In a hub-and-spoke network, spoke-administered thrombolysis reduces mechanical thrombectomy procedure time and number of passes

Abstract

Background

The utility of intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT) in large vessel occlusion stroke (LVO) is controversial. Some data suggest IVT increases MT technical difficulty. Within our hub-and-spoke telestroke network, we examined how spoke-administered IVT affected hub MT procedure time and pass number.

Methods

Patients presenting to 25 spoke hospitals who were transferred to the hub and underwent MT from 2018 to 2020 were identified from a prospectively maintained database. MT procedure time, fluoroscopy time, and pass number were obtained from operative reports.

Results

Of 107 patients, 48 received IVT at spokes. Baseline characteristics and NIHSS were similar. The last known well (LKW)-to-puncture time was shorter among IVT patients (4.3 ± 1.9 h vs. 10.5 ± 6.5 h, p < 0.0001). In patients that received IVT, mean MT procedure time was decreased by 18.8 min (50.5 ± 29.4 vs. 69.3 ± 46.7 min, p = 0.02) and mean fluoroscopy time was decreased by 11.3 min (21.7 ± 15.8 vs. 33.0 ± 30.9 min, p = 0.03). Furthermore, IVT-treated patients required fewer MT passes (median 1 pass [IQR 1.0, 1.80] vs. 2 passes [1.0, 2.3], p = 0.0002) and were more likely to achieve reperfusion in ≤2 passes (81.3% vs. 59.3%, p = 0.01). An increased proportion of IVT-treated patients achieved TICI 2b-3 reperfusion after MT (93.9% vs. 83.8%, p = 0.045). There were no associations between MT procedural characteristics and LKW-to-puncture time.

Conclusion

Within our network, hub MT following spoke-administered IVT was faster, required fewer passes, and achieved improved reperfusion. This suggests spoke-administered IVT does not impair MT, but instead may enhance it.

Introduction

While mechanical thrombectomy (MT) has revolutionized large vessel occlusion (LVO) stroke care, outcomes after stroke are related to many factors.^1–4 Over half of those undergoing MT still have poor long-term outcomes.^5,6 Therefore, it is important to optimize efficacy and minimize the risks of MT. Treatment with intravenous thrombolysis (IVT) prior to MT is controversial with ongoing debate about its benefits versus risks. Multiple recent randomized trials comparing MT with and without bridging IVT for patients presenting directly to MT-capable centers suggest bypassing IVT does not worsen outcomes.^7–9 However, there are no randomized trials assessing bridging IVT for patients with LVO in “hub-and-spoke” stroke networks where patients first present to “spoke” hospitals that can administer IVT but must subsequently transfer patients to MT-capable “hub” centers.

Several potential concerns of IVT have been raised, including how IVT may influence MT procedural difficulty and reperfusion success. ¹⁰ Specifically, IVT is thought to soften and fragment thrombi, and there is a theoretical potential that thrombus fragmentation may make MT more difficult and result in distal embolization that limits cerebral reperfusion.^10,11 Previous analyses addressing this topic have found conflicting results. Several studies demonstrated bridging IVT was associated with more expeditious MT, whereas others showed that MT took more time, required more passes, and was less likely to achieve adequate reperfusion.^12–18 These studies have not focused on patients with LVO first presenting to spoke hospitals, where there is more time for chemical thrombolysis before MT. Thus, we examined how spoke-delivered IVT influences MT procedural difficulty in our hub-and-spoke hospital system.

Methods

This study was compliant with the Health Insurance Portability and Accountability Act and was reviewed and approved by the hub site institutional review board. Informed consent was waived based on minimal patient risk and practical inability to perform the study without the waiver. The data that support the findings of this study will be made available from the corresponding author upon reasonable request and pending approval of the local institutional review board.

Patients with LVO who presented to 25 spoke hospitals from January 1, 2018 to June 30, 2020 were identified from our local Get With the Guidelines-Stroke (GWTG-Stroke) patient database. ¹⁹ The definitions applied are those used in the GWTG-Stroke database unless otherwise specified. Database elements were extracted from the medical records and include demographics, medical history, clinical presentations, imaging findings, treatments, and functional outcomes for consecutive patients. ²⁰ Inclusion criteria were pre-transfer spoke CTA-defined LVO and ASPECTS ≥6. Only patients that underwent MT were included, and patients that were found to have no LVO on hub arrival were excluded from analyses.

Presenting National Institutes of Health Stroke Scale (NIHSS) score was determined by the hub neurologist as described, with higher numbers reflecting increased clinical stroke severity. ²¹ All patients underwent head and neck CT and CTA at spoke hospitals prior to transfer.^22,23 Alberta Stroke Program Early CT score (ASPECTS) and presence of LVO on CTA were determined by a vascular neurologist and confirmed by a neuroradiologist. LVO was defined as occlusion of the internal carotid artery (ICA) terminus, first (M1) and proximal second (M2) segments of the middle cerebral artery or the basilar artery. ²⁴ Cervical ICA disease was defined as severe stenosis (>70%) or occlusion related to atherosclerosis or dissection. ²⁵ IVT treatment decisions at spokes were guideline-based at the discretion of a vascular neurologist through telemedicine. ²⁶ Alteplase was the only agent used for IVT in this study. MT treatment decisions at the hub were at the discretion of a vascular neurologist and a neurointerventionalist. Procedure time was defined as arterial puncture time to closure time. Fluoroscopy time was defined as the cumulative time fluoroscopy was used during the procedure, which was automatically measured and recorded by a technician.

Thrombolysis in Cerebral Infarction (TICI) scores were determined by a neurointerventionalist using the modified scale: 2a partial filling <50%, 2b partial filling ≥50%, 3 complete perfusion (available for all undergoing MT). ²⁷ Adequate reperfusion was defined as TICI 2b-3. ²⁸ Symptomatic intracerebral hemorrhage (ICH) was defined as any symptomatic intraparenchymal, intraventricular, or subarachnoid hemorrhage during hospitalization. ²⁹

Mean values with standard deviation range (SD) were reported for continuous variables. Median values with interquartile range (IQR) were reported for discreet variables. Percent and count were reported for categorical variables. Statistical differences were assessed using permutation resampling in which test statistics calculated from comparing groups of interest were compared to null distributions generated from 10 ⁵ random group permutations. ³⁰ Multivariable linear regression analysis and logistic regression analysis were used to correct for variables of interest. Unadjusted and adjusted regression coefficients and p values were reported for linear regression. Odds ratios were reported as unadjusted and adjusted odds ratios for all variables listed in each logistic regression analysis. Two-tailed p-values <0.05 were interpreted as statistically significant. All statistics were performed with RStudio (version 1.4).

Results

During the specified time period, 107 patients were transferred from a spoke hospital to the hub and received MT. Of those, 48 were treated with spoke-administered IVT (IVT n = 48, No IVT n = 59). Age, sex, racial, and medical comorbidities were equivalent between the IVT and No IVT groups (Table 1). NIHSS scores at presentation to the spoke and hub were not different between groups (median spoke NIHSS IVT = 16.5 (11.0,21.3), No IVT = 15.0 (8.0,20.0); median hub NIHSS IVT = 17.0 (11.0,22.0), No IVT = 15.0 (10.0,18.0)). There was no difference in LVO anatomical location distribution between groups (Table 1). As was expected, the LKW-to-puncture time was shorter among IVT-treated patients (4.3 ± 1.9 h vs. 10.5 ± 6.5 h, p < 0.00001). IVT did not result in increased symptomatic intracranial hemorrhage (IVT = 4% vs. No IVT = 8%, p = 0.23) (Table 2).

Table 1.

Demographics, medical history, presentations, treatments, and outcomes.

	Total		Spoke IVT		No Spoke IVT
	Median/Count/Mean	IQR/%/S.D.	Median/ Count/Mean	IQR/%/S.D.	Median/ Count/Mean	IQR/%/S.D.	p
Age	68	(58,79)	64	(57, 76)	70	(60, 80)	0.06
Female	47	44%	19	40%	28	47%	0.33
Black	6	6%	4	8%	2	3%	0.22
Hispanic	4	4%	1	2%	3	5%	0.32
Asian	1	1%	0	0%	1	2%	0.45
White	74	69%	30	63%	44	75%	0.14
Hypertension	67	63%	27	56%	40	68%	0.16
Diabetes	29	27%	12	25%	17	29%	0.51
Atrial Fibrillation	35	33%	13	27%	22	37%	0.22
Coronary Disease	16	15%	5	10%	11	19%	0.17
Prior Stroke/TIA	15	14%	4	8%	11	19%	0.09
Dyslipidemia	49	46%	21	44%	28	47%	0.70
Obesity/Overweight	39	36%	17	35%	22	37%	0.84
Renal Insufficiency	9	8%	5	10%	4	7%	0.51
Smoking	20	19%	10	21%	10	17%	0.45
NIHSS at Spoke (N = 89, 48, 41)	16.0	(10.0,21.0)	16.5	(11.0,21.3)	15.0	(8.0,20.0)	0.41
NIHSS at Hub	16.0	(10.5,20.0)	17.0	(11.0,22.0)	15.0	(10.0,18.0)	0.13
LKW-Telestroke, Hours (N = 105, 48, 57)	4.54	4.87	1.91	1.88	6.75	5.49	<0.0001
LKW-Puncture, Hours (N = 105, 48, 57)	7.66	5.80	4.33	1.87	10.46	6.49	<0.0001
IVT-Puncture, Minutes	116.1	39.0	116.1	39.0	-	-
sICH	7	7%	2	4%	5	8%	0.23
LVO location							0.33
ICA	28	26.2%	10	20.8%	18	30.5%
M1 MCA	54	50.5%	25	52.1%	29	49.1%
M2 MCA	18	16.8%	11	22.9%	7	11.9%
Basilar	7	6.5%	2	4.2%	5	8.5%

IQR interquartile range; TIA transient ischemic attack; NIHSS National Institutes of Health stroke scale; LKW last known well; sICH symptomatic intracerebral hemorrhage; LVO large vessel occlusion; ICA internal carotid artery; MCA middle cerebral artery; M1 first MCA segment; M2 s MCA segment.; LKW-Telestroke: LKW to telestroke consult time interval; LKW-Pucture: LKW to groin puncture time interval; IVT-Puncture: IVT administration to groin puncture time interval.

Table 2.

Procedural characteristics and reperfusion outcomes.

	Spoke IVT		No Spoke IVT
	Median/Count/Mean	IQR/%/S.D.	Median/Count/Mean	IQR/%/S.D.	P
Procedure Time (mins)	50.5	29.4	69.3	46.9	0.02
Fluoroscopy Time (mins)	21.7	15.8	33.0	30.9	0.03
Puncture-to-TICI 2b-3 time (N = 53, 47)	30.2	21.9	43.4	49.3	0.09
Pass Number	1	(1.0,2.0)	2	(1.0,3.0)	0.0002
Pass Number >2 (%)	39 / 48	81%	35/59	59%	0.01
TICI 2b-3 (%)	45 / 48	93.8%	47 / 58	81%	0.045

TICI thrombolysis in cerebral infarction, SD standard deviation, IQR interquartile range.

In patients that received IVT, mean MT procedure time was decreased by 18.8 min (50.5 ± 29.4 vs. 69.3 ± 46.7 min, p = 0.02) and mean fluoroscopy time was decreased by 11.3 min (21.7 ± 15.8 vs. 33.0 ± 30.9 min, p = 0.03). In addition to procedure time, we were interested in how IVT influenced the number of thrombectomy passes. We found that IVT-treated patients required less MT passes (median 1 pass [IQR 1.0, 1.80] vs. 2 passes [1.0, 2.3], p = 0.0002). Moreover, the proportion of IVT patients requiring 2 or few passes was significantly higher (81.3% vs. 59.3%, p = 0.01). In patients that received IVT at spokes, there was an increase in the proportion of patients achieving final TICI 2b-3 reperfusion after MT (93.9% vs. 83.8%, p = 0.045).

Spoke IVT-treated patients had shorter latencies between LKW and MT (Table 1), and we were interested in the influence of LKW-to-puncture delays on MT procedural characteristics. We found that LKW-to-puncture time was not significantly associated with procedure time, fluoroscopy time, or pass number in multivariable models that also included spoke-administered IVT (Table 3). Moreover, the association between spoke-administered IVT and these improved procedural variables remained significant when differences in LKW-to-puncture were accounted for (Table 3).

Table 3.

Associations of last known well (LKW)-to-puncture time and spoke-administered intravenous thrombolysis (IVT) with procedural difficulty.

	RC (95% CI)	p	aRC (95% CI)	p
Procedure Time
Spoke IVT	−18.8 (-34.1, -3.5)	0.02	-21.0 (-39.4, -2.7)	0.03
LKW-Puncture	0.01 (-0.01, 0.03)	0.43	-0.01 (-0.03, 0.02)	0.62
Fluoroscopy Time
Spoke IVT	-11.25 (-21.10, -1.39)	0.03	-11.93 (-23.63, -0.22)	0.049
LKW-Puncture	0.01 (-0.01, 0.02)	0.34	0.01 (-0.02, 0.02)	0.84
	OR (95%CI)	p	aOR (95%CI)	p
Passes ≤2
Spoke IVT	3.07 (1.25, 8.20)	0.02	3.65 (1.30, 11.00)	0.02
LKW-Puncture	1.00 (1.00, 1.00)	0.44	1.00 (1.00, 1.00)	0.58

Spoke IVT was associated with decreased procedure times, decreased fluoroscopy times, and decreased pass number even when controlling for LKW-to-puncture time intervals. LKW-to-puncture time was not associated with any of these procedural variables. Regression coefficients (RC) and adjusted regression coefficients (aRC) are shown of linear regression. Odds ratios (OR) and adjusted odds ratios (aOR) are shown for logistic regression. CI confidence interval, IVT intravenous thrombolysis, LKW last known well. LKW-Pucture: LKW to groin puncture time interval.

Discussion

In this retrospective analysis examining 107 MT candidates who first presented to a spoke hospital and were ultimately transferred to the hub hospital for MT, spoke-administered IVT was associated with decreased MT procedural time and pass number. Furthermore, spoke IVT-treated patients had improved reperfusion after MT and no increased symptomatic ICH.

Since randomized trials initially demonstrated marked effectiveness of MT for LVO, the role of bridging IVT has been challenged.^10,31–33 Recent trials have demonstrated that bypassing IVT before MT in patients with LVO who presented directly to MT-capable centers did not result in worse outcomes.^7–9 However, bypassing IVT before MT for patients with LVO presenting to spoke hospitals that can administer IVT but must transfer for MT is not supported by trial data.

Several concerns regarding bridging IVT have been raised.^10,31 There is concern that IVT may lead to LVO thrombus fragmentation, making thrombi more difficult to retrieve and causing distal embolization that limits reperfusion.^10,11,14 In addition, an association between IVT before MT and increased thrombectomy pass number and/or worsened reperfusion scores has been demonstrated in small retrospective studies.^11,14,34 Other analyses have demonstrated no benefit from bridging IVT, and the increased cost of IVT has been an argument to bypass IVT before MT.^35–37 However, conflicting studies suggest bridging IVT is associated with improved MT procedural speed and decreased thrombectomy pass number.^{12,13,15–18} Moreover, there is evidence that bridging IVT is associated with improved reperfusion and functional outcomes.^15,38–40 Discrepancies in prior analyses are likely due to multiple factors.

The trials comparing combined IVT with MT versus MT alone focused on patients with LVO who presented directly to MT-capable hub hospitals, where there is limited dwell time for chemical thrombolysis from IVT. Over such a short time period, IVT's effect is likely minimal and it is possible that IVT has a larger effect with the longer dwell times inherent to a spoke-to-hub interhospital transfer. In our study, the mean IVT bolus to puncture time was 116 min. In comparison, the median IVT to puncture time was 29 min in the DIRECT-MT trial. ⁸ Prior studies showed that 75% of recanalization events occur >30 min after IVT bolus, with 25% of recanalization events happening more than one hour after the IVT bolus. ⁴¹

The influence of bridging IVT on MT has important implications for stroke systems of care. While there has been an understandable focus on optimizing MT reperfusion success for those treated, optimizing outcomes for patients that are not treated with MT or do not achieve adequate reperfusion after MT are also important. Importantly, when patients are transferred for MT consideration some are ultimately not MT candidates. ³⁹ Moreover, MT fails to achieve adequate reperfusion in up to 15% of patients with LVO.^5,42,43 Furthermore, it has also been shown that IVT is associated with improved outcomes for patients with LVO requiring transfer for MT consideration regardless of whether MT is performed. ³⁹ Thus, the finding that bridging IVT facilitates MT in a spoke-and-hub network should encourage providers to administer IVT to patients with LVO at spoke hospitals when there are no contraindications.

Our study has several limitations. First, this is a retrospective study and patients were not randomized to receive IVT at the spoke. The patients who did not receive IVT had longer latencies between LKW and presentation. While LKW-to-puncture time did not appear to influence our variables of interest, there is potential for unrecognized confounders that we cannot control for because they were not available in our dataset, such as specific baseline antithrombotic status. Second, the reliance on telestroke-triaged patients with LVO represents an important but understudied variable in MT candidacy. Furthermore, our study included patients from a single telestroke network with unique geographical constraints. It is not clear how generalizable these results are to other telestroke networks in different locations. Importantly, our study is underpowered to detect small differences in rare events such as symptomatic ICH. Finally, as is the case with many stroke clinical trials, generalizability may be limited by a lack of diversity since this study is weighted toward non-Hispanic white patients.^7–9

Conclusions

Spoke IVT was associated with improved MT procedure time and reduced number of passes. Furthermore, spoke-administered IVT was associated with increased final TICI2b-3 reperfusion after MT. This suggests that thrombus fragmentation from IVT does not result in significant distal embolization. This study supports the continued use of IVT, as recommended by current American Heart Association guidelines, for any patient with LVO stroke requiring transfer for MT. Recent trials supporting the bypass of IVT at MT-capable centers may not apply to hub-and-spoke networks.