This cohort study assesses whether administration of intra-arterial urokinase is safe and improves reperfusion among patients who have undergone failed or incomplete mechanical thrombectomy.
Key Points
Questions
Is adjunctive administration of intra-arterial urokinase safe after failed or incomplete mechanical thrombectomy?
Findings
In this cohort study of 993 consecutive patients treated with mechanical thrombectomy, additional administration of intra-arterial urokinase (performed in 100 patients) was not associated with an increased risk of symptomatic intracranial hemorrhage (5.2% vs 6.9%) and was associated with higher rates of 90-day functional independence in fully adjusted models.
Meaning
In selected patients with incomplete or failed mechanical thrombectomy, adjunctive treatment with intra-arterial urokinase was safe, and further evaluation of this treatment approach seems warranted.
Abstract
Importance
Achieving complete reperfusion is a key determinant of good outcome in patients treated with mechanical thrombectomy (MT). However, data on treatments geared toward improving reperfusion after incomplete MT are sparse.
Objective
To determine whether administration of intra-arterial urokinase is safe and improves reperfusion after failed or incomplete MT.
Design, Setting, and Participants
This observational cohort study included a consecutive sample of patients treated with second-generation MT from January 1, 2010, through August 4, 2017. Data were collected from the prospective registry of a tertiary care stroke center. Of 1274 patients screened, 69 refused to participate, and 993 met the observational studies inclusion criteria of a large vessel occlusion in the anterior circulation. Data were analyzed from September 1, 2017, through September 20, 2019.
Intervention
One hundred patients received intra-arterial urokinase after failed or incomplete MT using manual microcatheter injections.
Main Outcomes and Measures
Primary safety outcome was the occurrence of symptomatic intracranial hemorrhage (sICH) according to the Prolyse in Acute Cerebral Thromboembolism II criteria. Secondary end points included 90-day mortality and 90-day functional independence (defined as modified Rankin Scale score of ≤2). Efficacy was evaluated angiographically, applying the Thrombolysis in Cerebral Infarction (TICI) scale.
Results
After exclusion of patients with posterior circulation strokes and those treated with intra-arterial thrombolytics only, 993 patients were included in the final analyses (median age, 74.6 [interquartile range, 62.6-82.2] years; 505 [50.9%] women). Additional intra-arterial urokinase was administered in 100 patients (10.1%). The most common reason for administering intra-arterial urokinase was incomplete reperfusion (TICI<3) after MT (53 [53.0%]). After adjusting for baseline characteristics underlying case selection, intra-arterial urokinase was not associated with an increased risk of sICH (adjusted odds ratio [aOR], 0.81; 95% CI, 0.31-2.13) or 90-day mortality (aOR, 0.78; 95% CI, 0.43-1.40). Among 53 cases of partial or near-complete reperfusion and treated with intra-arterial urokinase, 32 (60.4%) had early reperfusion improvement, and 18 of 53 (34.0%) had an improvement in TICI grade. Correspondingly, patients treated with intra-arterial urokinase had higher rates of functional independence after adjusting for the selection bias favoring a priori poor TICI grades in the intra-arterial urokinase group (aOR, 1.93; 95% CI, 1.11-3.37).
Conclusions and Relevance
In selected patients, adjunctive treatment with intra-arterial urokinase during or after MT was safe and improved angiographic reperfusion. Systemic evaluation of this approach in a multicenter prospective registry or a randomized clinical trial seems warranted.
Introduction
Successful reperfusion1,2—ideally complete (Thrombolysis in Cerebral Infarction grade 3 [TICI 3]) reperfusion3,4,5—is the most relevant and modifiable determinant of functional outcome in patients undergoing mechanical thrombectomy (MT) for acute ischemic stroke due to large-vessel occlusion. However, in almost every tenth patient, no reperfusion can be achieved2,6,7 and, according to data from the HERMES collaboration2 and large registry data,8,9 most patients treated successfully do not achieve TICI 3. Evaluation of adjunct treatment approaches after MT in cases of failed procedures6,7,10 or regimens geared toward achieving complete (TICI 3) instead of near-complete (TICI 2b) reperfusion may thus improve outcome.11,12
One promising treatment option in both scenarios is the administration of intra-arterial thrombolytics, using either intra-arterial tissue plasminogen activator (tPA) or intra-arterial prourokinase/urokinase.13,14,15,16,17,18,19,20,21 However, data on their safety and efficacy as adjuncts to second-generation MT devices are scarce.13,14,15,16 We hypothesized that intra-arterial urokinase administered during or after MT is safe in selected patients and promotes improvement of angiographically measured reperfusion in cases of failed or incomplete MT.
Methods
Study Cohort
All patients undergoing endovascular treatment who were included in the Bernese Stroke registry from January 1, 2010, through August 4, 2017, were included in the study review (n = 1274). Of those, 69 refused (in writing or orally) to make their data available for research. We excluded patients who were treated with intra-arterial urokinase (with or without intravenous tPA) only and patients presenting with posterior circulation large-vessel occlusion or distal anterior circulation vessel occlusions, leaving 993 patients treated with MT (Figure 1 provides further details). Use of the registry was approved by the local ethics committee (Kantonale Ethikkommission für die Forschung Bern). Patients gave written or oral consent for the use of their data for research. Before January 1, 2015, the need for consent was waived according to regulations by the Swiss Law and the local ethics committee.
Figure 1. Study Flowchart.
AC indicates anterior circulation; IA, intra-arterial; IVT, intravenous thrombolysis; and LVO, large-vessel occlusion.
In 100 patients (10.1%), additional intra-arterial urokinase was administered. Ninety days after the acute event, functional outcome was assessed by board-certified vascular neurologists during a routinely scheduled clinical visit or by a study nurse certified in administering the modified Rankin Scale (mRS) during a standardized telephone interview if the patient was unable to attend. Functional independence was defined as an mRS score of 2 or less. Day 90 follow-up data were available for 959 patients (96.6%).
Preinterventional Workup and Endovascular Treatment
Patients with suspected acute ischemic stroke underwent admission computed tomography (n = 445) or magnetic resonance imaging (n = 548), depending on comorbidities, patient adherence, and stroke severity. Further information on the preinterventional workup can be found in the eMethods in the Supplement. Endovascular treatment was performed with second-generation devices only, mostly using stent retrievers (eMethods in the Supplement). According to the Prolyse in Acute Cerebral Thromboembolism II (PROACT-II)17,18 and Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT)19 studies, urokinase (Medac GmbH and Opopharma Vertriebs AG) was injected manually before (PROACT-II) or next to and distal to (MELT) the thrombus, usually via the same microcatheter used to introduce the MT device. Availability and indications for use of urokinase in Switzerland and the United States can be found in the eMethods in the Supplement. In our study, the applied dose ranged from 50 000 to 1 000 000 IU (median dose, 300 000 IU). Normally, application of urokinase took approximately 45 to 60 minutes but was terminated if sequentially performed diagnostic angiograms taken during application of intra-arterial urokinase showed reperfusion.
Image Analysis
Final TICI grades were assessed by an independent research fellow blinded to the clinical data (J.K.). For analysis, the modified TICI scale was used, with TICI 2b defined as at least 50% reperfusion of the initially hypoperfused territory.22 When intra-arterial urokinase was administered after failed or incomplete MT, TICI grade was assessed before and after the intra-arterial urokinase administration. When no change in the TICI score had occurred from before to after intra-arterial urokinase administration, the rater had to assess whether any kind of angiographic improvement occurred compared with before administration of intra-arterial urokinase. All angiographic images were reviewed for periprocedural complications related to intra-arterial urokinase administration. According to the PROACT-II criteria, symptomatic intracranial hemorrhage (sICH) was defined as evidence of ICH with an increase of 4 points or more on the total National Institutes of Health Stroke Scale (NIHSS) or a 1-point increase in level of consciousness on the NIHSS.17
Statistical Analysis
Data were analyzed from September 1, 2017, through September 20, 2019. Univariable comparisons between patients with and without intra-arterial urokinase administration were performed using Mann-Whitney or Fisher exact tests. Data are displayed as frequency counts or median and interquartile range (IQR). Adjusted odds ratios (aORs) and corresponding 95% CIs of added intra-arterial urokinase for several outcome parameters were calculated using logistic regression adjusting for all baseline differences with 2-sided P < .15 in univariate analyses (model A). To estimate a potential association of intra-arterial urokinase with functional outcome, a second model (model B) was used with additional adjustment for difference regarding technical case selection (ie, longer door-to-groin intervals and poorer TICI grade). For TICI grade adjustments, the TICI grade before intra-arterial urokinase administration was used whenever intra-arterial urokinase was applied with the intention to improve the reperfusion status after terminated MT. Significance level was set to α = .05. All tests were 2 sided. Statistical analyses were conducted using SPSS, version 22.0 (IBM Corporation) or Stata, version 15.1 (StataCorp LLC).
Results
Study Population
After exclusion, 993 patients (median age, 74.6 [IQR, 62.6-82.2] years; 505 women [50.9%] and 488 men [49.1%]) were incorporated into the final analysis (Table 1). Patients presented with severe symptoms (median NIHSS score, 15 [IQR, 10-20]) and received preinterventional intravenous tPA in 419 cases (42.2%). Of 993 patients treated for anterior circulation large-vessel occlusion, 100 (10.1%) received intra-arterial urokinase during the endovascular procedure (median dose, 300 000 [IQR, 250 000-500 000] IU). Urokinase dose administered intra-arterially was lower in patients receiving preinterventional intravenous tPA (median, 250 000 [IQR, 250 000-500 000] vs 500 000 [IQR, 250 000-500 000] IU; P = .02). Intra-arterial urokinase was administered at a median of 275 (IQR, 229-313) minutes in 98 of 100 patients after symptom onset or after time last seen well, with 9 patients (9.0%) treated later than 6 hours after symptom onset. There was no correlation between symptom onset or time last seen well with intra-arterial urokinase administration and dose applied (Spearman ρ = 0.03; P = .77).
Table 1. Baseline and Procedural Characteristics.
| Characteristic | Treatment Group | P Value | Variable Included | |||
|---|---|---|---|---|---|---|
| All (N = 993) | MT Without Intra-arterial Urokinase (n = 893) | MT With Intra-arterial Urokinase (n = 100) | ||||
| Model Aa | Model Bb | |||||
| Baseline | ||||||
| Age, median (IQR), y | 74.6 (62.6-82.2) | 75.0 (63.0-82.5) | 71.1 (58.6-78.1) | .007 | Yes | Yes |
| Sex, female, No./total No. (%) | 505/993 (50.9) | 463/893 (51.8) | 42/100 (42.0) | .07 | Yes | Yes |
| Risk factors, No./total No. (%) | ||||||
| Arterial hypertension | 758/993 (76.3) | 682/893 (76.4) | 76/100 (76.0) | .90 | No | No |
| Diabetes | 195/985 (19.8) | 179/887 (20.2) | 16/98 (16.3) | .42 | No | No |
| Dyslipidemia | 643/993 (64.8) | 581/893 (65.1) | 62/100 (62.0) | .58 | No | No |
| Smoking | 233/993 (23.5) | 209/893 (23.4) | 24/100 (24.0) | .90 | No | No |
| Coronary artery disease | 204/991 (20.6) | 181/891 (20.3) | 23/100 (23.0) | .52 | No | No |
| Glucose level on admission, mg/dLc | 119 (103-142) | 119 (103-142) | 117 (106-139) | .73 | No | No |
| Platelet count, median (IQR), ×103/μLd | 215 (174-261) | 215 (173-259) | 215 (188-273) | .07 | Yes | Yes |
| Time from symptom onset to admission, median (IQR), mine | 138 (72-240) | 145 (77-250) | 83 (63-152) | <.001 | Yes | Yes |
| Admission MRI, No./total No. (%) | 548/993 (55.2) | 482/893 (54.0) | 66/100 (66.0) | .03 | Yes | Yes |
| DWI/NCT-ASPECTS, median (IQR)f | 8 (5-9) | 8 (5-9) | 7 (5-8) | .09 | Yes | Yes |
| DWI-ASPECTS, median (IQR)f,g | 8 (5-9) | 8 (6-9) | 7 (5-8) | .09 | No | No |
| NCT-ASPECTS, median (IQR)f,h | 8 (7-9) | 8 (7-9) | 8 (7-9) | .92 | No | No |
| Admission NIHSS score, median (IQR)i,j | 15 (10-20) | 15 (10-20) | 14 (9-20) | .57 | No | No |
| Occlusion site, No./total No. (%) | ||||||
| iICA or carotid-T/L | 273/993 (27.5) | 249/893 (27.9) | 24/100 (24.0) | .16 | Yes | Yes |
| M1 | 592/993 (59.6) | 535/893 (59.9) | 57/100 (57.0) | |||
| M2 | 128/993 (12.9) | 109/893 (12.2) | 19/100 (19.0) | |||
| Stroke cause, No./total No. (%) | ||||||
| Large-artery atherosclerosis | 102/993 (10.3) | 95/893 (10.6) | 7/100 (7.0) | .25 | No | No |
| Cardioembolic | 428/993 (43.1) | 381/893 (42.7) | 47/100 (47.0) | |||
| Other determined | 67/993 (6.7) | 56/893 (6.3) | 11/100 (11.0) | |||
| Unknown (complete workup) | 178/993 (17.9) | 159/893 (17.8) | 19/100 (19.0) | |||
| Unknown (incomplete workup) | 165/993 (16.6) | 154/893 (17.2) | 11/100 (11.0) | |||
| Multiple competing causes | 53/993 (5.3) | 48/893 (5.4) | 5/100 (5.0) | |||
| Treatment or procedure | ||||||
| IVT bridging, No./total No. (%) | 419/993 (42.2) | 376/893 (42.1) | 43/100 (43.0) | .92 | No | No |
| Door to groin time, median (IQR), mink | 92 (69-120) | 92 (69-119) | 95 (77-134) | .12 | No | Yes |
| General anesthesia, No./total No. (%) | 653/970 (67.3) | 592/877 (67.5) | 61/93 (65.6) | .73 | No | No |
| Extracranial stenting, No./total No. (%) | 134/991 (13.5) | 124/891 (13.9) | 10/100 (10.0) | .35 | No | No |
| Reason for intra-arterial urokinase administration, No./total No. (%) | ||||||
| Rescue after thrombectomy (TICI grade 0/1) | NA | NA | 15/100 (15.0) | NA | No | No |
| Improvement (TICI grade 2a/2b) | NA | NA | 53/100 (53.0) | |||
| Before or during first, second, or third stent-retriever deployment | NA | NA | 25/100 (25.0) | |||
| Treatment of ENTs | NA | NA | 7/100 (7.0) | |||
| Dose of intra-arterial urokinase, median (IQR), IU | 300 000 (250 000-500 000) | NA | 300 000 (250 000-500 000) | NA | No | No |
| Groin puncture to reperfusion, median (IQR), minl | 45 (30-73) | 43 (28-69) | 72 (47-111) | <.001 | No | Yes |
| Time from symptom onset to intra-arterial urokinase, median (IQR), minm | 275 (229-313) | NA | 275 (229-313) | NA | No | No |
| Final mTICI grade, No./total No. (%)n | ||||||
| 0 | 66/992 (6.7) | 61/892 (6.8) | 5/100 (5.0) | <.001 | No | Yes |
| 1 | 28/992 (2.8) | 21/892 (2.4) | 7/100 (7.0) | |||
| 2a | 112/992 (11.3) | 94/892 (10.5) | 18/100 (18.0) | |||
| 2b | 334/992 (33.7) | 280/892 (31.4) | 54/100 (54.0) | |||
| 3 | 452/992 (45.6) | 436/892 (48.9) | 16/100 (16.0) | |||
Abbreviations: ASPECTS, Alberta Stroke Program Early CT (Computed Tomography) Score; DWI, diffusion-weighted imaging; ENT, emboli to new territory; IA, intra-arterial; iICA, intracranial internal carotid artery; IQR, interquartile range; IVT, intravenous thrombolysis; M1, first segment of the middle cerebral artery; M2, second segment of the middle cerebral artery; MRI, magnetic resonance imaging; MT, mechanical thrombectomy; mTICI, modified Thrombolysis in Cerebral Infarction; NA, not applicable; NCT, noncontrast CT; NIHSS, National Institutes of Health Stroke Scale; TICI, Thrombolysis in Cerebral Infarction; T/L, T- or L-type iICA occlusion.
SI conversion factors: To convert glucose to millimoles per liter, multiply by 0.0555; platelets to ×109 per liter, multiply by 1.0.
Indicates adjusted for baseline differences.
Indicates adjusted for baseline differences and technical case selection variables.
Includes 958 patients.
Includes 977 patients.
Includes 963 patients.
Scores range from 0 to 10, with higher scores indicating less extent of early ischemic changes.
Includes 548 patients.
Includes 445 patients.
Scores range from 0 to 42, with higher scores indicating more severe neurological deficits.
Includes 990 patients.
Includes 985 patients.
Includes 933 patients.
Includes 98 patients.
For TICI grade adjustments, the TICI grade before intra-arterial urokinase was used whenever intra-arterial urokinase was applied with the intention to improve the reperfusion status after terminated MT.
Reasons for administration of intra-arterial urokinase consisted of (1) rescue after failed thrombectomy with multiple maneuvers (15 of 100 [15.0%]); (2) improvement of reperfusion (TICI 2a or 2b) in cases where residual occlusions were not reachable with mechanical devices (53 of 100 [53.0%]); (3) facilitation of clot removal before or during the first, second, or third stent-retriever deployment at the operators’ discretion (25 of 100 [25.0%]); or (4) treatment of emboli to new territory (7 of 100 [7.0%]). Patients who received intra-arterial urokinase were younger (median age, 71.1 [IQR, 58.6-78.1] vs 75.0 [IQR, 63.0-82.5]; P = .007) (Table 1), were less often female (42 of 100 [42.0%] vs 463 of 893 [51.8%]; P = .07), were admitted earlier (median, 83 [IQR, 63-152] vs 145 [IQR, 77-250] minutes; P < .001), and had a slightly higher median platelet count (215 × 103/μL [IQR, 188 × 103/μL-273 × 103/μL] vs 215 × 103/μL [IQR, 173 × 103/μL-259 × 103/μL]; P = .07). The intra-arterial urokinase group had numerically more distal occlusions; however, patients receiving intra-arterial urokinase had a median diffusion-weighted imaging Alberta Stroke Program Early CT Score of 7 (IQR, 5-8), whereas patients not receiving intra-arterial urokinase had a median score of 8 (IQR 6-9; P = .09). Inherent to the selection of cases (failed or incomplete reperfusion), groin puncture to reperfusion was longer in patients receiving intra-arterial urokinase (median, 72 [IQR, 47-111] vs 43 [IQR, 28-69] minutes; P < .001), and final TICI grades were overall worse (eg, TICI 3, 16 of 100 (16.0%] vs 436 of 892 [48.9%]; P < .001).
Safety
Occurrence of systemic bleeding was comparable between patients with and without intra-arterial urokinase (Table 2). The frequency of sICH according to PROACT-II criteria did not differ between the groups with and without intra-arterial urokinase (5 of 97 [5.2%] vs 60 of 875 [6.9%], respectively; P = .67). In patients undergoing direct MT (without intravenous tPA), the rate of sICH was comparable if intra-arterial urokinase was administered (4 of 55 [7.3%] vs 33 of 507 [6.5%]; P = .78), whereas in patients receiving intravenous tPA before MT, sICH rates were numerically lower in those with additional administration of intra-arterial urokinase (1 of 42 [2.4%] vs 27 of 368 [7.3%]; P = .33). The common OR for intra-arterial urokinase on sICH for both groups was estimated to be 0.74 (95% CI, 0.29-1.88), according to Mantel-Haenszel statistics, without significant evidence for heterogeneity across intravenous tPA strata (Breslow-Day test for homogeneity of OR across strata, P = .24). Asymptomatic bleeding was less frequent in patients receiving intra-arterial urokinase (15 of 92 [16.3%] vs 222 of 818 [27.2%]; P = .02), and mortality at day 90 tended to be lower (19 of 99 [19.2%] vs 235 of 860 [27.3%]; P = .09). After adjusting for baseline differences (model A), administration of intra-arterial urokinase was associated with reduced asymptomatic ICH (aICH) and no risk difference in terms of sICH (aOR, 0.81; 95% CI, 0.31-2.13) or mortality (aOR, 0.78; 95% CI, 0.43-1.40) (Table 2 and Figure 2). When the model was extended by technical and procedural characteristics (including TICI score bias [model B]), intra-arterial urokinase was not associated with an increased risk of sICH (aOR, 0.46; 95% CI, 0.15-1.42), but was associated with lower rates of aICH (aOR, 0.54; 95% CI, 0.29-0.99) and lower mortality (aOR, 0.48; 95% CI, 0.25-0.92) (Figure 2). In a sensitivity analysis, neither dose (median 250 000 [IQR, 125 000-425 000] vs 300 000 [IQR, 250 000-500 000] IU; P = .16) nor timing (median, 295 [IQR, 259-305] vs 267 [IQR, 223-320] minutes; P = .51) of intra-arterial urokinase administration was different between patients with and without sICH in the subgroup of patients receiving intra-arterial urokinase. Three patients in the urokinase subgroup had missing adjudication of sICH, in 2 because of early death after the intervention. Because we cannot exclude sICH in these patients, we performed a sensitivity analysis assuming that all 3 patients had sICH (worst-case scenario). Applying these assumptions, intra-arterial urokinase was still not associated with an increased risk of sICH (model A aOR, 1.32 [95% CI, 0.59-2.93]; model B aOR, 0.74 [95% CI, 0.29-1.86]) (eFigure 1 in the Supplement).
Table 2. Primary and Secondary Outcomes.
| Outcome | Treatment Group, No./Total No. (%) | P Value | Model Aa | Model Bb | ||||
|---|---|---|---|---|---|---|---|---|
| All (N = 993) | MT Without Intra-arterial Urokinase (n = 893) | MT With Intra-arterial Urokinase (n = 100) | ||||||
| No./Total No. | aOR (95% CI)c | No./Total No. | aOR (95% CI)c | |||||
| Poststroke seizures | ||||||||
| None | 943/990 (95.3) | 845/890 (94.9) | 98/100 (98.0) | .80 | NA | NA | NA | NA |
| Focal | 19/990 (1.9) | 18/890 (2.0) | 1/100 (1.0) | NA | NA | NA | NA | |
| Complex focal | 5/990 (0.5) | 5/890 (0.6) | 0/100 | NA | NA | NA | NA | |
| Generalized | 23/990 (2.3) | 22/890 (2.5) | 1/100 (1.0) | NA | NA | NA | NA | |
| Systemic bleeding | 13/992 (1.3) | 13/892 (1.5) | 0/100 | .63 | NA | Did not converge | NA | Did not converge |
| PROACT-II | ||||||||
| sICH | 65/972 (6.7) | 60/875 (6.9) | 5/97 (5.2) | .67 | 930/972 | 0.81 (0.31-2.13) | 877/972 | 0.46 (0.15-1.42) |
| aICH (excluding sICH) | 237/907 (26.1) | 222/815 (27.2) | 15/92 (16.3) | .02d | 869/907 | 0.53 (0.29-0.95) | 823/907 | 0.54 (0.29-0.99) |
| mRS score 0-2 at 90 de | 374/959 (39.0) | 329/860 (38.3) | 45/99 (45.5) | .19 | 917/959 | 1.00 (0.62-1.64) | 854/959 | 1.93 (1.11-3.37) |
| Mortality at 90 d | 254/959 (26.5) | 235/860 (27.3) | 19/99 (19.2) | .09 | 917/959 | 0.78 (0.43-1.40) | 854/959 | 0.48 (0.25-0.92) |
Abbreviations: aICH, asymptomatic intracranial hemorrhage; aOR, adjusted odds ratio; IA, intra-arterial; mRS, modified Rankin Scale; MT, mechanical thrombectomy; NA, not applicable; PROACT-II, Prolyse in Acute Cerebral Thromboembolism II trial; sICH, symptomatic ICH.
Indicates baseline model.
Indicates baseline and technical model.
Indicates aOR of intra-arterial urokinase administration.
P < .05, Fisher exact test.
Scores range from 0 to 6, with higher scores indicating more severe disability (6 indicates death).
Figure 2. Crude and Adjusted Odds Ratio of Intra-arterial (IA) Urokinase and Several Outcomes.
Crude and adjusted odds ratios (OR) and corresponding 95% CIs for safety outcomes (A) and functional independence (B) as outlined in the methods section. Adjustments for baseline characteristics (model A) tended to shift the point estimates in favor of the group without IA urokinase, whereas additional adjustments, for example, for poor reperfusion grade cases (model B) revealed a potential benefit of IA urokinase.
One sICH in the intra-arterial urokinase group was directly associated with the intra-arterial urokinase administration. In this case, vessel perforation and contrast-material extravasation occurred during intra-arterial urokinase administration in an M3-caliber vessel, resulting in symptomatic subarachnoid hemorrhage (eFigure 2 in the Supplement).
Efficacy
In failed thrombectomy cases (15 patients with TICI 0 or 1 after multiple deployments/removal), reperfusion status was improved with intra-arterial urokinase only (without additional mechanical maneuvers) in 8 (53.3%). This change in reperfusion was relevant to the TICI grade in all 8 (2 with TICI 0 improving to TICI 1; 3 with TICI 0 or 1 improving to TICI 2a; and 3 with TICI 1 improving to TICI 2b); however, successful reperfusion was achieved in only 3 of 15 patients (Figure 3). After partial or near-complete reperfusion (53 of 100; TICI 2a to 2b after mechanical maneuvers without mechanically reachable residual occlusions), reperfusion status was improved with intra-arterial urokinase in 32 cases (60.4%). This reperfusion improvement was relevant to the TICI grade in 18 of 53 cases (34.0%); 10 cases improved from TICI 2a to TICI 2b, and 8 cases improved from TICI 2a or 2b to TICI 3 (Figure 3 and example in eFigure 3 in the Supplement). In the remaining 14 of 32 cases with improvement, reperfusion status was improved, without a change in TICI scoring (example in eFigure 4 in the Supplement). In 1 case for whom reperfusion improvement was attempted, reperfusion worsened from TICI 2b to TICI 1 after reocclusion in the M1 segment during intra-arterial urokinase infusion into the inferior M2 trunk (case description in eFigure 5 in the Supplement). In patients in whom intra-arterial urokinase was administered for treatment of emboli to new territory (7 of 100), 4 of 7 (57.1%) had emboli that could be reperfused.
Figure 3. Reperfusion Improvement With Intra-arterial (IA) Urokinase After Failed and Incomplete Mechanical Thrombectomy.
TICI indicates Thrombolysis in Cerebral Infarction (TICI) grade. Shifts in grades are shown after administration of IA urokinase.
There was no difference in functional independence between patients treated with intra-arterial urokinase and those without (45 of 99 [45.5%] vs 329 of 860 [38.3%]; P = .19). Although there was no difference when adjusting for baseline differences only (aOR, 1.00; 95% CI, 0.62-1.64) (Table 2 and Figure 2), intra-arterial urokinase was found to be associated with functional independence (aOR, 1.93; 95% CI, 1.11-3.37) after adjusting for technical end points (ie, selection bias favoring poor TICI grades in the intra-arterial urokinase group).
Discussion
This study has the following main findings. (1) Administration of intra-arterial urokinase during or after MT appeared to be safe in selected patients without increasing the risk of systemic, symptomatic, or asymptomatic intracranial bleeding. (2) Although the change was not always relevant to the TICI grade, intra-arterial urokinase was often capable of improving the reperfusion status of patients, especially after incomplete reperfusion with MT. (3) After adjusting for imbalances regarding baseline and procedural factors underlying case selection, we observed associations between intra-arterial urokinase administration and improved functional outcome.
At present, whether intra-arterial thrombolysis is a safe and effective treatment option when applied as an adjunctive therapy to MT with and without prior administration of intravenous tPA is unclear. In the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN)23 and Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) trial,24 additional use of intra-arterial thrombolysis was allowed; however, no subgroup analyses have been published. Only a few observational studies to date13,15,16 have evaluated the safety and efficacy of intra-arterial thrombolysis after or during MT. Anadani et al16 described 67 patients treated with intra-arterial tPA at the discretion of the neurointerventionalist if complete recanalization could not be achieved by mechanical means. Hence, mostly successful but incomplete angiography patterns were treated with intra-arterial tPA in their study. There were no differences regarding good outcome, mortality, or parenchymal hemorrhage in patients treated with and without additional administration of intra-arterial tPA.16 The authors did not provide an angiographic efficacy analysis regarding dedicated reperfusion improvement after intra-arterial tPA, and a matched-pair analysis was confined to 86 patients only.16 Corroborating these findings, Heiferman et al15 did not observe an increased risk of hemorrhage after adjunctive intra-arterial tPA during or after MT, and angiographic reperfusion results tended to be better in patients receiving additional intra-arterial tPA. Recently, a secondary analysis from the North American Solitaire Stent-Retriever Acute Stroke registry13 showed improved reperfusion rates after failed MT with the Solitaire device (Medtronic), especially in M1 occlusions. However, the sICH rate was numerically higher in patients receiving additional intra-arterial tPA (13.9 vs 6.8%, P = .29). In addition, in the Solitaire With the Intention For Thrombectomy (SWIFT) trial,25 rescue with intra-arterial thrombolysis was associated with an increased risk of bleeding (OR of approximately 12), although most bleeding occurred in the group using the Merci coil retriever (Stryker Corporation).
In the present study, intra-arterial urokinase instead of intra-arterial tPA was administered. Intra-arterial urokinase has long been used as stand-alone intra-arterial treatment at our center26 based on early reports and evidence gained from the PROACT-II trial.17 In PROACT-II, recombinant prourokinase was associated with a 15% absolute benefit in functional independence and superior recanalization rates (66% vs 18%; P < .001).17 Especially in more distal occlusions, prourokinase was associated with a 3-fold increase in early reperfusion (53.6 vs 16.7%) compared with controls.18 Other trials have pointed in the same direction,19 and a meta-analysis21 suggested that intra-arterial fibrinolysis increases recanalization rates and good outcome without excess in mortality. The most severe complication of intra-arterial urokinase is sICH, which occurred in 10% of patients in the recombinant prourokinase group from the PROACT-II trial17 and in 5.2% in our cohort receiving intra-arterial urokinase as an adjunct treatment to MT. We did not find an increased risk of sICH, aICH, or systemic bleedings after intra-arterial urokinase administration, even after adjustment for differences in baseline factors driven by case selection. Interestingly, the rate of aICH was lower in patients receiving intra-arterial urokinase, the point estimates for sICH suggested a lower risk in the urokinase group, and the outcome of patients treated with intra-arterial urokinase tended to be better. Although we cannot exclude that these outcome differences are introduced by case selection (residual confounding), the effects tended to be more pronounced after adjustment for imbalances, further pointing toward a true benefit. Such a benefit may be explained by improved macrovascular reperfusion, lysis of downstream microemboli, or even neuroprotective effects of urokinase.27,28,29 A tendency for lower odds of aICH or sICH in patients treated with intra-arterial urokinase observed in adjusted analyses may be explained by improved reperfusion rates after intra-arterial urokinase administration, which have been associated with reduced rates of hemorrhagic complications before.30,31,32
In addition, the present study provides detailed information on the efficacy of intra-arterial urokinase in improving the reperfusion status after incomplete MT, observed in more than half of the cases, with 34.0% of TICI 2a and 2B cases being relevant to the TICI grade. Unequivocal evidence suggests that the better the reperfusion status, the better the clinical outcome of the treated patient,2,3,4 and strategies improving reperfusion more aggressively may thus be desirable.11 Because most vessel occlusions accountable for incomplete reperfusion are often not accessible with MT, additional treatment with intra-arterial thrombolytics with the intention to improve the reperfusion status may thus become more popular. Such pharmacological rescue cases must provide a good safety profile to not jeopardize the benefit already achieved with prior MT with and without intravenous tPA. We found 2 such incidences potentially related to intra-arterial urokinase administration (1 in situ reocclusion in the M1 segment, which is a rare finding,33 and 1 symptomatic subarachnoid hemorrhage).
In a few cases, intra-arterial urokinase was also administered after termination of the mechanical intervention owing to the inability to retrieve the clot after multiple attempts. Failed reperfusion most commonly occurs owing to the inability to retrieve the thrombus despite having established adequate intracranial and extracranial access.6,7 Rescue treatment options in these cases generally consist of bailout stenting34 or additional pharmacological treatment. Recent analyses have put forward that intra-arterial thrombolysis may facilitate subsequent mechanical reperfusion after initial device failure13 or may promote late recanalization at follow-up in failed thrombectomy cases.7
Before adjunctive treatment with intra-arterial thrombolytics during or after MT can be recommended, further evaluation of this approach in a prospective multicenter study or a randomized clinical trial35 seems warranted, and further data on the efficacy and safety of intra-arterial urokinase vs intra-arterial tPA in this particular situation appear necessary.
Limitations
The nonrandomized allocation of patients to receive intra-arterial urokinase is a major limitation of this observational study. On the one hand, there was a strong selection bias in the intra-arterial urokinase group toward patients who did not achieve complete reperfusion by mechanical means; on the other hand, intra-arterial urokinase was only administered if deemed safe by neurologists and neurointerventionalists in charge (eg, to younger patients). Given the large differences, the analyses are susceptible to overadjustment or residual confounding. Hence, the observed associations of lower aICH rates, better functional outcome, and reduced mortality in patients receiving intra-arterial urokinase should be interpreted cautiously. Furthermore, case selection was performed in consensus by the neurologists and neurointerventionalists, who had long-standing experience treating patients with intra-arterial urokinase.36 Therefore, the results and safety of case selection may not be easily transferable to other centers. Third, most patients were selected by magnetic resonance imaging results, even more so in the intra-arterial urokinase group. Last, 69 of 1274 patients screened refused to make their data available for research, and the attrition rate during follow-up in the final study population was 3.4%, which both may have led to further bias.
Conclusions
In selected patients, adjunctive treatment with intra-arterial urokinase during or after MT seems to be safe, harbors the potential to improve the reperfusion status of patients undergoing endovascular interventions, and may thus improve outcome. Although the nonrandomized nature of these observational data does not allow for treatment recommendations, the observed angiographic and clinical benefits stress the need for further evaluation of this approach in a multicenter prospective registry or a randomized clinical trial.
eMethods. Preinterventional Workup, Endovascular Treatment, and Details on Urokinase
eFigure 1. Adjusted Odds Ratios of IA Urokinase for Symptomatic Intracranial Hemorrhage (Assuming Worst-Case-Scenario for Missing Data)
eFigure 2. Severe Adverse Event During IA Urokinase Administration
eFigure 3. Improvement From TICI2b to TICI3 After IA Urokinase
eFigure 4. Improvement in Reperfusion After IA Urokinase Without TICI Change
eFigure 5. Early Reocclusion During IA Urokinase Administration
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods. Preinterventional Workup, Endovascular Treatment, and Details on Urokinase
eFigure 1. Adjusted Odds Ratios of IA Urokinase for Symptomatic Intracranial Hemorrhage (Assuming Worst-Case-Scenario for Missing Data)
eFigure 2. Severe Adverse Event During IA Urokinase Administration
eFigure 3. Improvement From TICI2b to TICI3 After IA Urokinase
eFigure 4. Improvement in Reperfusion After IA Urokinase Without TICI Change
eFigure 5. Early Reocclusion During IA Urokinase Administration