Abstract
Background:
There has been a growing interest in the use of Glycoprotein 2b/3a (GP2B3A) inhibitors in neuroendovascular procedures. However, clinical evidence for their prophylactic use is still sparse.
Purpose:
To assess the safety and efficacy of prophylactic GP2B3A inhibitor use and to compare the performance of GP2B3A inhibitors with oral dual antiplatelet (DAP) treatment in intracranial aneurysm patients treated with stent-assisted coil embolization or flow diversion.
Methods:
A systematic literature search was conducted in Ovid MEDLINE, Ovid Embase, Scopus, Web of Science, and Cochrane Central Register of Clinical Trials databases. Data collected included hemorrhagic and thromboembolic complication rates, mortality, good functional outcome, and rupture status. A random-effects model was fit for each outcome measure.
Results:
Thirteen studies comprising 1429 patients were included. The overall hemorrhagic complication rate of the GP2B3A cohort was 3.98% (95% CI= 1.58–7.42). The subgroup analysis comparing ruptured versus unruptured aneurysms in which GP2B3A antagonists were used did not show a significant difference in hemorrhagic complication rates (P-value= 0.504). Compared with the DAP group, the GP2B3A inhibitor cohort had significantly lower hemorrhagic complication rates (OR= 0.33; 95% CI= 0.13–0.85; P-value= 0.022). The thromboembolic complication rates were 6.63% (95% CI= 3.44–10.75) for the GP2B3A inhibitor group and 10.4% (95% CI= 7–13.8) for the DAP group. However, the difference was not statistically significant (OR= 0.52; 95% CI= 0.22–1.24; P-value= 0.142).
Conclusion:
Our results support that GP2B3A inhibitors are safe and effective in preventing ischemic complications associated with the endoluminal devices. Additionally, our findings indicate that GP2B3A inhibitors can be utilized as prophylactic agents regardless of the rupture status.
Introduction
The introduction of flow diverters and newer generation stents has led to a significant paradigm shift in the management of wide-necked intracranial aneurysms. Numerous studies, including clinical trials, have established the utility of flow diversion (FD) and stent-assisted coiling (SAC), with complete occlusion rates ranging between 73.6% and 88.2% (1, 2). However, flow diversion and SAC techniques also carry inherent risks that stem from the strong thrombogenicity of these implants. Therefore, a well-planned antithrombotic treatment is of paramount importance to prevent ischemic complications.
Various treatment strategies have been proposed to mitigate thromboembolic complications associated with SAC and FD. Endovascular treatment trials and many observational studies have utilized oral dual antiplatelet (DAP) treatment strategy with P2Y12 inhibitors, in addition to periprocedural anticoagulation (1–4). However, ischemic complications still remain a major source of mortality and permanent morbidity. Therefore, there has been growing interest in using more potent antiplatelets as prophylactic agents.
Glycoprotein 2b/3a (GP2B3A) inhibitors are rapid-acting parenteral drugs, and they offer several advantages over classic COX and P2Y12 inhibitors such as aspirin and clopidogrel (5, 6). GP2B3A inhibitors have a short half-life, and additionally, their effects are reversible. Therefore, they can be employed in emergent settings and can be discontinued without significant residual effects (5, 6). However, they are also very potent antiplatelets, and there are several small case series documenting severe hemorrhagic complications.
Literature on the prophylactic use of GP2B3A inhibitors consists of single treatment modality-focused (SAC or FD) observational studies, and unfortunately, no controlled trial or comprehensive study is available. In this meta-analysis, we sought to investigate the safety and efficacy of prophylactic GP2B3A inhibitor use in the treatment of intracranial aneurysms with endoluminal devices.
Methods
Search Strategy and Inclusion Criteria
This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (7). The literature was searched by a medical librarian for the concepts of endovascular treatment of intracranial aneurysms with GP2B3A inhibitors. Search strategies were created using a combination of keywords and standardized index terms. Searches were run on January 7, 2022 in Ovid Cochrane Central Register of Controlled Trials (1991+), Ovid Embase (1974+), Ovid Medline (1946+ including epub ahead of print, in-process & other non-indexed citations), Scopus (1823+), and Web of Science Core Collection (Science Citation Index Expanded 1975+ & Emerging Sources Citation Index 2015+). After excluding most conference abstracts, a total of 289 citations were retrieved. Deduplication was performed in the AutoLit platform (Nested Knowledge, St. Paul, MN). Full search strategies are provided in the Appendix. Additionally, the database search was supplemented by expert recommendations and reviewing the bibliographies of included papers.
Inclusion criteria were the following: English language, the prophylactic use of GP2B3A inhibitors, intracranial aneurysm treatment with endoluminal devices (FD and SAC techniques), and data availability on periprocedural and post-operative complications. Prophylactic use of GP2B3A inhibitors is defined as intraprocedural administration of these drugs with the aim of preventing ischemic complications. Both non-comparative (articles solely focused on GP2B3A inhibitors) and comparative studies (articles comparing GP2B3A inhibitors with other antiplatelets) were included in the meta-analysis. Additionally, for comparative studies, we set the following inclusion criteria: 1) prophylactic use of DAP as a control group, 2) intraprocedural loading of DAP for emergent cases (via nasogastric tube), 3) pre-treatment DAP loading, starting at least 3–5 days before the procedure for elective cases.
Literature reviews, systematic reviews, meta-analyses, case reports, case series consisting of < 10 patients, abstracts, conference papers, and in vitro studies were excluded. Articles solely focused on coil embolization or coiling articles not providing separate outcomes for SAC or FD techniques were also excluded. Additionally, studies using GP2B3A inhibitors to treat ischemic complications were excluded. Finally, non-comparative studies were excluded from the comparative analysis between GP2B3A inhibitor and DAP treatments to provide more reliable results (8, 9).
The authors completed the initial title and abstract screening independently. Duplicates and overlapping data (studies published on the same registry) were omitted. Next, two investigators independently performed the full-text screening (CB. MS). In case of conflict, the senior author (DFK with more than 20 years of experience) resolved the disagreement. The literature search, initial and full-text screening, and data extraction were performed with the AutoLit platform (Nested Knowledge, St. Paul, MN).
Outcome variables
We extracted the data on hemorrhagic and ischemic complications, mortality, rupture status, and functional outcome. Since GP2B3A inhibitors have a well-established potency compared to DAP, the primary objective of this meta-analysis was to compare hemorrhagic complication rates among patients treated with GP2B3A inhibitors and DAP.
Good clinical outcome was defined as a modified Rankin Scale score of ≤ 2 at 90 days or a Glasgow Outcome Score of ≥ 4 at discharge. Hemorrhagic complications were described as any new or worsening intracranial hemorrhage and extracranial hemorrhages, including groin hematoma, genitourinary or gastrointestinal bleeding. Any imaging-proven ischemic events were defined as thromboembolic complications. Studies including ruptured and unruptured aneurysms were categorized as “mixed” studies if separate data were not available for both groups.
Risk of Bias
Two authors evaluated the quality of included comparative articles using the Newcastle-Ottawa Scale for case-control studies (CB, MS). Although this tool was designed for comparative studies, we modified its selection questions using four criteria: 1) Did the study include all patients or a selected sample? 2) study design (retrospective or prospective) 3) was the clinical and imaging data satisfactory? 4) Were the treatment protocols described thoroughly?
Statistical Analysis
Using R software version 4.1.3, we calculated prevalence rates and odds ratios (ORs) with their corresponding 95% confidence intervals (CI). A random-effect model was used to pool all data in the presence of significant heterogeneity; otherwise, the fixed-effect model was used. Heterogeneity was assessed using Q statistics and the I2 test, where I2 > 50% or P-value < 0.05 were considered significant. Moreover, we conducted subgroup analyses based on the treated aneurysm status (ruptured or not) to explore possible sources of heterogeneity and investigate subgroup-related outcome differences. Whenever the pooled studies were ten or more (10), publication bias (Egger’s regression test) was tested (11, 12). For Egger’s regression test, P-value < 0.1 was considered significant, and Trim and Fill method was used to adjust for publication bias whenever found (13).
Results
Study characteristics
Our initial search identified 289 studies. After removing duplicates via the AutoLit platform (Nested Knowledge, Inc.), a total of 156 articles were screened for inclusion. We excluded 144 articles after initial and full-text screenings. Additionally, 1 record was identified through expert recommendation. A total of 13 articles were included in this meta-analysis (Figure 1). Of these, 9 were non-comparative(14–22), and 4 were comparative studies (23–26).
Figure 1.
PRISMA flow chart.
Six studies investigated the utility of prophylactic GP2B3A inhibitor treatment in ruptured aneurysms and emergent settings (17–20, 22, 24). Three studies were focused on unruptured aneurysms and elective operations (16, 23, 25). The remaining four articles included both ruptured and unruptured aneurysms (14, 15, 20, 26). Seven studies utilized SAC technique in the endovascular treatment of intracranial aneurysms (15, 17–19, 21, 24, 26), and three studies used the FD technique (14, 16, 25). Remaining three studies used FD and SAC techniques but did not provide separate outcomes (20, 22, 23).
Treatment protocols and baseline characteristics of the included studies are summarized in Supplementary Table 1. Eleven studies only provided data for intraprocedural prophylactic tirofiban treatment (14, 15, 17–22, 24–26). On the other hand, Levitt et al. (23) used abciximab, and Deng et al. (16) provided data for both eptifibatide and tirofiban use. Of these 13 included studies, 9 used GP2B3A loading dose (14, 16–19, 21, 24–26). All included studies, except Levitt et al., used post-procedural maintenance GP2B3A infusion, which was continued for 2 to 48 hours. After post-procedural GP2B3A infusion, all of the included studies, including Levitt et al., employed DAP to prevent long-term ischemic complications. Clopidogrel and aspirin were the most commonly employed DAP options.
Quality assessment
According to the modified Newcastle-Ottawa Scale, three studies had moderate to high risk of bias (14, 15, 20), and the risk of bias was low in the remaining eleven articles. All included articles had a retrospective design. The second most common issue was in comparability. Four studies included ruptured and unruptured aneurysms but did not provide separate outcomes based on rupture status (14, 15, 20, 26). Additionally, nine studies had a single-arm design; and a total of four articles directly compared the prophylactic utility of GP2B3A inhibitors and DAP (23–26). Results of the quality assessment were presented in Supplementary Table 2.
Outcomes of prophylactic GP2B3A inhibitor treatment
Hemorrhage
Thirteen studies with 1429 intracranial aneurysm patients reported hemorrhage rates following the use of prophylactic GP2B3A antagonists. Overall, hemorrhage rate was 3.98% (95% CI= 1.58–7.42); however, significant heterogeneity was observed among the included studies (I2= 87%; P-value< 0.001). On further subgroup analysis, hemorrhage rates were comparable regardless of the aneurysms’ rupture status (P-value= 0.504), with 2.5%, 4.3%, and 6.50% for ruptured aneurysms, unruptured aneurysms, and a combination of both, respectively. Moreover, the overall heterogeneity could not be explained by the difference in rupture status, where the residual heterogeneity remained significant (P-value< 0.001) (Figure 2). There was no significant risk of bias, as shown by Egger’s regression test (P-value= 0.682).
Figure 2.
Forest plot of hemorrhagic complications.
Thromboembolic events
There were 13 studies reporting thromboembolic events within 1429 intracranial aneurysm patients following the use of prophylactic GP2B3A antagonists. Overall, ischemic event rate was 6.63% (95% CI= 3.44–10.75); however, significant heterogeneity was observed among the included studies (I2= 83%; P-value< 0.001). The subgroup analysis based on the aneurysm rupture status did not show significant differences (P-value= 0.463), with 8.13%, 8.96%, and 3.32% for ruptured aneurysms, unruptured aneurysms, and a combination of both, respectively. Moreover, the overall heterogeneity could not be explained by the difference in rupture status, where the residual heterogeneity remained significant (P-value< 0.001) (Figure 3).
Figure 3.
Forest plot of thromboembolic events.
Good functional outcome
Eight studies with 934 intracranial aneurysm patients reported the functional outcomes (modified Rankin Scale 0–2 or Glasgow Outcome Score ≥4) rates following the use of prophylactic GP2B3A antagonists. Overall, 92.49% (95% CI= 84.70–97.67) of the patients achieved good functional outcome at discharge; however, significant heterogeneity was observed among the included studies (I2= 92%; P-value< 0.001). On further subgroup analysis of rupture status, there were statistically significant differences, with good outcome rates of 83.80%, 99.52%, and 95.20% for ruptured aneurysms, unruptured aneurysms, and a combination of both, respectively. Moreover, the overall heterogeneity was partially explained by the difference in rupture status, where the residual heterogeneity dropped down from I2 of 92% to 77% (Figure 4).
Figure 4.
Forest plot of favorable clinical outcomes.
Mortality
Ten studies with 1173 intracranial aneurysm patients reported mortality rates following the use of prophylactic GP2B3A antagonists. Overall, mortality rate was 1.84% (95% CI= 0.23–4.93); however, significant heterogeneity was observed among the included studies (I2= 88%; P-value< 0.001). On further subgroup analysis, mortality rates were higher in ruptured and mixed aneurysm groups (P-value< 0.001), with 3.29%, 0%, and 1.96% for ruptured aneurysms, unruptured aneurysms, and a combination of both, respectively. Moreover, the overall heterogeneity could not be explained by the difference in rupture status, where the residual heterogeneity remained almost the same (I2= 86%; P-value< 0.001) (Figure 5). There was no significant risk of bias, as shown by Egger’s regression test (P-value= 0.774).
Figure 5.
Forest plot of mortality.
GP2B3A inhibitors versus DAP
Four studies with 923 patients compared hemorrhage rates in patients using prophylactic GP2B3A antagonists to those using DAP. Overall, GP2B3A antagonists group showed lower hemorrhage rates as compared to those used DAP (OR= 0.33; 95% CI= 0.13–0.85; P-value= 0.022), with no heterogeneity was detected among the pooled studies (I2= 0%; P-value= 0.762) (Figure 6A)
Figure 6.
Comparison of prophylactic GP2B3A inhibitor and DAP treatment.
Four studies with 923 patients compared the rates of thromboembolic events in patients using prophylactic GP2B3A antagonists to those using DAP. Overall, both treatment regimens showed comparable results (OR= 0.52; 95% CI= 0.22–1.24; P-value= 0.142); nevertheless, with a significant heterogeneity was detected among the included studies (I2= 61%) (Figure 6B). The thromboembolic complication rates were 6.24% (95% CI= 3.62–9.50) for the GP2B3A inhibitor group and 10.4% (95% CI= 7–13.8) for the DAP group (Figure 6B).
Only two studies with 531 patients compared the functional outcome in patients using prophylactic GP2B3A antagonists to those using DAP. Overall, the results were comparable among both treatment groups (OR= 1.52; 95% CI= 0.50–4.58; P-value= 0.458), with no heterogeneity was detected among the pooled studies (I2= 0%; P-value= 0.630) (Figure 6C).
Mortality rates in patients using prophylactic GP2B3A antagonists were compared to those using DAP in three studies with 742 patients. Overall, the results were comparable among both treatment groups (OR= 0.41; 95% CI= 0.10–1.69; P-value= 0.216), with no heterogeneity was detected among the pooled studies (I2= 0%; P-value= 0.216) (Figure 6D). The thromboembolic complication rate of the DAP cohort was 10.4% (95% CI= 7–13.8).
Stent Assisted Coiling versus Flow Diversion
Ten studies with 1217 patients provided hemorrhagic and ischemic complication data separately for endovascular treatment techniques (3 studies 322 patients for FD and 7 studies 895 patients for SAC). The SAC cohort’s overall ischemic event rate was 4.91% (95% CI= 1.72–9.63), and this rate was 3.73% (95% CI= 0.55–9.56) for the FD group. However, the difference between the two techniques was not statistically significant (p=0.706, Supplementary Figure 1). Overall hemorrhagic complication rates of SAC and FD cohorts were 2.48% (95% CI= 1.19–4.21) and 4.23% (95% CI= 0–16.59), respectively, and the difference between the two groups was not statistically significant (p=0.659, Supplementary Figure 2).
Discussion
This current meta-analysis of the prophylactic use of GP2B3A antagonist in aneurysm treatment with endoluminal devices identified several important findings. First, the hemorrhagic complication rate associated with GP2B3A antagonists was low overall, did not differ between ruptured and unruptured aneurysms, and, somewhat surprisingly, was actually lower than that seen with DAP therapy. On the other hand, rates of thromboembolic events with GP2B3A antagonists were not insignificant and were not statistically significantly lower than those seen with DAP therapy. Granted, the number of comparative studies between GP2B3A antagonists and DAP agents was small, and the majority of these studies did show significant reductions in thromboemboli using GP2B3A antagonists. Taken together, these findings provide comfort to those considering use of GP2B3A antagonists in both ruptured and unruptured aneurysms from the standpoint of hemorrhagic complications, but that additional studies will need to be undertaken to confidently demonstrate improved efficacy in avoidance of thromboemboli with GP2B3A agents in place of DAP therapy.
GP2B3A inhibitors were initially used in the rescue treatment of intraprocedural thromboembolic complications (5). With growing literature on GP2B3A inhibitors’ safety and efficacy in neuroendovascular procedures, interventionalists have also started using GP2B3A inhibitors as prophylactic agents, especially in emergent settings where DAP loading is not feasible. Recent consensus statements and comprehensive national surveys suggest that GP2B3A inhibitors have become interventionalists’ first choice in the emergent treatment of ruptured aneurysms with endoluminal devices (27, 28). However, data regarding the prophylactic GP2B3A inhibitor treatment data are significantly less robust for unruptured aneurysms than ruptured aneurysms. Even though a few observational studies have suggested that GP2B3A inhibitors can be employed in elective operations, no observational study or meta-analysis has compared the prophylactic utility of GP2B3A inhibitors for ruptured and unruptured aneurysms. In order to address this lack of evidence, we performed a subgroup analysis based on rupture status and found that prophylactic treatment with GP2B3A inhibitors is safe, regardless of rupture status.
A recent meta-analysis by Xiang et al. compared the performance of prophylactic tirofiban and DAP treatments for the SAC of intracranial aneurysms and found that hemorrhagic complication rates of tirofiban and DAP treatments are similar (29). However, in our study, the GP2B3A group had a significantly lower hemorrhagic complication rate than the DAP group. These conflicting findings between the two studies might be due to two main methodological differences. First, that same meta-analysis was limited to SAC procedures only, even though FD is rapidly growing in utilization (1, 3, 4). In our current study, we have extended the analysis to all relevant endoluminal aneurysm devices, including both SAC and FD. Second, since the indirect comparisons using single-arm studies are open to confounding bias (8, 9), we performed our comparative analysis using double-arm studies only (GP2B3A inhibitors versus DAP). Platelet function quickly recovers after cessation of GP2B3A inhibitor infusion, and this allows operators to adapt to high hemorrhage risk clinical scenarios. Therefore, we believe that lower hemorrhage rates of the GP2B3A inhibitors might be due to their reversible effects and rapid offset of action.
Xiang et al. suggested that prophylactic tirofiban treatment was associated with significantly lower thromboembolic complication rates than DAP treatment for SAC procedures (29). In our meta-analysis, thromboembolic complications rates were 6.24% (95% CI= 3.62–9.50) for GP2B3A inhibitor cohort and 10.4% (95% CI= 7–13.8) for DAP group. However, the difference did not reach significance in our comparative analysis (OR= 0.52; 95% CI= 0.22–1.24; P-value= 0.142). Therefore, our findings suggest that both prophylactic treatment strategies can be employed after clinical reasoning, especially if the DAP loading is possible. However, it is important to note some of the included studies employed GP2B3A inhibitors in high thrombosis risk patients after platelet function testing. Additionally, given the retrospective nature of the included studies, interventionalists might have preferred GP2B3A inhibitors in challenging cases and emergent settings. Therefore, further studies are needed to compare the prophylactic utility of GP2B3A inhibitors and DAP.
In the subgroup analysis of the GP2B3A inhibitor cohort, ischemic event rates did not significantly change with rupture status. However, ruptured aneurysm cases had significantly higher mortality and lower favorable outcome rates compared to patients with unruptured aneurysms. Nevertheless, these findings must be taken with precaution as ruptured aneurysms are associated with more severe clinical presentations and high pre-treatment mRS and GOS scores. It is important to note that, despite the high hemorrhage risk of acutely ruptured aneurysms, we did not find a significant difference in hemorrhagic complications between ruptured and unruptured aneurysm patients who received GP2B3A inhibitors. Therefore, our findings suggest that GP2B3A inhibitors are equally effective and safe for ruptured and unruptured aneurysms. Due to the different design characteristics of intracranial stents and flow diverters, we also compared the ischemic event and hemorrhagic complication rates of FD and SAC techniques in patients who received prophylactic GP2B3A inhibitors. However, the differences in hemorrhagic and ischemic complications did not significantly change with the endovascular treatment technique.
Our meta-analysis had several limitations. First, GP2B3A inhibitor treatment protocols varied across studies. Second, most of the studies provided infusion and bolus rates. However, total doses or procedure length data were not available in the included studies. Efficacy and safety outcomes of the GP2B3A group can significantly change with the treatment protocol and total dose. Third, interventionalists might have preferred lower GP2B3A inhibitor doses to treat ruptured aneurysms depending on the timing and severity of subarachnoid hemorrhage. Fourth, good clinical outcome definition was heterogeneous across included studies, and the timing of the assessment was substantially varying. Fifth, ruptured aneurysm cases present with significant pre-treatment disability. Therefore, using mRS 0–2 or GOS >4 thresholds might underestimate the effect of endovascular treatment. For this reason, we tried to present pre-treatment disability scores along with score shifts after treatment. However, unfortunately, these outcomes were not presented in most of the included studies. Sixth, flow diverters have significantly higher mesh density than intracranial stents. Therefore, the efficacy of GP2B3A inhibitors might be different for SAC and FD techniques. Finally, GP2B3A inhibitor and DAP treatment cohorts contained different drugs, which may exhibit different safety and efficacy profiles.
Periprocedural hemorrhagic and ischemic events remain a major source of morbidity and mortality after FD and SAC. Even though recent studies suggest that interventionalists prefer GP2B3A inhibitors in emergent stenting procedures, the literature on prophylactic GP2B3A inhibitor treatment is still sparse. Our study supports that GP2B3A inhibitors are safe and effective as prophylactic agents regardless of the rupture status. However, further research is still needed to establish the additional benefit of prophylactic GP2B3A inhibitor treatment over classic DAP regimens.
Supplementary Material
Supplementary Figure 1. Thromboembolic event rates with different endovascular treatment techniques.
Supplementary Figure 2. Hemorrhagic complication rates with different endovascular treatment techniques.
Acknowledgements
Nested Knowledge, Inc. (St. Paul, MN) provided software access for this study.
Funding
Research reported in this publication was supported by the National Institute Of Neurological Disorders And Stroke of the National Institutes of Health under Award Number R01NS076491. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Conflict of interests
RK received research support from NIH, Cerenovus, Stryker, Sensome, Neurogami, MIVI Biosciences, Monarch Medical, Endovascular Engineering; DFK received research support from Microvention, Medtronic, Monarch Medical, Balt, Neurogami, Cerenovus and has ownership interest in Superior Medical Experts, Nested Knowledge, Conway Medical.
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Associated Data
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Supplementary Materials
Supplementary Figure 1. Thromboembolic event rates with different endovascular treatment techniques.
Supplementary Figure 2. Hemorrhagic complication rates with different endovascular treatment techniques.