Rate of Symptomatic Intracerebral Hemorrhage Related to Intravenous tPA Administered Over Telestroke Within 4.5-Hour Window

Abstract

Background:

Intravenous tissue plasminogen activator (tPA) remains the cornerstone medical treatment for acute ischemic stroke. The establishment of telestroke technology has allowed patients presenting to hospitals that lack expert stroke care to be evaluated and receive tPA. The safety of tPA administered through telestroke has been evaluated only when tPA is given within the 3-h window of last known normal. The purpose of this study is to evaluate the safety of tPA when administered through telestroke within a 4.5-h window.

Methods:

A retrospective analysis on the prospectively collected database for all patients who received tPA at the Medical University of South Carolina Comprehensive Stroke Center (MUSC) (hub), as well as the MUSC telestroke network partner hospitals (spokes), was performed. Collected data included demographics, baseline characteristics, time from last known well to tPA administration, and symptomatic intracerebral hemorrhage (sICH) rates. Logistic regression was used to examine the odds of a sICH in patients at spoke sites compared with the hub controlling for patient stroke severity, gender, age, and race.

Results:

A total of 830 patients were identified. Median National Institute of Health Stroke Scale was significantly higher among patients treated at the hub (9 vs. 8, p = 0.013), and the hub treated a higher percentage of nonwhite patients (p = 0.039). sICH occurred in 27 (4.8%) in the spoke group and 10 (3.8%) in the hub group (p = 0.523). Logistic regression results found no significant difference in the odds of sICH if tPA is given in a spoke site.

Conclusions:

Our study shows similar rates of sICH when intravenous tPA is administered at spokes through telestroke network compared with the hub.

Introduction

Intravenous tissue plasminogen activator (tPA) is one of the two mainstay treatments approved for acute ischemic stroke (AIS).^1,2 One of the main limitations of tPA is the time window during which it can be administered.^3,4 tPA has Food and Drug Administration approval to be used in the treatment of AIS within 3 h of last known normal¹; however, its safety and efficacy have been well demonstrated when administered in the 3–4.5-h window.⁵

Since the inception of telestroke, access to expert stroke opinion has been made readily available particularly for patients living in rural areas, allowing them to receive tPA.^6,7 Through this network, a stroke expert at the hub hospital remotely evaluates patients presenting with AIS symptoms at spoke sites.

Few previous studies evaluated the safety of tPA when administered through telestroke network.^7,8 A recent meta-analysis included seven prospective studies that evaluated tPA safety through telestroke.⁹ This study showed that the rate of symptomatic intracerebral hemorrhage (sICH) related to tPA is similar when administered at hub when compared with spokes; however, all the available studies evaluated tPA safety within the 3-h window only.

The aim of this study is to compare the rate of sICH related to tPA when administered at spokes through the Medical University of South Carolina Comprehensive Stroke Center (MUSC) telestroke network within the 4.5-h window with that at the hub hospital. In addition, we examine sICH rates when tPA is given within 3 h versus 3–4.5 h at the spoke hospital controlling for patient baseline stroke severity score, gender, age, and race.

Methods

Study Sites

The overall design, clinical, and operational outcomes of the MUSC telestroke program have been described previously.^10,11 In brief, the MUSC telestroke program was established in 2008. The number of participating sites covered by the MUSC telestroke hub has increased from 6 spoke sites in 2008 to 24 sites in December 2016. Between May 2008 and December 2016, a total of 10,494 consults were performed.

Data Collection

The study was deemed to fall under a quality improvement and was exempt from Institutional Review Board review. Statistical analysis was conducted in STATA 14 software system.

The prospectively maintained MUSC telestroke registry and a hub export from the electronic medical record were interrogated. Collected variables included patient demographics (age, gender, and race), baseline National Institute of Health Stroke Scale (NIHSS), time from last known well to tPA administration, and occurrence of an sICH.

sICH is reported in all patients during their hospitalization and is routinely extracted for the telestroke data set by the program coordinators. sICH was defined as parenchymal hematoma 2 (PH2) with computed tomography-based classification according to the European Cooperative Acute Stroke Study II study (ECASII).³ The rates of sICH were compared between the two settings (hub vs. spokes). Within the data set, occurrence of sICH was coded as 1 if the patient had an sICH and 0 if the adverse outcome did not occur. Independent variables included the patient location (hub or spoke), time from symptom onset to needle (coded as 1 if >180 min and 0 if 180 min or less), NIHSS admission score, gender (female = 1, male = 0), age in years, and race (coded as white = 1 or nonwhite = 0).

Statistical Analysis

Baseline demographic characteristic and stroke severity on presentation measured by NIHSS were compared in both groups using t-tests for continuous variables and chi-squared test for categorical variables. The differences in unadjusted sICH rates were compared between the hub and spoke patients using chi-squared test. We examined the effect of the independent variables on the likelihood of having an sICH using logistic regression.

Results

As shown in Figure 1, the combined database included 10,494 patient consultations occurring between May 2008 and December 2016. Patients who were not eligible for tPA (n = 8,067) and those who received mechanical thrombectomy (n = 752) were excluded from the study. To ensure we have reliable data on occurrence of sICH, we also excluded from our sample telestroke tPA patients who were not transferred to the hub (n = 645). Finally, 200 consultations were excluded for missing information such as NIHSS on presentation, and time to treatment.

Fig. 1.

Selection of patients included in the study between 2008 and 2016 (n = 830). tPA, Intravenous tissue plasminogen activator.

Of the 830 patients, 566 received tPA at spoke sites and then were transferred to the hub, and 264 received tPA at the hub. Patient characteristics are presented in Table 1. Median NIHSS was significantly higher among patients treated at the hub (9 vs. 8, p = 0.013), and the hubs treated a higher percentage of nonwhite patients (p = 0.039). Otherwise baseline characteristics were similar in both treatment groups. There was no significant difference in the percentage of patients who received tPA in the 180–270-min window between the two groups. tPA was administered within 3 h for 436 (77.0%) of spoke patients and 198 (75%) of hub patients. One-hundred thirty patients (23.0%) versus 66 (25.0%) received tPA between 3 and 4.5 h from last known normal at the spoke and hub hospitals, respectively (p = 0.521).

Table 1.

Patient Characteristics (n = 830)

DEMOGRAPHIC VARIABLE	SPOKE (N = 566)	HUB (N = 264)	p
Age (mean)	65.6	65.5	0.906
NIHSS admission (mean)	10.8	9.8	0.0522
NIHSS admission (median)	9	8	0.013
Race			0.039
White, n (%)	339 (59.9)	138 (52.3)
Nonwhite, n (%)	227 (40.1)	126 (47.7)
Gender			0.55
Female, n (%)	294 (51.9)	143 (54.2)
Male, n (%)	272 (48.1)	121 (45.8)
Symptom to needle			0.521
<180 min, n (%)	436 (77.0)	198 (75.0)
180–270 min, n (%)	130 (23.0)	66 (25.0)

NIHSS, National Institute of Health Stroke Scale.

Results of the unadjusted comparison of bleed rates found no significant relationship with the length of time between symptom onset and treatment. A bleed occurred in 28 (4.4%) of patients who were treated within 3 h and in 9 (4.6%) of those administered between 3 and 4.5 h after first stroke symptom (p = 0.917).

Results of the logistic regression found no significant differences in the odds of sICH for spoke hospital patients compared with hub patients (p = 0.571) (Table 2). In addition, the odds of sICH were not significant for tPA administration in 3–4.5 h compared with <3 h of last known normal (p = 0.882).

Table 2.

Logistic Regression Results Odds of Symptomatic Intracerebral Hemorrhage

VARIABLE	OR	SE	p	95% CI
Spoke^a	1.24	0.47	0.571	0.59	2.62
Symptom to needle >180 min^b	1.06	0.42	0.882	0.49	2.30
NIHSS admissions score	1.03	0.02	0.165	0.99	1.07
Female	0.97	0.33	0.918	0.49	1.90
Age	1.03	0.01	0.053	1.00	1.05
White	0.99	0.35	0.981	0.50	2.00

OR of sICH for spoke telemedicine patients compared with hub patients.

Referent group <180 min symptom to needle.

CI, confidence interval; OR, odds ratio; SE, standard error; sICH, symptomatic intracerebral hemorrhage.

Discussion

Our study shows that the rate of sICH related to tPA administered at spoke hospitals through telestroke is similar to that when administered at the hub hospital within 4.5 h of last known normal. Our study also shows that there is no difference in the rate of sICH between the hub and spoke hospitals when tPA is administered between 0 and 3 h when compared with within 3–4.5 h of last known normal. To our knowledge, this is the first study to report the safety of tPA through telestroke delivered within 4.5 h of last known normal, specifically the 3–4.5-h window.

Our results are consistent with previous studies that reported the safety of tPA through telestroke.^8,9 A study by Switzer et al.¹² evaluated the safety, feasibility, and treatment times of tPA administered through telestroke. The authors included 50 patients treated within 3 h of the last known normal and found a 2% sICH rate. Another study by Pervez et al.⁸ evaluated the complications and outcomes of patients treated with tPA through telestroke and compared them with those at the regional stroke center. Of 296 patients, 181 (61.1%) received tPA within 3 h of last known normal at spoke hospital and 115 (38.9) at the hub center. The investigators found that mortality rate of sICH and functional outcomes were not different between the two groups.

Our study is unique in that we included patients who received tPA within 4.5 h of last known normal. We further compared the rates of sICH between the patients treated in the 0–3-h with those treated in the 3–4.5-h windows and found no significant difference. This indicates that tPA has similar safety profile when administered over telestroke within the 4.5-h window.

Our study has several limitations. The main limitation is the retrospective non randomized study design. The design is strengthened by utilizing patients who arrive through the hub emergency department as a comparison group. The study also depends on registry data and data limitations prevent us from having complete access to patient outcomes for those who do not transfer to the Academic Medical Center. To strengthen the data accuracy, we limit the study to those patients who were treated at a spoke site and transferred to the hub. Preliminary assessment found no statistically significant difference in the bleed rates of those patients who remained in the spoke sites versus transferring to the hub (p = 0.0778). Although a quality assurance assessment is conducted to compare with the medical record, there is still potential for error and missing data. Therefore, we are unable to comment on the sICH rates for patients who remain in partner hospitals. In addition, future studies should evaluate other complications such as systemic and non-sICH bleeding.

Conclusions

In conclusion, the present data demonstrate that the odds of an adverse event, sICH, when tPA is delivered through telestroke are not significantly different when given in 0–4.5-h window compared with those of patients at a hub hospital. This is a promising finding for those patients who are located in rural or remote locations and who would otherwise not have access to tPA within the 4.5-h administration window. A prospective study is needed to confirm our findings.

Footnotes

Disclosure Statement

No competing financial interests exist.

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