariates for the adjusted models: (1) patient characteristics: age, sex, race-ethnicity, insurance, comorbidities (atrial fibrillation/flutter, previous stroke and transient ischemic attack, history of coronary artery disease/myocardial infarction, heart failure, carotid stenosis, diabetes mellitus, peripheral artery disease, hypertension, dyslipidemia, renal insufficiency, and smoking), antiplatelet or anticoagulant, onset-to-arrival times, door-to-needle times, admission systolic blood pressure, heart rate, glucose, and stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS); and (2) hospital characteristics: geographic region, urban/rural, total bed number, annual ischemic stroke volume, teaching status, and stroke center certification.

IVT-to-EVT time was modeled as continuous variable.

^†

Cause-specific model was used for readmission to account for competing risk of death.

- Data were not available because there were too few events to fit the adjusted model.

We further analyzed the associations of door-to-EVT times with outcomes in the IVT+EVT group (Table S8). Every 30-minute increase of door-to-EVT times was associated with higher odds of zero home-time in a year (aOR, 1.07; 95% CI, 1.01–1.13), less home-time among those discharged to home (aOR, 0.94 per 1% of 365 days; 95% CI, 0.90–0.98), and higher all-cause mortality (aHR 1.05; 95% CI 1.00–1.09), but not all-cause readmission (aOR 1.02; 95% CI 0.98–1.05). This associations held true in the sensitivity analysis excluding transferred patients (Table S9).

Secondary Analysis: EVT+IVT with Shorter DTN Times Had Better Outcomes than EVT Only

As a secondary analysis, we compared the outcomes among patients treated with IVT+EVT at different DTN times versus those treated with EVT only. As shown in Supplemental Table S10, there were no significant differences between the two groups in terms of patient age, sex, race/ethnicity, most comorbidities, and stroke severity as measured by NIHSS. However, the IVT+EVT group had lower prevalence of atrial fibrillation, prior stroke, heart failure, and antiplatelet or anticoagulant prior to admission compared to the other groups. In addition, the IVT+EVT group had longer door-to-EVT time (median 102 vs 79, standardized difference 44.64), but shorter onset-to-EVT time (median 176 vs 245, standardized difference 39.19). The median annual EVT volume of the treating hospitals for the IVT+EVT group was lower than that for the EVT only group (48 vs 56, standardized difference 25.41). Adjusted outcome analyses were performed after patients were stratified by onset-to-EVT times and the results are provided in Table 6. Among patients treated with onset-to-EVT 180 minutes and less, combined therapy with DTN ≤30, 45, and 60 minutes had significantly more home-time in a year (median 310, 304, and 286 days, respectively; aOR 1.48, 1.47, and 1.39 per 1% of 365 days) compared to EVT only group (median 225 days). DTN ≤45 or 60 minutes was associated with significantly lower 1-year mortality (aHR 0.76 and 0.81, respectively) compared to EVT-only group. This association held true for onset-to-EVT 181–300 minute group and in the sensitivity analysis excluding transferred patients (Table S11). Adjusted analyses were not performed in some subgroups due to small numbers of events.

Table 6.

Secondary Analysis: Outcomes in EVT only Cohort vs EVT+IVT Cohort by Door-to-Needle Times

	EVT Only	EVT+IVT
	Ref	DTN≤30 min	DTN≤45 min	DTN≤60 min	DTN>60 min

Onset-to-EVT ≤180 min

90-day Home-Time (HT)

Median [IQR]	28 [0, 74]	61 [2, 83]	58 [1, 81]	53 [0, 80]	28 [0, 75]

HT=0, never discharged to home after acute stroke, aOR (95% CI)		0.80 (0.60, 1.05)	0.82 (0.66, 1.03)	0.87 (0.71, 1.07)	-

HT>0, per 1% increase of home-time among those ever discharged to home, aOR (95% CI)		1.33 (1.10, 1.60)	1.32 (1.14, 1.53)	1.29 (1.13, 1.49)	-

One-year Home-Time

Median [IQR]	225 [3, 341]	310 [13, 354]	304 [8, 352]	286 [6, 351]	250 [0, 344]

HT=0, never discharged to home after acute stroke admission, aOR (95% CI)		0.74 (0.54, 1.01)	0.84 (0.66, 1.07)	0.86 (0.69, 1.07)	-

HT>0, per 1% increase of home-time among those ever discharged to home, aOR (95% CI)		1.48 (1.20, 1.82)	1.47 (1.24, 1.74)	1.39 (1.18, 1.62)	-

1-year mortality, aHR (95% CI)		-	0.76 (0.65, 0.89)	0.81 (0.70, 0.94)	-

1-year readmission^*, aHR (95% CI)		-	0.85 (0.74, 0.98)	0.90 (0.79, 1.03)	-

Onset to EVT 180–300 min

90-day Home-Time

Median [IQR]	16 [0, 71]	49 [0, 79]	39 [0, 76]	36 [0, 75]	18 [0, 69]

HT=0, never discharged to home after acute stroke, aOR (95% CI)		-	0.84 (0.67, 1.05)	0.82 (0.67, 1.00)	-

HT>0, per 1% increase of home-time among those ever discharged to home, aOR (95% CI)		-	1.29 (1.09, 1.52)	1.20 (1.03, 1.39)	-

1-year Home-Time

Median [IQR]	186 [0, 338]	283 [2, 351]	274 [2, 348]	272 [2, 347]	209 [0, 337]

HT=0, never discharged to home after acute stroke, aOR (95% CI)		-	0.88 (0.68, 1.14)	0.90 (0.72, 1.13)	-

HT>0, per 1% increase of home-time among those ever discharged to home, aOR (95% CI)		-	1.58 (1.31, 1.91)	1.53 (1.30, 1.81)	-

1-year mortality, aHR (95% CI)		-	-	0.75 (0.64, 0.88)	-

1-year readmission^*, aHR (95% CI)		-	-	0.81 (0.70, 0.94)	-

Onset to EVT >300 min ^†

90-day Home-Time
Median [IQR]	14 [0, 71]	30 [0, 77]	18 [0, 73]	18 [0, 73]	1 [0, 56]

1-year Home-Time
Median [IQR]	174 [0, 338]	278 [10, 346]	265 [2, 344]	253 [1, 345]	40 [0, 327]

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Abbreviations: IVT, intravenous thrombolytic therapy; EVT, endovascular thrombectomy; Ref, reference; IQR, interquartile range; aOR, adjusted odds ratio; aHR, adjusted hazard ratio; CI, confidence interval.

HT=0 refers to patients who either died or were unable to be discharged to home from acute hospital or post-acute care facility due to severe disability.

HT>0 refers to those ever discharged to home. Median home-time were calculated among patients with HT>0.

A two stage model were used for each home-time comparison, producing two adjusted odds ratios (ORs). EVT Only group within each onset-to-EVT time category was used as the reference. The ORs for “HT=0” indicated the ORs for having zero home-time in each DTN subgroup of the IVT+EVT group compared with EVT Only group; values lower than one indicated that IVT+EVT had lower odds of zero home days, a favorable outcome. The ORs for “home-time>0, 1% increase” indicated the ORs of a one percent (of 90 days or 365 days) increase in the proportion of home-time in the IVT+EVT group compared with EVT Only group among those who were discharged to home; values higher than one indicated that IVT+EVT had higher odds of additional days spent at home, a favorable outcome.

Covariates for the adjusted models: (1) patient characteristics: age, sex, race-ethnicity, insurance, comorbidities (atrial fibrillation/flutter, previous stroke and transient ischemic attack, history of coronary artery disease/myocardial infarction, heart failure, carotid stenosis, diabetes mellitus, peripheral artery disease, hypertension, dyslipidemia, renal insufficiency, and smoking), antiplatelet or anticoagulant, onset-to-EVT times, admission systolic blood pressure, heart rate, glucose, and stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS); and (2) hospital characteristics: geographic region, urban/rural, total bed number, annual ischemic stroke volume, teaching status, and stroke center certification.

Cause-specific model was used for readmission to account for competing risk of death.

^†

Adjusted model could not be constructed because there were too few events.

- Data were not available because there were too few events to fit the adjusted model.

The mRS at discharge is provided in Figure 2. The proportion of patients achieving good functional outcomes at discharge, defined as an mRS of 0–2, increased as DTN times shortened in the IVT+EVT group (22.3%, 23.4%, and 25.0%, for DTN ≤60, 45, and 30 minutes, respectively), compared to 16.4% in EVT only group (p<0.001 for each). This outcome benefit in the IVT+EVT group dissipated at DTN >60 minutes (18.0%, p=0.404). This directionality was also observed at 90 days, but data missing rates were high (Figure S3).

Discussion

This large nationwide study of U.S. older patients treated with IVT only and, importantly, IVT+EVT combined therapy demonstrated that shorter DTN times for IVT are associated with greater chance of being discharged to home, more time at home, and lower all-cause mortality within a year after acute ischemic stroke. The odds are modest in the IVT only group and greater in the IVT+EVT group. The results in the IVT only cohort confirmed that home-time, a novel functional outcome measure, has the same associations with DTN times as traditional outcome measures such as all-cause mortality and readmission.⁴ The results of the IVT+EVT combined treatment cohort is the first study to demonstrate that each 15-minute increase in DTN times, even followed by EVT, is associated with less home-time and higher mortality in a year. The secondary analysis suggests that, for IVT+EVT combined treatment, when IVT is given with DTN≤60 minutes and onset-to-EVT≤300 minutes, is associated with more home-time and lower mortality than EVT alone. Patients treated with combined therapy at shorter DTN times (up to 60 minutes) are more likely to achieve functional independence at discharge and 90 days.

This study provides important new information on the association of DTN times with outcomes in patients who also underwent EVT. Prior studies of DTN times have either excluded patients who had EVT or were based on small sample sizes or highly selected populations. A prior study from the HERMES collaboration found, like ours, that DTN delays are associated with worse outcomes in patients treated with EVT.³¹ However, that study was small (only 601 patients) and was performed in a highly selected trial population that was probably not representative of the patients treated in routine clinical practice. These novel findings have important implications for stroke systems of care and quality improvement. The findings demonstrate the importance of maintaining and strengthening focus on reducing DTN times in the era of highly effective EVT.

DTN time has been set as the target of the AHA/ASA Target:Stroke national quality initiative because it is directly under the control of hospital stroke teams and systems of care.^3,9,26 Our previous study has shown that shorter DTN times, as well as achieving the Target:Stroke pre-specified DTN time targets of ≤45 minutes and ≤60 minutes are associated with lower 1-year all-cause mortality and readmission after stroke.⁴ These findings are extended in the current study with home-time as a functional outcome measure that has been prioritized by stroke survivors.^19,20 These results support current guidelines to initiate IVT after noncontrast computed tomography (CT).³⁰ Advanced imaging, such as CT angiogram and magnetic resonance imaging (MRI), including perfusion imaging, should not delay the thrombolytic therapy. Importantly, the current study added novel data proving that among patients treated with IVT+EVT combined therapy, accelerated DTN times are associated with clinically significant lower risk of zero home-time (never discharged to home due to death or long-term care facility stay), more days at home, and lower mortality within a year. Every 15-minute delay in IVT administration, even with concurrent modern EVT treatment, is associated with less home-time and higher all-cause mortality in 1 year. These results also support the increased use of pre-hospital thrombolytic therapy in mobile stroke units, which provide fast thrombolytic treatment.^32,33 The greater effect of DTN times among the IVT+EVT combined treatment group might have been due to a synergistic effect of IVT and EVT. Systemic thrombolysis facilitates early recanalization of thrombectomy procedure and the recanalization of large vessels by EVT facilities IVT to lyse distal or hard-to-reach clots.³⁴ Pooled analyses of trials of EVT with and without alteplase, a thrombolytic agent, showed trends toward better functional outcomes in those who received both. However, it is also possible that patients with large vessel occlusion have greater disability and provide greater scope for demonstrating an effect of shorter DTN times.

Our study provides novel information to support the current guidelines that both IVT and EVT should be provided for eligible patients and IVT should not be delayed because of planned EVT.^30,35 This is the first study to demonstrate the time effect of IVT prior to EVT by modeling DTN time as a continuous variable and taking advantage of the nationwide real-practice database with a patient population an order of magnitude larger than clinical trials. A subanalysis of the randomized clinical trials suggested that among 203 patients that received combined therapy, the 90-day mortality was higher with DTN >1 hour vs 0–1 hour, but functional outcomes did not differ.³⁶ The positive associations of shorter DTN times with more home-time and lower mortality among the patients receiving IVT+EVT treatment are indirect evidence that IVT before EVT has beneficial effect. Further, the secondary analysis comparing combined therapy vs EVT alone provides a direct indication that, when EVT is started within 5 hours of stroke onset and IVT is given within 60 minutes of hospital arrival, combined therapy may offer more home-time and lower mortality than EVT alone. These findings are strengthened by the analysis of mRS at discharge and 90 days follow-up in which more patients receiving combined treatment with shorter DTN times achieved good functional outcomes than patients receiving EVT only. The outcome benefits dissipate with DTN times longer than 60 minutes. While this finding needs to be confirmed in randomized clinical trials due to the potential selection bias in retrospective studies, it is in agreement with another study using GWTG-Stroke showing that patients treated with IVT+EVT were more likely to achieve home discharge, independent ambulation at discharge, and lower in-hospital mortality than EVT alone.¹⁸ It should be noted that the data missing rates of 90-day mRS are high in GWTG-Stroke database although the missing rates are similar across subgroups. Therefore, the mRS analysis should be considered exploratory and as a support of the primary outcome analyses. Patients with missing mRS are likely alive because mortality data are well captured in Medicare files. This discrepancy might have contributed to the high mortality rate in our mRS analyses, in addition to the less strict patient selection in real-world EVT practice and older age in our cohort (age ≥65 years). However, the directionality of 90-day mRS is similar to discharge mRS, which has a low missing rate and has been shown to be highly predictive of 90-day outcomes.³⁷

Our study was designed to complement the limitations of randomized clinical trials and provide important additional data to guide reperfusion therapy. Among the six non-inferiority trials comparing EVT alone vs combined therapy, two trials demonstrated non-inferiority and the other four did not.^10–15 The generalizability of the trials were limited by the wide non-inferiority margin, modest sample size, excluding transferred patients, workflow limitations, and the high performing nature of the enrolling hospitals.^10–15,38 Furthermore, the trials could not account for the time-dependent benefit of either IVT or EVT treatment. The current study, an order of magnitude larger in size, offers substantially more power to study this complex treatment paradigm. We found statistically and clinically significant benefit in functional outcomes and mortality with faster IVT administration before EVT. In concert with prior studies, ^5–8 our results demonstrate that faster EVT treatment is associated with more home-time and lower mortality during the 1 year follow-up period. Our overall results indicate that IVT-to-EVT times may have a modest association with home-time, after controlling for patient and hospital factors. Limited by the small number of patients getting EVT immediately after IVT (within 30 minutes), we were unable to study the effect of a very short IVT-to-EVT interval. Another consideration is that the use of advanced imaging, such as CT perfusion imaging (CTP), MRI, or MRI perfusion imaging, in patient selection for EVT may temper the associations of IVT-to-EVT times with outcomes. In other words, advanced imaging selection may select patients with slow infarct progression for EVT, which would reduce the strength of association with time and, therefore, such study results would be a conservative estimate. Patients with poor collateral blood flow on CT angiogram (CTA) are more likely to have early infarct progression and become ineligible for EVT or have poor outcomes after EVT.³⁹ Advanced imaging selection are often used to determine EVT eligibility when patients present within 6 to 24 hours after stroke onset, in which better collaterals lead to slower stroke progression and better functional outcomes.⁴⁰ For patients who have EVT within 6.5 hours from stroke onset, the benefit of a shorter time to recanalization is independent of baseline collateral status.⁶ The current study only included patients with EVT started within 7 hours of stroke onset in which perfusion imaging were not recommended. However, some patients might still have been selected based on advance imaging. Unfortunately, the results of advance imaging are not available in the GWTG-Stroke database.

Based on these results, to improve outcomes in patients treated with IVT+EVT, it is necessary to reduce in-hospital delays in both IVT and EVT, and move quickly from the start of IVT infusion to arterial puncture and EVT.

Limitations

This study has several limitations. First, in order to obtain long-term outcomes, this study only included Medicare fee-for-service beneficiaries aged 65 and older who were treated at GWTG-Stroke participating hospitals, with complete data linked in these two databases. Previous work has demonstrated that patients in the linked GWTG-Stroke/Medicare database are representative of the national Medicare ischemic stroke population.³⁰ However, the results may not be generalizable to younger patients or other hospitals or countries. Second, although outcome analyses adjusted for patient-level and hospital-level factors, including stroke severity and onset-to-EVT time for EVT treatment, there might be residual measured and unmeasured confounding including functional status prior to the index stroke, social determinants of health (such as housing, marriage status, availability of care providers at home, income, education level, and pollution), and institutional practice patterns that may influence DTN times or outcomes. Third, the secondary analysis comparing IVT+EVT vs EVT should be interpreted with caution and as hypothesis generating because of the imbalance in patient characteristics and potential selection bias. However, the signals may inform future clinical trial design in studying the effect of IVT before EVT to allow patient randomization based on DTN times. Fourth, the study was limited to patients receiving intravenous thrombolytics within 4.5 hours and EVT within 7 hours of onset and may not be applicable to reperfusion therapy for stroke of unknown last known well or wake-up stroke when magnetic resonance imaging or computerized tomography perfusion scans are needed to determine eligibility.^41–43 Fifth, during the study period, alteplase was used in most U.S. hospitals as the intravenous thrombolytic agent so the results may not be generalizable to other thrombolytic agents such as tenecteplase. Finally, the study used several pre-specified outcomes. The findings should be interpreted as exploratory given the absence of statistical correction for multiple comparisons.

Conclusions

Among patients aged 65 years or older with acute ischemic stroke, shorter DTN times for IVT are associated with more time at home and lower mortality in patients treated with IVT alone, as well as with IVT+EVT combined therapy. These findings support further efforts to accelerate thrombolytic therapy in all eligible patients, including EVT candidates.

Supplementary Material

Supplemental Publication Material

NIHMS1897658-supplement-Supplemental_Publication_Material.pdf^{(731.4KB, pdf)}

Clinical Perspective.

What is New?

In this large cohort study of patients (aged ≥65 years) treated with intravenous thrombolytic therapy (IVT) within 4.5 hours and endovascular thrombectomy (EVT) within 7 hours of acute ischemic stroke onset, shorter door-to-needle times for IVT were associated with more days at home and lower mortality during one year follow-up.
Among patients treated with IVT+EVT combined therapy, each 15-minute increase in door-to-needle times was associated with fewer days at home and higher all-cause mortality in a year.
Guideline recommended door-to-needle times (≤30, 45, and 60 minutes) for IVT were associated with better outcomes after IVT+EVT combined therapy.

What Are the Clinical Implications?

Intravenous thrombolytic should be administered as early as possible and should not be delayed even among patients who may undergo EVT treatment.
These findings support further efforts to accelerate thrombolytic administration in all eligible patients, including potential EVT candidates.

Source of funding

The Get With The Guidelines^®-Stroke (GWTG-Stroke) is provided by the American Heart Association/American Stroke Association. GWTG-Stroke is sponsored, in part, by Novartis, Novo Nordisk, AstraZeneca, Bayer, Tylenol and Alexion, and AstraZeneca Rare Disease.

The funders/sponsors had no role in the design and conduct of the study; analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclosures:

Dr. Man, Solomon, Alhanti, and Smith reported no relevant disclosure.

Dr. Mac Grory received funding from the National Institutes of Health (K23HL161426).

Dr. Uchino reported being on data safety monitoring board for clinical trials sponsored by Genentech, Inc. and Evaheart, Inc. Consultant for Abbott Laboratories, Inc.

Dr. Saver reported receiving research support from the National Institute of Health and the American Heart Association; receiving contracted hourly payments from Medtronic, Stryker, Cerenovus, and Boehringer Ingelheim (prevention only) and stock options from Rapid Medical for service on clinical trial steering committees advising on rigorous trial design and conduct; an employee of the University of California which holds a patent on an endovascular devices for stroke.

Dr. Xian reported receiving research funding from the American Heart Association and Genentech and honoraria from Boeheim Ingelheim.

Dr. Bhatt disclosed the following relationships - Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent.) Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda.

Schwamm reported serving on the American Heart Association/ GWTG stroke systems of care advisory group and American Stroke Association Advisory Committee; stroke systems consultant to the Massachusetts Department of Public Health; scientific consultant regarding trial design and conduct to Genentech (late window thrombolysis, member of steering committee TIMELESS NCT03785678); member of a Data Safety Monitoring Board (DSMB) for Penumbra (MIND NCT03342664); Diffusion Pharma (PHAST-TSC NCT03763929); National PI or member of National Steering Committee for Medtronic (Stroke AF NCT02700945); PI, StrokeNet Network NINDS (New England Regional Coordinating Center U24NS107243); Co-I, The Impact of Telestroke on Patterns of Care and Long-Term Outcomes, NINDS (R01NS111952).

Dr. Hussain reported serving on the scientific advisory board and Clinical events committee of Cerenovus, the principal investigator of Medtronic Core lab, data safety monitoring board for Stryker Neurovascular, and Clinical events committee of Rapid Medical.

Dr. Fonarow reported receiving research support from the Patient Centered Outcome Research Institute and the National Institutes of Health, and employee of University of California which holds a patent on an endovascular device for stroke.

Nonstandard Abbreviations and Acronyms

IVT: intravenous thrombolytic therapy
EVT: endovascular thrombectomy
DTN: door-to-needle
HT: home-time
GWTG: Get With The Guidelines
IVT-to-EVT: from initiation of IVT bolus to arterial puncture of EVT
Onset-to-EVT: from last known well to arterial puncture of EVT

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Associated Data

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

Supplementary Materials

Supplemental Publication Material

NIHMS1897658-supplement-Supplemental_Publication_Material.pdf^{(731.4KB, pdf)}

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PERMALINK

Shorter Door-to-Needle Times are Associated with Better Outcomes after Intravenous Thrombolytic Therapy and Endovascular Thrombectomy for Acute Ischemic Stroke

Shumei Man, MD, PhD

Nicole Solomon, PhD

Brian Mac Grory, MB, BCh, BAO, MRCP

Brooke Alhanti, PhD

Ken Uchino, MD

Jeffrey L Saver, MD

Eric E Smith, MD, MPH

Ying Xian, MD, PhD

Deepak L Bhatt, MD, MPH

Lee H Schwamm, MD

Muhammad Shazam Hussain, MD

Gregg C Fonarow, MD

Abstract

Background:

Methods:

Results:

Conclusions:

Methods

Data Source and Study Population

Outcomes

Data Analysis

Results:

Shorter DTN Times were associated with more Home-Time and lower Mortality and Readmission in Patients Treated with IVT Only.

Table 1.

Figure 1. Adjusted Spline Plots of Door-to-Needle Time vs 90-day Home-Time.

Table 2.

Shorter DTN Times were associated with more Home-Time and lower Mortality in IVT+EVT Combined Therapy

Table 3.

Table 4.

IVT-to-EVT Times and Door-to-EVT times were also associated with Outcomes in IVT+EVT Combined Treatment

Table 5.

Secondary Analysis: EVT+IVT with Shorter DTN Times Had Better Outcomes than EVT Only

Table 6.

Figure 2. Secondary Analysis: Modified Rankin Scale (mRS) at Discharge among IVT+EVT vs EVT Only Group.

Discussion

Limitations

Conclusions

Supplementary Material

Clinical Perspective.

What is New?

What Are the Clinical Implications?

Source of funding

Disclosures:

Nonstandard Abbreviations and Acronyms

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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