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Review
Effect of antiplatelet therapy and platelet function testing on hemorrhagic and thrombotic complications in patients with cerebral aneurysms treated with the pipeline embolization device: a review and meta-analysis
  1. Susana L Skukalek1,
  2. Anne M Winkler2,
  3. Jian Kang3,
  4. Jacques E Dion4,
  5. C Michael Cawley5,
  6. Adam Webb6,
  7. Mark J Dannenbaum7,
  8. Albert J Schuette8,
  9. Bill Asbury9,
  10. Frank C Tong10
  1. 1Departments of Neurosurgery and Radiology, The Emory Clinic, Atlanta, Georgia, USA
  2. 2Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
  3. 3Department of Biostatistics and Bioinformatics, Emory Rollins School of Public Health, Atlanta, Georgia, USA
  4. 4Departments of Radiology and Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA
  5. 5Departments of Neurosurgery and Radiology, Emory University School of Medicine, Atlanta, Georgia, USA
  6. 6Departments of Neurology and Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA
  7. 7Department of Neurosurgery, The University of Texas at Houston, Houston, Texas, USA
  8. 8Department of Neurosurgery, Tripler Army Medical Center, Honolulu, Hawaii, USA
  9. 9Emory University Hospital, Atlanta, Georgia, USA
  10. 10Departments of Radiology and Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA
  1. Correspondence to Dr S L Skukalek, Departments of Neurosurgery and Radiology, The Emory Clinic, 1365B Clifton Road, Suite 2200, Atlanta, GA 30322, USA; susana.skukalek{at}emoryhealthcare.org

Abstract

Purpose The pipeline embolization device (PED) necessitates dual antiplatelet therapy (APT) to decrease thrombotic complications while possibly increasing bleeding risks. The role of APT dose, duration, and response in patients with hemorrhagic and thromboembolic events warrants further analysis.

Methods A PubMed and Google Scholar search from 2009 to 2014 was performed using the following search terms individually or in combination: pipeline embolization device, aneurysm(s), and flow diversion, excluding other flow diverters. Review of the bibliographies of the retrieved articles yielded 19 single and multicenter studies. A statistical meta-analysis between aspirin (ASA) dose (low dose ≤160 mg, high dose ≥300 mg), loading doses of APT agents, post-PED APT regimens, and platelet function testing (PFT) with hemorrhagic or thrombotic complications was performed.

Results ASA therapy for ≤6 months post-PED was associated with increased hemorrhagic events. High dose ASA ≤6 months post-PED was associated with fewer thrombotic events compared with low dose ASA. Post-PED clopidogrel for ≤6 months demonstrated an increased incidence of symptomatic thrombotic events. Loading doses of ASA plus clopidogrel demonstrated a decreased incidence of permanent symptomatic hemorrhagic events. PFT did not show a statistically significant relationship with symptomatic hemorrhagic or thrombotic complications.

Conclusions High dose ASA >6 months is associated with fewer permanent thrombotic and hemorrhagic events. Clopidogrel therapy ≤6 months is associated with higher rates of thrombotic events. Loading doses of ASA and clopidogrel were associated with a decreased incidence of hemorrhagic events. PFT did not have any significant association with symptomatic events.

  • Aneurysm
  • Complication
  • Flow Diverter

https://doi.org/10.1136/neurintsurg-2014-011145

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    Introduction

    The pipeline embolization device (PED; ev3, Plymouth, Massachusetts, USA) received approval from the Food and Drug Administration in 2011 for the treatment of wide necked, large and giant, and non-saccular cerebral aneurysms difficult to treat with traditional open neurosurgical or coil based endovascular treatments. The PED is a flexible self-expanding construct that consists of a braided, multi-alloy, cylindrical mesh with 30–35% metal surface area coverage and functions to divert flow from the aneurysm. Once deployed, it induces aneurysm thrombosis and promotes endothelialization of the device within the parent vessel.1 The pivotal Pipeline for Uncoilable or Failed Aneurysms trial (PUFS)2 proved the efficacy of PED, with 78 subjects (73.6%) meeting the primary endpoint of complete occlusion of the target aneurysm and ≤50% stenosis of the parent artery at the target location, as well as a good safety profile.2 However, six patients (5.6%) experienced a major ipsilateral stroke or neurological death.2 The reported incidence of peri- and post-procedural stroke and hemorrhage varies in published PED studies, but the occurrence of distal ipsilateral hemorrhage has also emerged as a specific complication related to flow diversion. Several mechanisms have been implicated as possibly contributing to these risks, including the size of the delivery device, the degree of vascular manipulation in deployment of the device, altered pressure dynamics from redirected flow, and hemorrhagic conversion of ischemic embolic events as a result of dual antiplatelet therapy (APT).3

    Dual APT has been associated with a reduction in thromboembolic events, but has also been implicated as a potential factor contributing to the rates of ischemic and hemorrhagic complications associated with PED placement.4 Current APT protocols used in PED patients have been adopted from the cardiology and interventional radiology literature. Given the comparatively higher rate of intracranial hemorrhage with PED placement compared with cardiac and peripheral procedures, APT regimens should ideally be tailored to the neurovascular aneurysm population, to balance the need for prevention of thromboembolic complications while minimizing the relatively higher risk of iatrogenic bleeding.

    APT dose, duration of post-procedural APT, loading doses of antiplatelet agents, and use and type of platelet function testing (PFT) to assess APT non-responsiveness varies among PED treating centers. Non-responsiveness to conventional doses of aspirin (ASA) and clopidogrel therapy may contribute to suboptimal platelet inhibitory effects and be associated with ischemic complications.

    The purpose of this study was to review how clinical preparation for PED treatment is established across treating facilities and to identify associations between ASA dose, APT regimens, including loading doses of one or multiple agents, post-PED dual APT duration, and inclusion of PFT with hemorrhagic or thrombotic adverse events.

    Methods

    A search in PubMed and Google Scholar from 2008 to 2014 was performed using the following search terms individually or in combination: pipeline embolization device, aneurysm(s), and flow diversion. Other flow diversion devices were excluded from this review. A search through the bibliographies of the retrieved articles was performed to identify any other potentially relevant articles. Nineteen studies, including international and national, single and multicenter trials, were included in this review. A meta-analysis was performed to identify associations between ASA dose, use of loading doses of antiplatelet agents, post-PED dual APT regimens and length of therapy, and inclusion of PFT with hemorrhagic or thrombotic adverse events. Studies with both ruptured and unruptured aneurysms were included.

    ASA dose was divided into two categories: low dose ASA was defined as 160 mg or less and high dose ASA was defined as 300 mg or greater. The clopidogrel dose was 75 mg for all studies. Use of loading doses of ASA and clopidogrel were identified. Alternative medications (eg, prasugrel, ticagrelor, ticlopidine, abciximab) were administered where contraindications to conventional APT existed, such as non-responsiveness or allergic reactions. The effects of post-PED management using low versus high dose ASA and clopidogrel regimens were compared from studies where dual APT was continued for 6 months or less compared with those treating for more than 6 months. Use of PFT, including VerifyNow (Accumetrics Inc, San Diego, California, USA), as well as conventional platelet aggregometry was also investigated.

    Hemorrhagic events were defined as either subarachnoid hemorrhage or intracerebral hemorrhage, and categorized as asymptomatic versus symptomatic; symptomatic events were further stratified as transient symptomatic events or symptomatic events associated with permanent disability or mortality. Thrombotic events were defined as central retinal artery occlusion, thromboembolic events and infarcts, and complete and partial in-stent thrombosis. Similarly, thromboembolic events were categorized as asymptomatic versus symptomatic. Symptomatic events were further stratified to include transient symptomatic events or symptomatic events associated with permanent disability or mortality.

    The number of events and total number of patients within each category were combined across 19 studies. The percentages of each event (yes vs no) were computed and their differences were assessed by χ2 proportional tests. All analyses were implemented in statistical software R. The significance level was set to 0.05 for all of the statistical tests.

    Results

    Overall, 19 studies were published from 2009 to 2014, and together included a total of 1110 patients of whom 30 had ruptured aneurysms and 1080 had unruptured aneurysms. A summary of these studies is given in table 1.5–17 ,2–4 ,18–20 There were 720 women and 264 men in the reporting studies, and mean patient age was 56 years. A total of 744 patients had anterior circulation aneurysms and there were 362 patients with posterior circulation aneurysms. Aneurysm size ranged from <7 mm to >25 mm, with a mean aneurysm size of 11.44 mm. Aneurysms included saccular, non-saccular, dissecting, wide necked, fusiform, blister, and circumferential.

    View this table:
    Table 1

    Summary of studies

    Pre-procedurally, 7 of 19 (36.8%) studies utilized low dose ASA (<160 mg) and 9 of 19 (47.4%) used high dose ASA (>300 mg). One study (5.3%) did not include specific dosing information regarding pre-procedure antiplatelet medication dosing. One study (5.3%) only used loading doses of ASA or clopidogrel. One study (5.3%) used varied APT regimens. All studies initiated 75 mg of clopidogrel. Nine studies (47.3%) did not routinely administer loading doses of ASA or clopidogrel pre-procedurally and either administered low dose or high dose ASA and 75 mg of clopidogrel for 2–10 days prior to PED treatment. Five of 19 (26.3%) studies primarily used loading doses in the setting of emergent cases or clopidogrel hyporesponsiveness. Six studies (31.6%) used either loading doses of ASA and clopidogrel or abciximab pre-procedurally or started dual APT for 2–7 days prior to PED treatment.

    Post-procedurally, low or high dose ASA was continued from 3 months to indefinitely in 17 out of 19 studies (89.5%). Clopidogrel was continued from 6 weeks to 1 year post-procedurally. Eight of 19 studies (42.1%) utilized PFT using platelet aggregometry, VerifyNow, or Multiplate (Verum Diagnostica GmbH, Munich, Germany) to determine clinical preparedness for PED treatment. Two studies (10.5%) did not routinely perform PFT. The overall results are summarized in table 2.

    View this table:
    Table 2

    Proportional tests for difference in percentages of events for different groups and different antiplatelet therapy regimens

    Hemorrhagic events

    Symptomatic and transient

    The rate of symptomatic transient post-PED hemorrhage was 4.05% overall. A higher rate of symptomatic transient post-PED hemorrhage (4.7%) was associated with administration of high dose ASA for 6 months or less (p=0.02, n=381). In contrast, the rate of symptomatic transient hemorrhage (2.7%) was lower for patients who continued high dose ASA therapy for more than 6 months (p=0.05, n=446). The rate of symptomatic transient hemorrhagic events (5.6%) was higher in patients who were given low dose ASA for 6 months or less (p=0.08, n=285) although statistical significance was not achieved. Between those centers utilizing PFT and those who did not, there was no statistically significant relationship with symptomatic transient post-PED hemorrhage (3.9% and 4.0%, respectively).

    Symptomatic and permanent or mortality

    The overall rate of symptomatic permanent hemorrhagic events or mortality was 3.09%. Administration of loading doses of ASA pre-procedurally was associated with a lower rate of symptomatic permanent hemorrhage or death (2.0%) (p=0.05, n=449) compared with those patients who were not loaded (3.9%). The use of clopidogrel loading doses pre-PED was also associated with a lower rate of these events (2.3%) compared with those were not loaded (4.4%). A higher incidence of symptomatic permanent hemorrhagic events or death (3.7%) was seen in patients given high dose ASA post-PED for 6 months or less (p=0.03, n=381) as well as in those who received low dose ASA (4.6%) for 6 months or less (p=0.05, n=285). In patients who received high dose ASA for more than 6 months, there was a decreased incidence (2.0%) (p=0.07, n=446) of symptomatic permanent or deaths secondary to hemorrhagic events although statistical significance was not achieved. Again, there was no statistically demonstrable relationship between symptomatic permanent hemorrhagic events or death in patients who received pre-procedure PFT (2.7%) and those who did not (3.0%) (p=0.77).

    Asymptomatic

    The overall rate of asymptomatic hemorrhagic events was 0.29%. In 739 patients who received clopidogrel for 6 months or less, there was a lower incidence (0.3%) (p=0.03) of asymptomatic hemorrhagic events compared with those who received clopidogrel therapy for more than 6 months (1.1%).

    Thrombotic events

    Symptomatic and transient

    The overall rate of symptomatic transient thrombotic events was 3.67%. There was a lower incidence (3.2%) of symptomatic transient thrombotic events in patients who received high dose aspirin pre-procedurally (p=0.01, n=687) and post-PED (3.6%) (p=0.04, n=588) compared with those patients who were given low dose ASA (5.6%). In patients who received clopidogrel therapy for 6 months or less, there was a statistically significant increased incidence (4.2%) of symptomatic transient thrombotic events (p=0.001, n=739) compared with patients who received clopidogrel therapy for more than 6 months (2.3%). There was no statistically demonstrable relationship between symptomatic transient thrombotic events in patients who received pre-procedure PFT (4.1%) and those who did not (3.0%) (p=0.25).

    Symptomatic and permanent or mortality

    Overall, there was a 1.35% rate of symptomatic permanent thrombotic events or mortality. A statistically significant increased incidence (3.5%) of symptomatic permanent thrombotic events or mortality was seen in patients who received low dose ASA pre-procedurally (p<0.001, n=229) compared with those patients who received high dose ASA therapy (0.7%) (p<0.001, n=687). Fewer symptomatic permanent thrombotic events or death (0.8%) were also noted in patients who received loading doses of clopidogrel pre-procedurally (p=0.01, n=646) compared with those who did not (2.3%). Post-procedurally, an increased incidence (3.6%) of symptomatic permanent thrombotic events or death in patients given low dose ASA post-PED (p<0.001, n=252) was noted compared with a decreased incidence of symptomatic permanent thrombotic events (0.7%) (p=0.0002, n=588)) in those given high dose ASA. In patients who experienced symptomatic permanent thrombotic events or death, length of post-PED high (2.4%) and low (2.5%) dose ASA therapy was linked to an increased incidence of events when patients were treated for 6 months or less (high: p=0.0002, n=381) compared with those who received greater than 6 months of ASA (0.7%) (high: p=0.02, n=446 and low: p=0.01, n=285, respectively). Again, there was no statistically demonstrable relationship between symptomatic permanent thrombotic events in patients who received pre-procedure PFT (1.5%) and those who did not (1.4%).

    Asymptomatic

    The overall rate of asymptomatic thrombotic events was 1.93%. Loading doses of both ASA and alternative medications (eg, prasugrel, ticagrelor, ticlopidine, abciximab) were associated with an increased incidence of asymptomatic thrombotic events (2.9% (p=0.002, n=449) and 5.5% (p=0.04, n=73), respectively). In patients who were treated with high dose ASA post-PED, there was a decreased incidence (1.0%) of asymptomatic thrombotic events (p=0.03, n=381) compared with those who received ASA therapy for more than 6 months (3.1%) (p<0.001, n=446). Conversely, patients who were treated with clopidogrel for 6 months or less post-PED were noted to have an increased incidence (2.4%) of asymptomatic thrombotic events (p<0.001, n=739) compared with those patients who received clopidogrel therapy for more than 6 months (0.0%) (p=0.26, n=88)). In patients who underwent PFT, a statistically significant increased incidence (3.6%) of asymptomatic thrombotic events (p<0.001, n=412) was noted compared with those patients who did not undergo PFT.

    Overall rates of both hemorrhagic and thrombotic complications were analyzed as a function of time from 2009 to 2014, and are summarized in table 3. There were no reported complications in 2009.5 The most notable decrease in complications was seen in patients who experienced symptomatic thrombotic events, with rates of 16.67% in 2010 and 5.66% in 2014. From 2010 to 2014, there was an overall decrease in symptomatic hemorrhagic events from 5.56% to 3.77%. There were no asymptomatic hemorrhagic events reported in 2009, 2010, or 2014, and the highest event rate was reported in 2013 (0.52%). Patient with symptomatic permanent thrombotic events or mortality demonstrated similar rates (5.56%) in 2010 and 2014, with decreases in these events noted from 2011 to 2013. There was an increase in asymptomatic thrombotic event rates ranging from no events reported in 2009–2010 to 7.55% reported in 2014.

    View this table:
    Table 3

    Overall complication rates from 2009 to 2014

    Discussion

    This review and meta-analysis was conducted to address whether hemorrhagic or thrombotic complications in patients treated with the PED were associated with APT dosing both pre- and post-procedurally, including use of loading doses of APT, duration of post-PED APT, and use of PFT. Across the PED treating centers included in this analysis, variations exist in dual APT management. Heterogeneous practice patterns regarding APT have been attributed to the introduction of newer antiplatelet agents, controversy over PFT, and the inherent thrombotic and hemorrhagic complications associated with flow diverters.21 In this review, for patients who experienced an increased incidence of both transient and permanent symptomatic hemorrhagic events, length of ASA therapy for 6 months or less post-PED seemed to have the greatest impact. Loading doses of both ASA and clopidogrel pre-PED were associated with an overall decreased incidence of symptomatic permanent hemorrhagic events. The mechanisms by which these findings can be explained are difficult to discern. Dual APT alone is a risk factor for spontaneous intraparenchymal hemorrhage (IPH) but the rates of cerebral hemorrhage in patients on dual APT are higher in those undergoing treatment with the PED.22 Delayed ipsilateral IPH has more recently been identified as a phenomenon specific to treatment with the PED. The occurrence of hemorrhagic conversion of procedural or post-procedural strokes, alteration of arterial pulse pressure waves predisposing patients to downstream hemorrhages, and the more recent findings of hydrophilic foreign embolic materials in the vasculature of patients with delayed IPH22 further highlights the complexity and multifactorial risk factors contributing to hemorrhagic events in this patient population.

    In patients who experienced symptomatic permanent thrombotic events or death, high dose ASA was associated with fewer events both pre- and post-procedurally. Increased duration of both low and high dose ASA therapy post-PED was associated with a decreased incidence of symptomatic permanent thrombotic events. Clopidogrel therapy administered for 6 months or less was associated with an increased incidence of both symptomatic and asymptomatic thrombotic events and a decreased incidence of asymptomatic hemorrhagic events. Loading doses of clopidogrel were also associated with fewer symptomatic permanent thrombotic events or death, but loading doses of ASA or alternative medications (eg, prasugrel, ticagrelor, ticlopidine, abciximab) were associated with an increased incidence of asymptomatic thrombotic events. These findings would support the use of high dose ASA (>160 mg) and clopidogrel therapy for at least 6 months. In addition, loading doses were associated with a decreased incidence of hemorrhagic events, but this association and mechanism should be further explored.

    Eight of 19 centers performed PFT, identified variable clopidogrel response, and used algorithm adjusted APT regimens in preparation for PED deployment. Of the 412 patients undergoing pre-procedural PFT, a statistically significant increase in asymptomatic thrombotic events was noted; however, PFT had no impact on symptomatic transient or permanent hemorrhagic or thrombotic events. The use of PFT to determine clinical preparedness for treatment with the PED is of interest due to the individual variability that exists in the antiplatelet response to clopidogrel and the concern for clopidogrel hypo- and hyper-responsiveness. The results of this meta-analysis highlight the importance of duration of clopidogrel therapy post-PED and use of clopidogrel loading doses prior to PED treatment over PFT in minimizing the risks of thrombotic adverse events. In addition, the use of PFT does not appear to have any association with clinical outcomes other than asymptomatic thrombotic events, but warrants further prospective investigation.

    Multiple factors surrounding the use of APT must be considered when utilizing the PED as the treatment of choice for patients with intracranial aneurysms. APT protocols used in clinical practice in preparation for PED have been adopted from the cardiology and interventional radiology literature. Several factors have been shown to influence clopidogrel response in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions. Some extrinsic factors include clopidogrel under-dosing in patients undergoing coronary stents and the timing between medication administration and measurement of PFT. In patients with ACS undergoing coronary stenting, the literature has consistently demonstrated that 4–30% of patients do not demonstrate an adequate antiplatelet response using conventional doses of clopidogrel.23 Clopidogrel induced inhibition is known to be dependent on both dose and time. In healthy patients, a 75 mg dose of clopidogrel takes 3–7 days to reach maximum antiplatelet effect whereas using a single 400 mg dose of clopidogrel achieves maximum platelet inhibition after 2–5 h with no further increase with 600 mg.24

    The timing of PFT is also important when determining clinical preparedness for treatment. In one study,24 patients who were initially considered non-responders to clopidogrel at 24 h post-loading dose were later found to be responders at 30 days. Although platelet reactivity and APT non-responsiveness have been well studied in the cardiovascular literature in patients with ACS undergoing percutaneous coronary interventions, it has not been as extensively studied in patients with cerebral aneurysms undergoing treatment with flow diversion devices. In patients treated with the PED, additional prospective research is needed to determine what doses of ASA and clopidogrel are necessary to achieve optimal platelet inhibition. In addition, ensuring that an adequate length of time is allotted between the initiation of loading dose regimens or maintenance APT regimens and intervention to achieve optimal platelet inhibition may be necessary when determining whether a patient has been optimized prior to treatment.

    Finally, it has been suggested that overall hemorrhagic and thrombotic complication rates have decreased since the inception of the PED use with increased operator familiarity. Our data would suggest that the most notable improvement in complications was seen in the rates of transient thrombotic complications (table 3). This may be due in part to the large size and complexity of the aneurysms treated in the early cohort of patients, including aneurysms that had been previously treated surgically or endovascularly, necessitating the use of more devices, longer procedure times, and potentially higher downstream embolic complications. The analysis also suggests that overall transient and permanent hemorrhagic complications have slightly decreased over time, but rates of permanent thrombotic complications remain relatively unchanged.

    Conclusion

    The pipeline embolization device offers an effective treatment option for complex intracranial aneurysms; however, both hemorrhagic and thrombotic complications are associated with the use of this device. While the multiple factors contributing to these complications are not entirely understood, clarity over the use of dual APT and PFT in this patient population may help to minimize future complications. The results of this analysis would suggest the following:

    • High dose ASA for more than 6 months to minimize permanent thrombotic complications as well as permanent and transient hemorrhagic complications.

    • Clopidogrel therapy for more than 6 months to minimize rates of thrombotic events.

    • Loading doses of ASA and clopidogrel pre-procedurally to potentially decrease the incidence of hemorrhagic events; however, this association and mechanism should be further explored.

    • Use of PFT did not appear to have any significant association with clinical outcomes other than asymptomatic thrombotic events, but this also warrants further prospective investigation.

    While there are no broadly accepted practice patterns addressing dual APT and PFT in the PED literature, developing evidence based guidelines that are specific to this unique patient population is of paramount importance. Of particular interest is the use and selection of PFT with conventional platelet aggregometry versus point of care testing with VerifyNow. While our analysis suggests that PFT has minimal effects on clinical outcomes, identification of patients with variable clopidogrel response to dual APT, reliability of PFT, thresholds, and use of algorithm adjusted protocols remains controversial. Future investigation should focus on prospective randomized trials assessing the clinical utility of PFT and on examining APT and antiplatelet responses via platelet aggregometry versus point of care to determine their effects on clinical outcomes in this population.

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    Footnotes

    • Contributors Each author read and contributed to the paper. All coauthors of this paper meet the criteria of the International Committee of Medical Journal Editors (ICMJE) recommendations 2013.

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed.