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Abstract
Background Clopidogrel bisulfate and aspirin are routinely administered as dual antiplatelet agents for many neurointerventional procedures, especially for intravascular stent placement. Many patients are non-responsive to clopidogrel, either secondary to drug interactions or from variations of cytochrome P450 enzymes. Prasugrel (brand name Effient, Eli Lilly and Company, Indianapolis, IN, USA) is a new antiplatelet agent that has been utilized extensively in patients undergoing cardiovascular procedures but its safety and efficacy during neurointerventional procedures have not been evaluated.
Objective To examine whether prasugrel is a safe and effective alternative to clopidogrel for neurointerventional procedures, especially in those patients who are either non-responders or allergic to clopidogrel.
Methods The medical records of all patients undergoing neurointerventional procedures at our institution who received prasugrel between January 2009 and July 2011 were retrospectively reviewed. A systematic chart review was performed and the following data were recorded: demographics, aneurysm location, endovascular techniques, peri- and post-procedural complications, hemorrhagic complications, clinical outcome and angiographic outcome.
Results 16 patients undergoing neurointerventional procedures received prasugrel over a 2 year interval. All patients who had follow-up studies of P2Y12 inhibition had immediate therapeutic response to prasugrel. There were no complications related to ischemic or intracranial hemorrhage.
Conclusion Prasugrel is a viable alternative to clopidogrel for patients undergoing neurointerventional procedures who are non-responders to clopidogrel. Further study is needed to evaluate the safety, efficacy and cost-effectiveness of prasugrel compared with clopidogrel for patients undergoing neurointerventional procedures.
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Introduction
Since the advent of Guglielmi detachable coils in 1991, endovascular techniques have played an integral role in the treatment of neurovascular disease.1 Intracranial stents (Neuroform, Boston Scientific, Natick, Massachusetts, USA; Enterprise, Codman and Shurtleff, Raynham, Massachusetts, USA; Wingspan, Boston Scientific) allow for the treatment of wide necked aneurysms as well as intracranial atherosclerosis.2 Extracranial stenting continues to play a major role in the treatment of extracranial atherosclerosis within carotid and vertebral systems.3 The greatest risk associated with neurointerventional procedures is thromboembolism and related cerebral infarction. Pyysalo et al 4 performed MRI on patients undergoing endovascular occlusion of ruptured and unruptured cerebral aneurysms. They showed that 19% of patients with unruptured aneurysms and 41% of patients with ruptured aneurysms had ischemic lesions in the postoperative period. Similar complications have been seen in those undergoing treatment of cardiovascular disease. In recent studies, 6% of acute coronary syndrome (ACS) patients undergoing balloon angioplasty and stenting had stent thrombosis.5 ,6 Although the etiology of thromboembolism is clearly multifactorial and in some cases is due to flow abnormalities, hypercoagulable states, endothelial injury and abnormal viscosity, it is clear that platelet reactivity is integral to thrombus formation.
To reduce thromboembolic complications, patients undergoing neurointerventional procedures can be placed on antiplatelet agents unless these agents are contraindicated. Kang et al 7 showed that pretreatment with clopidogrel bisulfate (Bristol-Myers Squibb, New York, New York, USA) reduces the thromboembolic rate by 41.2% in patients undergoing elective neurointerventional procedures. Clopidogrel and aspirin (Bayer, Leverkusen, Germany) are used routinely to reduce platelet reactivity during and after neurointerventional procedures. Aspirin is an irreversible inhibitor of cyclooxygenase I (COX-I), leading to decreased production of prostaglandins as well as thromboxane A2 while modifying cyclooxygenase II (COX-II) and increasing production of anti-inflammatory lipoxins. Decreased production of prostaglandins and thromboxane decreases platelet reactivity, thus reducing the probability of thromboembolism. Clopidogrel is a prodrug belonging to the thienopyridine class of antiplatelet medications. Once activated by the cytochrome P450 system, the active metabolite binds to the P2Y12 receptor, thus inhibiting ADP mediated receptor activation. Clopidogrel with or without the use of aspirin has been shown to significantly reduce the rate of thromboembolic complications associated with neurointerventional procedures.7–9 However, identical doses of clopidogrel have been shown to produce different levels of platelet inhibition among individuals.10 Certain loss of function polymorphisms within the cytochrome P450 system are responsible for this diverse response. Although widely debated, studies have suggested that common medications such as proton pump inhibitors (PPIs) may cause reduced platelet inhibition from clopidogrel.11–17
The heterogeneous response to clopidogrel among individuals has led to the development of newer thienopyridine antiplatelet agents, such as prasugrel. Prasugrel also acts by inhibiting ADP receptor mediated activation of platelets. Unlike clopidogrel, which requires a two step process of activation, prasugrel only requires a one step activation and thus has been shown to have fewer drug interactions, offer more effective platelet inhibition and does not have the heterogeneous response among individuals.18–25 This has led to extensive study of prasugrel in comparison with clopidogrel in the ACS patient population. However, there has been no formal study of prasugrel use in patients undergoing neurointerventional procedures. We performed a retrospective analysis to better define the safety and efficacy of prasugrel use in clopidogrel non-responders who have undergone neurointerventional procedures.
Methods
Following approval by the institutional review board, a retrospective cohort study was undertaken of all patients who underwent neurointerventional procedures that were treated with prasugrel during the period January 2009 to July 2011. A systematic chart review was performed and the following data were recorded: demographics, aneurysm location, endovascular techniques, peri- and post-procedural complications, hemorrhagic complications, clinical outcome and angiographic outcome.
All patients included in this study were treated for unruptured cerebral aneurysms. Patients provided consent for endovascular occlusion with possible use of a balloon or stent. All patients not allergic to clopidogrel were pretreated with 75 mg of clopidogrel and at least 81 mg of aspirin for at least 1 week prior to the procedure, except for one patient who received 300 mg of clopidogrel the day before the procedure and then 75 mg on the day of the procedure. On the day of the procedure, patients underwent aspirin and clopidogrel antiplatelet assays (VerifyNow; Accumetrics, Inc, San Diego, California, USA). Clopidogrel responders were those patients who had >20% platelet P2Y12 receptor inhibition and aspirin responders were those with aspirin reaction units of 350–550. Patients who were clopidogrel non-responders were administered 40 mg of prasugrel orally and maintained postoperatively at 5–10 mg once a day.
Interventional procedures were performed under general endotracheal anesthesia and all cases were monitored with somatosensory evoked potentials, EEG and brainstem auditory evoked responses specifically for posterior circulation aneurysms as well as posterior communicating artery aneurysms. All aneurysms were accessed via a micropuncture technique with catheterization of the common femoral artery. Once the ideal projections were determined based on biplane images (Siemens Artis, Berlin, Germany), endovascular occlusion was initiated. For wide necked aneurysms, stenting or balloon assistance techniques were utilized.
During the procedure, patients were heparinized to maintain an activated clotting time between 250 and 300 s. After completion of the procedure, the patient's femoral sheaths were removed utilizing an Angio-Seal device (St Jude Medical, St Paul, Minnesota, USA) once the post-procedure neurological evaluation was satisfactory. Patients were then transferred to the post-anesthesia care unit where heparin (500 units/h) and dextran-40 (20 ml/h) were started once the partial thromboplastin time (PTT) was <100. This anticoagulation protocol was continued for 12–18 h, after which it was discontinued and the patients were discharged to home on postoperative day 1.
Patients were continued on the antiplatelet agents for 3 months unless they had a stent placed, in which case the clopidogrel or prasugrel would be continued for 6 months and aspirin indefinitely. Patients were clinically followed at 4 weeks post-embolization and then at 6 months and 12 months. All patients underwent follow-up cerebral angiography at 6 months, and then followed accordingly to evaluate for recurrence or parent vessel stenosis.
Results
Sixteen patients underwent neurointerventional procedures and received prasugrel as the antiplatelet agent (table 1). Ages ranged from 24 years to 78 years with a mean age of 55.75 years. Fourteen patients were women (87.5%) and two were men (12.5%). Three patients (18.8%) were allergic to clopidogrel while the remainder were non-responders to clopidogrel based on the P2Y12 inhibition assay. Mean inhibition within the clopidogrel non-responders before the utilization of prasugrel was 2%.
Demographics of a 16 patient study group who received prasugrel antiplatelet therapy
Of the non-responders, 13 patients had an additional P2Y12 inhibition assay following administration of prasugrel. All of these patients had therapeutic inhibition of P2Y12 with the loading dose of prasugrel (40 mg). Ten of the 13 patients had at least 50% inhibition (77% with >50% inhibition; figure 1). Thirteen patients were treated for intracranial aneurysms (81.3%), one patient had an intracranial stenosis treated with stenting and two patients had extracranial carotid artery pathology treated with stent technology. Only one patient (7.7%), who was a clopidogrel non-responder, was concomitantly taking a PPI. This PPI was continued after the patient was switched from clopidogrel to prasugrel, and therapeutic P2Y12 inhibition was maintained. Only one patient (7.7%) was an aspirin non-responder and a clopidogrel non-responder.
Bar graph illustrating per cent P2Y12 inhibition achieved with clopidogrel and prasugrel in patients receiving both medications, for whom a P2Y12 assay was performed after administration of prasugrel.
Clinical follow-up ranged from 1 month to 1 year, with a mean follow-up of 4.4 months. The duration of prasugrel therapy ranged from 1 month to more than 6 months, with a mean of 3 months. None of the patients had intracranial bleeding complications. One patient had a retroperitoneal hematoma that was diagnosed 2 days following aneurysm treatment. This patient was noted to have a high femoral puncture site, based on femoral angiography, and the patient's femoral sheath was left in place after the procedure secondary to a high PTT. When the PTT dropped below 100, an Angio-Seal device was placed without any immediate complications. Afterward, the patient then complained of significant back pain and she was objectively found to have a decrease in hematocrit. CT of the abdomen revealed a large retroperitoneal hematoma, which was managed conservatively without the need for blood transfusion. This patient's retroperitoneal hematoma could have been explained by a multitude of reasons: high femoral puncture, multiple anticoagulants and possible failure of the Angio-Seal.
Discussion
Use of dual antiplatelet therapy combining clopidogrel and aspirin has become a common treatment during percutaneous coronary interventions (PCIs) and neurointerventional procedures requiring stenting or deposition of Onyx (ev3, Irvine, California, USA) within a cerebral aneurysm.7 ,9 Clopidogrel requires a two step activation process, thus leading to a heterogeneous response in platelet inhibition secondary to allelic variability in the cytochrome P450 system as well as non-therapeutic interactions with PPIs. Individuals with certain cytochrome P450 polymorphisms have been shown to have reduced platelet inhibition function with the use of clopidogrel. Specifically, this lack of response was found to be associated with the CYP2C19 genotype. Individuals with heterozygous loss of function of this gene were found to have a marked reduction in clopidogrel related platelet inhibition. Moreover, these individuals were found to have a higher rate of major adverse cardiac events, including myocardial infarctions and increased probability of in-stent thrombosis following PCI. The CYP3A5*3 genotype may also play a role in a lack of clopidogrel platelet inhibition; however, less so than the CYP2C19 genotype.
This unpredictable response to clopidogrel has made rapid point of care laboratory tests of drug efficacy necessary to identify clopidogrel non-responders.26 These assays have been studied extensively and validated against light transmission aggregometry, the gold standard laboratory test. Correlation coefficients in the study by Bouman et al 26 ranged from 0.7 to 0.8 for the VerifyNow assay in comparison with light transmission aggregometry. Since prasugrel and clopidogrel both inhibit P2Y12 receptors, the VerifyNow point of care assay has been validated to confirm platelet inhibition for both medications with correlation coefficients of 0.8–0.97.27 ,28 Such quantitative assays of platelet inhibition have also been positively correlated with clinical outcome. A decreased amount of P2Y12 inhibition on VerifyNow assays has been directly associated with increased morbidity and mortality in the periprocedural time period following PCI, thus confirming greater platelet inhibition qualitatively as well as quantitatively.29–31 Such positive correlations make the VerifyNow assay an effective validated test to determine a patient's antiplatelet response to administration of either prasugrel or clopidogrel.
Clopidogrel has also been associated with significant drug interactions with PPIs, leading to less platelet inhibition. Use of both clopidogrel and a PPI has been associated with worse overall morbidity and mortality following all cause ACS. Patients using these two medications have also been found to have higher rates of major adverse cardiac events following PCI. Omeprazole in particular has been found to cause significant decline in clopidogrel induced platelet inhibition, with other PPIs such as pantoprazole causing less inhibition.
Prasugrel is a new thienopyridine antiplatelet agent that irreversibly binds to platelet P2Y12 receptors, causing inhibition of platelet aggregation by blocking linkage of platelets via glycoproteins IIb/IIIa.10 Prasugrel has been advocated as an antiplatelet agent in vascular procedures, given the variable efficacy and the potential for common drug interactions that are seen with clopidogrel. Prasugrel has not been associated with decreased platelet inhibition or increased cardiovascular events in individuals with cytochrome P450 variants who were found to be clopidogrel non-responders.10 ,32 Also, there has been no evidence that concomitant use of prasugrel with PPIs causes any decrease in platelet inhibition.18 ,19
These findings have led to large trials in cardiovascular patients that have compared prasugrel with clopidogrel in both healthy individuals and patients with ACS. In those studies, prasugrel has been shown to result in a greater degree of platelet inhibition in a less variable manner, as well as to have a faster onset of platelet inhibition compared with clopidogrel. The degree of additional platelet inhibition from prasugrel over clopidogrel is especially marked in CYP2C19 heterozygotes (clopidogrel non-responders). Prasugrel was studied and found to be safe for PCI. This led to a large multicenter study that showed prasugrel was associated with markedly reduced rates of cardiovascular events following ACS but with more bleeding complications in select patient populations. This benefit of reduced rates of cardiac complications was confirmed following PCI and was found to be especially important in the diabetic patient population. These promising results were shown to have a more favorable cost–benefit analysis compared with clopidogrel, given there were fewer rehospitalizations when prasugrel was used versus clopidogrel.
Within our patient population, all patients who were placed on prasugrel had therapeutic antiplatelet assays on the first point of care testing (within 60–120 min of administration). Most patients had a greater degree of platelet inhibition than previously observed in clopidogrel responders. Furthermore, none of the patients treated with prasugrel had thrombotic or ischemic events. This was true for all patients who underwent coiling with or without the use of a stent. Prasugrel seems to provide immediate therapeutic antiplatelet activity and protection against thromboembolism.
Nevertheless, some authors warn against the use of prasugrel in patients with a history of stroke, given the potentially higher incidence of hemorrhage.33 ,34 None of our patients had preoperative cerebral ischemia, and none of our patients had any evidence of intracranial hemorrhage. All patients who had a P2Y12 inhibition study performed after taking prasugrel had a therapeutic response in our patient population. While our study is limited by the small number of patients analyzed, it suggests that prasugrel may be a safe effective alternative to clopidogrel in patients who are either allergic or are non-responders to clopidogrel.
Our study design is limited by the small sample size as well as the retrospective nature of data collection. While none of our patients had major adverse events using prasugrel, this does not definitively show that prasugrel is as effective, or more effective, than clopidogrel in the neurovascular patient population. Rather, a larger study powered to show a statistical significance of prasugrel over clopidogrel in the neurovascular patient population is required.
Conclusions
With such promising results from our small number of patients, it is conceivable to use prasugrel as an alternative to clopidogrel in patients undergoing elective neurointerventional procedures. If non-inferiority could be proven in a larger series, given the greater degree of P2Y12 receptor inhibition and consistent therapeutic effect, one could make the argument to universally use prasugrel over clopidogrel and not perform antiplatelet assays. A prospective randomized controlled trial of aspirin plus clopidogrel versus aspirin plus prasugrel would be required to determine the safety and efficacy of this antiplatelet agent in the neurovascular patient population, although this would be an expensive and lengthy process. In the interim, we should aim to build a large registry of patients undergoing neurointerventional procedures while being maintained on prasugrel to determine its safety and therapeutic profile in the future.
References
Footnotes
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Competing interests None.
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Ethics approval Ethics approval was provided by the University of Michigan Institutional Review Board.
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Provenance and peer review Not commissioned; externally peer reviewed.