Abstract
Introduction
The aim of this study was to test the hypothesis that intravenous tirofiban improves functional outcomes without promoting the risk of intracranial hemorrhage (ICH) in stroke secondary to basilar artery occlusion (BAO) receiving endovascular thrombectomy.
Methods
Patients with acute BAO stroke who were treated with endovascular thrombectomy and had tirofiban treatment information were derived from “BASILAR”: a nationwide, prospective registry. All eligible patients were divided into tirofiban and no-tirofiban groups according to whether tirofiban was used intravenously. The primary endpoint was the 90-day severity of disability as assessed by the modified Rankin scale score. Safety outcomes were the frequency of ICH and mortality.
Results
Of 645 patients included in this cohort, 363 were in the tirofiban group and 282 were in the no-tirofiban group. Thrombectomy with intravenous tirofiban reduced the 90-day disability level over the range of the modified Rankin scale (adjusted common odds ratio, 2.08; 95% confidence interval (CI), 1.45–2.97; p < 0.001). The 90-day mortality of patients in the tirofiban group was lower than that in the no-tirofiban group (41.6% vs. 52.1%; adjusted hazard ratio, 0.60; 95% CI, 0.47–0.77; p < 0.001). The frequency of any ICH (6.7% vs. 13.7%; p = 0.004) and symptomatic ICH (4.8% vs. 10.1%; p = 0.01) in the tirofiban group was significantly lower than that in the no-tirofiban group.
Conclusions
In patients with acute BAO stroke who underwent endovascular treatment, intravenous tirofiban might be associated with favorable outcome, reduced mortality, and a decreased frequency of ICH.
Keywords: Acute ischemic stroke, Basilar artery occlusion, Platelet glycoprotein IIb/IIIa inhibitor, Endovascular treatment
Introduction
Acute basilar artery occlusion (BAO) accounts for only 5% of all large vessel occlusion strokes, but it is a catastrophic emergency condition, leading to morbidity and mortality as high as 80% [1, 2]. Recently, a growing number of studies have shown that recanalization approaches such as intravenous thrombolysis and endovascular treatment increase the successful reperfusion rate and improve functional outcomes in acute ischemic stroke patients secondary to BAO [3, 4, 5, 6]. However, recombinant tissue plasminogen activator increases the production of plasmin and thrombin, which may lead to platelet activation and promote thrombosis. On the other hand, mechanical thrombectomy with stent-retriever, balloon angioplasty, and stenting may result in endothelium injury and disruption of atherosclerotic plaques, which may also activate platelets and give rise to reocclusion.
Tirofiban is a non-peptide glycoprotein IIb/IIIa receptor inhibitor with high selectivity that reversibly blocks platelet aggregation. The efficacy and safety of tirofiban has been proved in acute coronary syndrome during percutaneous coronary intervention [7, 8, 9]. Based on the positive findings, an increasing number of neurointerventionists have assessed the role of intravenous tirofiban as an adjunctive medication of endovascular treatment in treating large vessel occlusion stroke [10, 11, 12, 13, 14, 15]. Nevertheless, the study results are conflicting. Moreover, most studies included acute ischemic stroke patients with large vessel occlusion in the anterior circulation. The data regarding intravenous tirofiban for BAO undergoing endovascular treatment is still sparse.
A direct comparison of endovascular treatment with versus without tirofiban in acute BAO has not been performed in a prospective cohort study or randomized controlled trial to date. We therefore sought to determine the efficacy and safety of intravenous tirofiban in the treatment of acute ischemic stroke patients due to BAO who underwent endovascular treatment. We hypothesize that intravenous tirofiban as an adjunctive treatment of endovascular thrombectomy will further improve the neurological outcomes without increasing the risk of intracranial hemorrhage (ICH) as compared with endovascular thrombectomy alone.
Methods
Study Design and Patient Selection
The Endovascular Treatment for Acute BASILAR Artery Occlusion Study (BASILAR) is a prospective, nationwide registry conducted in China from January 2014 to May 2019. A total of 829 consecutive patients with acute ischemic stroke caused by radiologically confirmed BAO within 24 h of symptom onset were recruited from 47 comprehensive stroke centers. Detailed information on the patient selection criteria of the BASILAR registry is provided in the online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000527483). BASILAR is registered on the Chinese Clinical Trial Registry (http://www.chictr.org.cn; ChiCTR1800014759). The study rationale, protocol, and primary results of the BASILAR registry have been described previously [6]. The study was approved by the Medical Ethics Committee of the Third Military Medical University and was performed in compliance with the Declaration of Helsinki. The signed consent forms were provided by all patients or their legal representatives. All imaging data were evaluated by an independent Imaging Core Laboratory which was blinded to the treatment information.
All eligible patients included in the present cohort were from the BASILAR registry and treated with endovascular treatment of whom the data on tirofiban treatment was available. Patients were dichotomized into two groups, the tirofiban group and the no-tirofiban group, according to whether they received intravenous tirofiban treatment or not.
Endovascular Treatment
Intravenous thrombolysis was administered to thrombolysis-eligible patients before the endovascular procedure. Endovascular procedures included mechanical thrombectomy with stent-retriever and/or local aspiration devices, intra-arterial medications (alteplase, urokinase, and tirofiban), etc. If the above approaches fail to recanalize the occluded vessel, rescue therapy with balloon angioplasty with or without stenting can be conducted. The procedure and anesthesia modality were at the discretions of the neurointerventionists. If the patient had already received intravenous thrombolysis prior to endovascular treatment, antiplatelet therapy with 100 mg aspirin with or without 75 mg clopidogrel was administered orally after 24 h of intravenous thrombolysis. Otherwise, antiplatelet therapy was initiated within 24 h.
Tirofiban Administration
In generally, tirofiban therapy was recommended under the following conditions: (1) endovascular therapy with balloon angioplasty with or without stenting was performed during the procedure; (2) substantial reperfusion (defined as expanded Thrombolysis in Cerebral Infarction [eTICI] grade of 2b, 2c, or 3) [16] was achieved after three or more attempts of stent-retriever for presumed endothelium injury or instant reocclusion; (3) prevention of reocclusion due to large artery atherosclerosis stroke which is at high risk of reocclusion; and (4) prevention of distal embolization during procedure. During or after thrombectomy, the recommended regimen of intravenous tirofiban treatment was 0.4 μg/kg/min for 30 min followed by 0.1 μg/kg/min for up to 24 h.
Outcomes
The primary efficacy outcome was the disability level at 90 days, as assessed on the modified Rankin scale (mRS, ranging from 0 [no symptoms] to 6 [death]). Other efficacy outcomes were (1) the score on the mRS at 1 year, (2) the proportion of favorable outcomes (defined as a score of 0–3 on the mRS) at 90 days and 1 year, (3) the proportion of functional independence (a score of 0–2 on the mRS) at 90 days and 1 year, and (4) the proportion of excellent outcome (a score of 0–1 on the mRS) at 90 days and 1 year. The mRS score was adjudicated by two certified site neurologists who were unaware of the treatment information using the mRS calculator via telephone or outpatient interview [17]. Appraisal disagreements were resolved by consensus. The technical efficacy outcome was substantial reperfusion at the final angiogram.
Safety outcomes included (1) mortality at 90 days and 1 year and (2) frequency of any ICH and symptomatic ICH within 48 h. ICH was assessed according to the Heidelberg Bleeding Classification [18]. Symptomatic ICH was diagnosed if the new detected ICH was associated with any of the following situations: (1) National Institutes of Health Stroke Scale (NIHSS) score increased more than 4 points compared with before neurological deterioration; (2) NIHSS score increased more than 2 points in one category; or (3) worsening led to intubation, hemicraniectomy, extraventricular drain placement, or any other major procedures. In addition, there was no explanation for the worsening of symptoms other than the detected ICH.
Statistical Analysis
Comparison of baseline characteristics, treatment profiles, efficacy and safety outcomes were performed between the two treatment groups using the χ2 test and Mann-Whiteney U test as appropriate. The effect size of the primary outcome was common odds ratio and estimated with ordinal logistic regression. The effect size of other efficacy outcomes and ICH were risk ratios, which was estimated using the modified Poisson regression model. The mortality ratios (hazard ratios) were estimated with the use of the Cox proportional-hazards model and Kaplan-Meier survival estimator. The adjusted models were controlled for age, atrial fibrillation, posterior circulation-Alberta Stroke Program Early Computed Tomography Score (pc-ASPECTS) and NIHSS score at admission, time from symptom onset to treatment, occlusion site, balloon angioplasty with or without stenting, substantial reperfusion achieved after three or more attempts, stroke etiology, sex, intra-arterial thrombolysis, postoperative anticoagulation, and time from groin puncture to recanalization. For safety outcomes (any ICH and symptomatic ICH), in addition to adjusting for the above-mentioned factors, intravenous thrombolysis was also included in the multivariable Poisson regression model. The unadjusted and adjusted effect size (common odds ratio, risk ratios and hazard ratios) and corresponding 95% confidence interval (CI) were reported. Missing data for baseline pc-ASPECTS, balloon angioplasty with or without stenting, substantial reperfusion achieved after three or more attempts, and time from groin puncture to recanalization were imputed with the use of multiple imputations. Patients missing data for 1-year mRS scores were imputed with worst scenarios. If the patients were known to be alive, a score of 5 was assigned. Otherwise, a score of 6 was assigned. The corresponding survival days are calculated according to the date of the last follow-up. Complete case analysis was conducted by deleting patients who lost to 1-year follow-up to evaluate the results consistency. We analyzed the heterogeneity of the tirofiban treatment effect within subgroups: age (≤64 or >64 years), sex (women or men), NIHSS score (≤26 or >26), pc-ASPECTS (≤7 or >7), occlusion site (distal, middle, proximal basilar artery, or the fourth segment of vertebral artery), stroke etiology (large artery atherosclerosis, cardioembolism, or other or unknown), and time from onset to treatment (≤246 or >246 min). All tests were two-sided with p < 0.05 considered statistically significant. All analyses were conducted using IBM SPSS Statistics for Windows version 23.0 (IBM Corp., Armonk, NY) and figures were drawn using Microsoft Office Excel 2019 (Redmond, WA). The Kaplan-Meier curves were drawn by MedCalc Statistical Software version 19.4.1 (MedCalc Software Ltd, Ostend, Belgium).
Results
Characteristics of the Patients
Of a total of 829 patients enrolled in BASILAR registry, 182 patients were treated with standard medical treatment alone and 2 patients with missing tirofiban treatment data were excluded, while the remaining 645 patients treated with endovascular treatment were included in this study cohort. The median age of the 645 patients was 64 (interquartile range, 56–73) years; 482 patients (74.7%) were men. Of 645 patients, 363 patients were in the tirofiban group and 282 in the no-tirofiban group. All patients completed the 90-day follow-up, but 17 and 15 patients in the tirofiban group and the no-tirofiban group, respectively, had no 1-year follow-up data (online suppl. Fig. S1).
Baseline characteristics and treatment profiles are provided in Table 1. Patients treated with tirofiban were younger (63 vs. 65 years; p = 0.018), less often had a history of atrial fibrillation (11.3% vs. 33.3%; p < 0.001), and had a higher median pc-ASPECTS at baseline (8 vs. 8; p = 0.003) than patients treated without tirofiban. Compared with the no-tirofiban group, patients in the tirofiban group had a lower rate of occlusion of the distal basilar artery (26.4% vs. 44.3%; p < 0.001) and higher rates of occlusion of the proximal basilar artery (20.7% vs. 11.3%; p = 0.002). Patients treated with tirofiban received less frequency of intra-arterial thrombolysis (8.0% vs. 18.8%; p < 0.001), more often rescue therapy (47.4% vs. 23.4%; p < 0.001), had a higher proportion of substantial reperfusion (84.6% vs. 75.5%; p = 0.004), and a longer median puncture to recanalization time (112 vs. 97 min; p < 0.001). In terms of postoperative antithrombotic therapy, the frequency of anticoagulation in the tirofiban group was lower than that in the no-tirofiban group (0.3% vs. 8.5%; p < 0.001).
Table 1.
Characteristics and treatment profiles of included patients
| Tirofiban (n = 363) | No-tirofiban (n = 282) | p value | |
|---|---|---|---|
| Demographic characteristics | |||
| Age, median (IQR), years | 63 (56–71) | 65 (58–74) | 0.018 |
| Male sex, n. (%) | 282 (77.7) | 200 (70.9) | 0.05 |
| Medical history, n. (%) | |||
| Hypertension | 263 (72.5) | 187 (66.3) | 0.092 |
| Atrial fibrillation | 41 (11.3) | 94 (33.3) | <0.001 |
| Coronary heart disease | 54 (14.9) | 51 (18.1) | 0.273 |
| Diabetes mellitus | 89 (24.5) | 59 (20.9) | 0.281 |
| Hyperlipidemia | 125 (34.4) | 89 (31.6) | 0.442 |
| Ischemic stroke | 77 (21.2) | 62 (22.0) | 0.813 |
| Stroke etiology, n. (%) | |||
| Large artery atherosclerosis | 275 (75.8) | 142 (50.4) | <0.001 |
| Cardioembolism | 59 (16.3) | 113 (40.1) | |
| Unknown | 13 (3.6) | 6 (2.1) | |
| Other | 16 (4.4) | 21 (7.4) | |
| Imaging characteristics | |||
| Pc-ASPECTS, median (IQR)1 | 8 (7–9) | 8 (7–10) | 0.003 |
| PC-CS score, (IQR)2 | 4 (3–6) | 5 (4–6) | 0.068 |
| Occlusion site, n. (%) | |||
| Distal basilar artery | 96 (26.4) | 125 (44.3) | <0.001 |
| Middle basilar artery | 112 (30.9) | 82 (29.1) | |
| Proximal basilar artery | 75 (20.7) | 32 (11.3) | |
| Vertebral artery-V4 segment | 80 (22.0) | 43 (15.2) | |
| Clinical examination at arrival | |||
| NIHSS score, median (IQR) | 27 (17–33) | 27 (16–34) | 0.826 |
| Systolic blood pressure, median (IQR), mm Hg3 | 150 (135–167) | 150 (131–166) | 0.632 |
| Serum glucose, median (IQR), mmol/L4 | 7.5 (6.2–9.6) | 7.3 (6.1–9.6) | 0.406 |
| Treatment profiles | |||
| Intravenous thrombolysis, n. (%) | 62 (17.1) | 57 (20.2) | 0.309 |
| Intra-arterial thrombolysis, n. (%) | 29 (8.0) | 53 (18.8) | <0.001 |
| Number of retrieval attempts, median (IQR)5 | 1 (1–2) | 1 (1–2) | 0.884 |
| Rescue therapy, n. (%)6 | 172 (47.4) | 66 (23.4) | <0.001 |
| Postoperative anticoagulation therapy, n. (%) | 1 (0.3) | 24 (8.5) | <0.001 |
| Onset to treatment time, median (IQR), min | 250 (122–410) | 241 (141–373) | 0.803 |
| Onset to recanalization, median (IQR), min7 | 451 (323–644) | 430 (334–621) | 0.518 |
| Puncture to recanalization, median (IQR), min7 | 112 (78–158) | 97 (63–137) | <0.001 |
IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; pc-ASPECTS, posterior circulation-Alberta Stroke Program Early Computed Tomography Score; PC-CS, Posterior Circulation Collateral Score.
Data were missing from 3 patients in the tirofiban group.
Data were missing from 1 patient in the tirofiban group.
Data were missing from 1 patient in the tirofiban group and 2 in the no-tirofiban group.
Data were missing from 52 patients in the tirofiban group and 50 in the no-tirofiban group.
Data were missing from 26 patients in the tirofiban group and 26 in the no-tirofiban group.
Rescue therapy was defined as failure of primary means of thrombectomy (e.g., stent-retriever or local aspiration) and balloon angioplasty and/or stenting was used.
Data were missing from 3 patients in the tirofiban group.
Efficacy Outcomes
Endovascular thrombectomy plus intravenous tirofiban, as compared with endovascular thrombectomy alone, was associated with a favorable shift in the entire distribution on the modified Rankin scale both at 90 days (adjusted common odds ratio, 2.08; 95% confidence interval (CI), 1.45–2.97; p < 0.001) and 1 year (adjusted common odds ratio, 2.12; 95% CI, 1.44–3.12; p < 0.001). Figure 1 shows the distribution of mRS scores at 90 days and 1 year. Patients who received tirofiban were more likely to have favorable outcomes (90 days: adjusted risk ratio, 1.14; 95% CI, 1.03–1.26; p = 0.01; 1 year: adjusted risk ratio, 1.16; 95% CI, 1.04–1.29; p = 0.008) and functional independence (90 days: adjusted risk ratio, 1.10; 95% CI, 1.00–1.20; p = 0.04; 1 year: adjusted risk ratio, 1.12; 95% CI, 1.02–1.24; p = 0.02) than those who did not. In addition, patients in the tirofiban group were 1.15 times (95% CI, 1.05–1.25; p = 0.002) and 1.10 times (95% CI, 1.02–1.19; p = 0.01) more likely to achieve substantial reperfusion and an 1-year excellent outcome, respectively, than the no-tirofiban group. There were no significant differences in other efficacy outcomes between groups (Table 2). Subgroup analyses of mRS at 90 days and 1 year indicated that age, sex, baseline ASPECTS, occlusion site, and stroke etiology had modification effects on tirofiban treatment (Figure 2; online suppl. Fig. S2).
Fig. 1.
Distribution of modified Rankin scale score. Horizontal stacked bar graphs show the distribution of modified Rankin scale scores at 90 days and 1 year. Bars are labeled with proportions.
Table 2.
Multivariate regression analysis: association of tirofiban with clinical outcomes
| Tirofiban (n = 363) | No-tirofiban (n = 282) | Effect size | Adjusted effect size (95% CI) | p value1 | |
|---|---|---|---|---|---|
| 90-day outcomes | |||||
| Median modified Rankin scale score (interquartile range) | 5 (2–6) | 6 (2–6) | Common odds ratio | 2.08 (1.45–2.97) | <0.001 |
| Modified Rankin scale score of 0–3 – n. (%) | 119 (32.8) | 87 (30.9) | Risk ratio | 1.14 (1.03–1.26) | 0.01 |
| Modified Rankin scale score of 0–2 – n. (%) | 100 (27.5) | 76 (27.0) | Risk ratio | 1.10 (1.00–1.20) | 0.04 |
| Modified Rankin scale score of 0–1 – n. (%) | 69 (19.0) | 64 (22.7) | Risk ratio | 0.98 (0.91–1.06) | 0.65 |
| Mortality – n. (%) | 151 (41.6) | 147 (52.1) | Hazard ratio | 0.60 (0.47–0.77) | <0.001 |
| Any ICH – n. (%) | 24/356 (6.7) | 38/278 (13.7) | Risk ratio | 0.50 (0.29–0.85) | 0.01 |
| Symptomatic ICH – n. (%) | 17/356 (4.8) | 28/278 (10.1) | Risk ratio | 0.43 (0.23–0.81) | 0.009 |
| Technical efficacy outcome | |||||
| Substantial reperfusion at final angiogram – n. (%) | 307 (84.6) | 213 (75.5) | Risk ratio | 1.15 (1.05–1.25) | 0.002 |
| 1-year outcomes | |||||
| Median modified Rankin scale score (interquartile range) | 6 (2–6) | 6 (2–6) | Common odds ratio | 2.12 (1.44–3.12) | <0.001 |
| Modified Rankin scale score of 0–3 – n. (%) | 130 (35.8) | 88 (31.2) | Risk ratio | 1.16 (1.04–1.29) | 0.008 |
| Modified Rankin scale score of 0–2 – n. (%) | 110 (30.3) | 79 (28.0) | Risk ratio | 1.12 (1.02–1.24) | 0.02 |
| Modified Rankin scale score of 0–1 – n. (%) | 82 (22.6) | 56 (19.9) | Risk ratio | 1.10 (1.02–1.19) | 0.01 |
| Mortality – n. (%) | 192 (52.9) | 175 (62.1) | Hazard ratio | 0.62 (0.49–0.78) | <0.001 |
p values pertain to adjusted common odds ratios, risk ratios, and hazard ratios.
Fig. 2.
Analysis of 90-day mRS in subgroups. The forest plot shows the effect size in the favorable outcome (adjusted common odds ratio were analyzed according to ordinal logistic regression model and adjusted for age, baseline NIHSS score, baseline pc-ASPECTS, atrial fibrillation, time from symptom onset to treatment, occlusion site, balloon angiography with or without stenting, substantial reperfusion achieved after three or more attempts, stroke etiology, sex, intraarterial thrombolysis, postoperative anticoagulation, and time from groin puncture to recanalization) across seven subgroups. The thresholds for age, baseline NIHSS score, baseline pc-ASPECTS, and onset to treatment time were chosen at the median. BA, basilar artery; CE, cardioembolism; CI, confidence interval; LAA, large artery atherosclerosis; NIHSS, National Institutes of Health Stroke Scale; pc-ASPECTS, posterior circulation-Alberta Stroke Program Early Computed Tomography Score; VA-V4, the fourth segment of vertebral artery.
Safety Outcomes
An absolute reduction was observed in the 90-day mortality that favored tirofiban treatment (41.6% vs. 52.1%; absolute difference, −10.5%; 95% CI, −18.3% to −2.8%; adjusted hazard ratio, 0.60; 95% CI, 0.47–0.77; p < 0.001). The similar findings were observed at extended follow-up to 1 year (52.9% vs. 62.1%; absolute difference −9.2%; 95% CI, −16.8% to −1.5%; adjusted hazard ratio, 0.62; 95% CI, 0.49–0.78; p < 0.001). Online supplementary Figure S3 shows the Kaplan-Meier estimates of the probability of death at 90 days and 1-year. Complete case analysis, excluding patients lost to 1-year follow-up, yielded similar results (online suppl. Fig. S4 and Table S1). We observed evidence of treatment effect modification by age, sex, occlusion site, and stroke etiology in the subgroup analyses for both 90-day and 1-year mortality (online suppl. Fig. S5, S6). The risk of any ICH (6.7% vs. 13.7%; p = 0.004; adjusted risk ratio, 0.50; 95% CI, 0.29–0.85; p = 0.01) and symptomatic ICH (4.8% vs. 10.1%; p = 0.01; adjusted risk ratio, 0.43; 95% CI, 0.23–0.81; p = 0.009) in the tirofiban group was significantly lower than that in the no-tirofiban group.
Discussion
Using data from the nationwide BASILAR registry, we investigated whether treatment of acute ischemic stroke patients secondary to BAO with intravenous tirofiban combined with endovascular treatment is beneficial or increases any risks to functional outcomes. Our results showed that, after adjusting for confounding factors, intravenous tirofiban is more likely resulting in a lower disability level, associated with reduced mortality and a lower risk of ICH. The treatment effect of intravenous tirofiban on clinical neurological outcomes is sustained for at least 1 year. Accordingly, the use of intravenous tirofiban may play an important role in achieving better functional outcomes.
Currently, acute ischemic stroke has not been approved as an indication for tirofiban by the Food and Drug Administration, but tirofiban has been used frequently in clinical practice. However, controversial findings have been yielded regarding the role of intravenous tirofiban therapy in acute ischemic stroke patients treated with endovascular treatment. Two observational studies indicated that increased symptomatic ICH and poor outcomes were observed after the use of tirofiban [10, 12]. Conversely, several studies showed that tirofiban therapy had relationship with improved neurological outcomes without promoting symptomatic ICH and mortality [11, 13, 14]. The Intravenous Tirofiban Before Endovascular Thrombectomy for Acute Ischemic Stroke (RESCUE BT) is an investigator-initiated, multicenter, randomized, placebo-controlled, double-blind trial, which is the first and only trial to date aiming to assess the efficacy and safety of intravenous tirofiban prior to endovascular treatment in patients with acute ischemic stroke due to large vessel occlusion in the anterior circulation. The trial results showed that intravenous tirofiban did not reduce the disability severity and were associated with increased any ICH, which had been presented as the opening main event in the International Stroke Conference 2022 [19, 20, 21]. Nevertheless, most patients included in the above-mentioned studies had anterior circulation large vessel occlusion stroke, and only a minority had BAO. Therefore, the generalizability of these findings to posterior circulation stroke is of limited value. In a retrospective study of 120 patients with vertebrobasilar occlusion, 37 patients (30.8%) were treated with tirofiban, and the remaining 83 patients (69.2%) received abciximab therapy, another glycoprotein IIb/IIIa inhibitor. The results suggested that intravenous tirofiban or abciximab was safe in treating patients with vertebrobasilar occlusion stroke and did not improve clinical outcomes [22]. To date, prospective data on intravenous tirofiban combined with endovascular treatment for BAO are very limited. Our cohort study, for the first time, provided data for this important issue.
The results of this cohort revealed that, after adjusting confounders, patients who received intravenous tirofiban were more likely to obtain an improved functional outcome than those who did not. The following reasons may explain these findings. First, baseline characteristics such as age and pc-ASPECTS were not balanced between the two groups. Age is a crucial independent predictor for neurological outcomes, with younger age being associated with more likely to have favorable functional outcomes [23]. Patients in the tirofiban group were younger than those in the non-tirofiban group. Pc-ASPECTS is another important predictor; lower scores indicate more severe early ischemic changes of brain tissue [24]. Patients who received tirofiban treatment had higher pc-ASPECTS compared with those who did not. Second, intravenous tirofiban with endovascular thrombectomy significantly improved substantial reperfusion rates, which also contributed to an increase in the proportion of favorable outcomes and a reduction in mortality. Third, the proportion of ICH in the tirofiban group was significantly lower than that in the no-tirofiban group, which was beneficial for the tirofiban group to achieve good outcomes. Last, patients enrolled in the BASILAR registry had severe strokes with a median baseline NIHSS score of 27. Therefore, the efficacy of intravenous tirofiban with endovascular procedures is more reflected in the reduction of mortality rather than recovery to mild to severe stroke (e.g., mRS score of 0–3). Moreover, we observed multiple prognostic factors have a modification effect on the efficacy of tirofiban in the prespecified subgroup analysis, which provides a basis for patients’ selection for tirofiban treatment and clinical trial design.
In this study, the risk of any and symptomatic ICH was found to be higher in patients treated without tirofiban. Similar result was observed in another multicenter observational study [15]. However, this is different from a recently published randomized controlled trial of endovascular thrombectomy with or without tirofiban in acute ischemic stroke due to large vessel occlusion [19]. The following points may account for this unusual result. First, tirofiban is more commonly prescribed for large-arterial atherosclerotic stroke rather than cardioembolic stroke (75.8% vs. 16.3%), which might decrease the risk of ICH. Besides, patients in the no-tirofiban group received intra-arterial thrombolysis more frequently than those in the tirofiban group during endovascular procedures. In addition, after endovascular thrombectomy, the proportion of patients receiving anticoagulation therapy was higher in the no-tirofiban group than in the tirofiban group. Lastly, the proportion of patients receiving intravenous thrombolysis with alteplase or urokinase prior to endovascular thrombectomy was numerically higher in the no-tirofiban group than in the tirofiban group. The above confounders may increase the risk of ICH in the no-tirofiban group. Although this result may not be reliable, it at least revealed that the use of tirofiban in posterior circulation stroke was safe.
Strengths of our cohort consisted of the large scale of patients extracted from the BASILAR nationwide registry with long-term follow-up outcomes. Nevertheless, this study had inherent limitations due to its non-randomized controlled design in nature. Although multivariate regression analyses were performed to mitigate selection bias, unknown confounders could not be controlled. Accordingly, the findings should be interpreted with caution, especially given the lower incidence of any and symptomatic ICH in the tirofiban group after adjustment for confounders. Moreover, all patients in this cohort were from China, which has a high incidence of large artery atherosclerosis. Therefore, the results may not be generalized to other populations directly.
Conclusion
In conclusion, our study indicated that intravenous tirofiban might be associated with improved functional outcomes and a lower risk of ICH after adjustment for confounding factors. The therapeutic effects can last for at least 1 year. Randomized controlled trials are needed to confirm these findings.
Statement of Ethics
The present study was approved by the Institutional Review Board of the Second Affiliated Hospital of The Third Military Medical University (2013-087-01) and was performed with the participants’ written informed consent in compliance with the Helsinki Declaration.
Conflict of Interest Statement
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Funding Sources
The study was supported by the National Natural Science Foundation of China (Nos. 82001265 and 81901236), the Joint Medical Research Project of Chongqing Science and Health Commission (2020FYYX206), and the Natural Science Research Key Project of Higher Education of Anhui Province (No. KJ2020A0337). The funders/sponsors had no role in the study design, data collection, analysis and interpretation, or writing this manuscript. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Author Contributions
Junjie Yuan, Tao Wang, Qiong Chen, and Renliang Meng designed the study protocol, analyzed data, and prepared the manuscript with support from Deping Wu, Jinrong Hu, Zhaojun Tao, Dongjing Xie, Yan Tian, Qin Han, Yuan Fu, Ling Zuo, Min Zhang, Weipeng Dai, Wei Deng, Xianjun Huang, Hongfei Sang, Xinggang Feng, and Zhongming Qiu, who also advised the study planning, developed the theoretical content, interpreted the results, and approved the final manuscript.
Data Availability Statement
The data that support the findings of this study are not available on the ethical grounds. Further inquiries can be directed to the corresponding author.
Supplementary Material
Supplementary data
Funding Statement
The study was supported by the National Natural Science Foundation of China (Nos. 82001265 and 81901236), the Joint Medical Research Project of Chongqing Science and Health Commission (2020FYYX206), and the Natural Science Research Key Project of Higher Education of Anhui Province (No. KJ2020A0337). The funders/sponsors had no role in the study design, data collection, analysis and interpretation, or writing this manuscript. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary data
Data Availability Statement
The data that support the findings of this study are not available on the ethical grounds. Further inquiries can be directed to the corresponding author.
