Abstract
Aim: To evaluate the feasibility and impact of using CYP2C19 genotype to guide selection of antiplatelet therapy in patients undergoing intracranial aneurysm treatment with a flow diversion stent in a real-world clinical setting.
Patients & methods: A single-center, retrospective, observational cohort study was conducted in 112 patients undergoing intracranial aneurysm repair with flow-diversion stenting from 2014 to 2021. Data were abstracted from health records. The frequency of clopidogrel or alternative therapy (ticagrelor or prasugrel) use was compared across CYP2C19 status (intermediate or poor metabolizer [IM/PM] vs. normal, rapid, or ultrarapid metabolizer [NM/RM/UM]).
Results: In the study population, CYP2C19 genotype testing was performed on 110 (98.2%) patients; of these, 106 (97.2%) had results available prior to the stent procedure and 28 (25.5%) were IM/PMs. Alternative therapy was used more frequently in IM/PMs compared with NM/RM/UMs (57.1 vs. 8.5%, respectively, p < 0.0001). The frequency of thromboembolic events over 12 months did not significantly differ across clopidogrel-treated IM/PMs, clopidogrel-treated NM/RM/UMs and patients on alternative therapy (p = 0.352); although, event numbers were low.
Conclusion: A pre-emptive CYP2C19 genotyping strategy to guide antiplatelet therapy selection in intracranial aneurysm repair patients is feasible in a real-world clinical setting. Larger studies are needed to assess the impact on clinical outcomes.
Keywords: : antiplatelet therapy, clopidogrel, CYP2C19, flow-diversion stenting, intracranial aneurysm, neurointerventional procedures, pharmacogenomics, stenting
Tweetable Abstract
This study offers new insight into how CYP2C19 genotyping can be used to more precisely select antiplatelet therapy in neurovascular disease patients undergoing intracranial aneurysm repair with flow diversion stenting.
Plain language summary
Article highlights.
Clopidogrel, a prodrug metabolized by CYP2C19, is indicated to prevent thromboembolic complications after neurointerventional procedures.
While clinical implementation of CYP2C19 genotype-guided antiplatelet therapy selection improves clinical outcomes in patients undergoing percutaneous coronary intervention, the feasibility and utility of this precision medicine strategy in patients undergoing neurointerventional procedures such as intracranial aneurysm repair remains unclear.
This single-center retrospective study evaluated the feasibility of using CYP2C19 genotype to guide selection of antiplatelet therapy in 112 patients undergoing intracranial aneurysm treatment with a flow diversion stent in a real-world clinical setting.
At our institution, a high rate of pre-emptive CYP2C19 testing prior to flow diversion stenting was observed.
In accordance with Clinical Pharmacogenetics Implementation Consortium guideline recommendations, prescribers were significantly more likely to select alternative therapy (such as ticagrelor) compared with standard therapy (clopidogrel) in patients with a CYP2C19 no function allele.
The number of thromboembolic and clinically significant bleeding events over 12 months were low and did not significantly differ across CYP2C19-antiplatelet therapy groups.
Collectively, these results demonstrate the feasibility of using genotype results to guide antiplatelet therapy selection in patients undergoing intracranial aneurysm repair at an institution that previously implemented CYP2C19 testing in patients undergoing a percutaneous coronary intervention procedure.
These results can inform future multicenter investigations evaluating the effectiveness and safety of CYP2C19 genotype guided antiplatelet selection to prevent thromboembolic complications in the setting of neurointerventional procedures.
1. Introduction
Approximately 3% of the population, or 168,000,000 people worldwide, harbor a saccular unruptured intracranial aneurysm (UIA) [1,2]. These focal segments of brain arteries are dilated due to weakness in the arterial wall and are often discovered incidentally during neuroimaging. Although only 0.3% of UIAs rupture per year, resulting in subarachnoid hemorrhage (SAH), UIA rupture causes significant morbidity and mortality among middle-aged persons [1,2]. The poor prognosis of aneurysm rupture demonstrates the need for safe and efficacious repair procedures to prevent early loss of productive life years. Surgical clipping and endovascular interventional procedures are standard of care for preventative aneurysm repair and acute treatment after aneurysm rupture [3,4]. More recently, flow diversion stents like the Pipeline Embolization Device (PED) have been designed to improve aneurysm obliteration rates, especially in large complex aneurysms. Since gaining US FDA approval in 2011, the PED has become a first line treatment option for several aneurysm morphologies [5–7]. However, the large metallic surface area of flow diversion stents introduces an elevated risk of thromboembolism during the periprocedural period [8].
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor for 6–12 months is standard of care to prevent thromboembolic complications associated with flow diversion stents [8,9]. Clopidogrel, the most widely prescribed P2Y12 inhibitor in the setting of neurointerventional procedures [9], is a prodrug that requires hepatic bioactivation by the CYP2C19 enzyme to exert its antiplatelet effect. CYP2C19 no function alleles, which are common and vary in frequency across different ancestral groups, are important contributors to inter-individual variability in clopidogrel response [10,11]. Patients carrying either one CYP2C19 no function allele (CYP2C19 intermediate metabolizers, IMs) or two CYP2C19 no function alleles (CYP2C19 poor metabolizers, PMs) comprise approximately 30% of American and European, 35% of African and 60% of East Asian populations [10]. CYP2C19 IMs and PMs have reduced clopidogrel active metabolite formation, inhibition of platelet aggregation and clinical effectiveness compared with normal metabolizers (NMs) without a CYP2C19 no function allele [12].
Use of CYP2C19 genotyping to guide antiplatelet therapy selection has shown clinical benefit in patients undergoing percutaneous coronary intervention (PCI) and most recently in patients with ischemic stroke [11,13,14]. Accordingly, the Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines recommend use of alternative P2Y12 inhibitors, such as ticagrelor, in CYP2C19 IMs and PMs without contraindications [12]. Implementation of precision medicine strategies that utilize CYP2C19 genotyping to guide P2Y12 inhibitor selection in patients undergoing PCI, although not widely adopted, is becoming increasingly common in clinical practice [15]. The risk of thromboembolic events following intracranial aneurysm repair, combined with significant rates of clopidogrel non-responsiveness, suggests a potential clinical benefit of CYP2C19 genotype-guided antiplatelet therapy selection in the setting of neurointerventional procedures. However, the clinical utilization and impact of CYP2C19 genotyping to guide antiplatelet therapy selection in patients undergoing a neurointerventional procedure has not been well-studied.
The primary objective of this study was to evaluate the feasibility of using CYP2C19 genotype to guide selection of antiplatelet therapy in patients undergoing intracranial aneurysm treatment with a flow diversion stent in a real-world clinical setting. A secondary objective was to explore the association of CYP2C19 genotype and antiplatelet therapy selection on major thromboembolic and bleeding outcomes over 12 months following aneurysm treatment with a flow diversion stent. The present study provides novel insight into the clinical use of CYP2C19 genotype in patients undergoing a neurointerventional procedure and sets the foundation for future studies to assess the impact of this strategy on clinical outcomes.
2. Methods
2.1. Study population
Patients who underwent intracranial aneurysm repair with a flow diversion stent, were prescribed DAPT and received follow-up imaging at the University of North Carolina at Chapel Hill (UNC) Medical Center from April 2014 through January 2021 were included in this retrospective, observational cohort study. Flow diversion stents used at UNC Medical Center include the pipeline embolization device (PED) and Surpass Evolve-Flow Diverter (SE-FD). Out of 114 potentially eligible patients identified in the study period, 2 (1.8%) were excluded due to flow diversion use for treatment of a pseudoaneurysm. Therefore, the final study population was comprised of 112 patients, which represented all available patients at our institution during the 7-year study period that met the inclusion criteria. Although a subset of patients underwent more than one flow diversion procedure over time, the initial procedure during the study period was considered the index procedure utilized for data collection and analysis. This study was approved by the UNC Biomedical Institutional Review Board. Because data were collected via retrospective electronic health record (EHR) review, informed consent was not required.
2.2. CYP2C19 genotype testing & P2Y12 inhibitor prescribing
Genotyping for the CYP2C19*2, *3 and *17 variant alleles was performed as part of clinical care and returned as a clinical laboratory test by the UNC McLendon Molecular Genetics Laboratory, as previously described in the setting of PCI at our institution [16,17]. Similar to PCI, the decision to order a CYP2C19 genotype test in patients undergoing intracranial aneurysm repair with a flow diversion stent was made at the discretion of the treating physician. Briefly, genomic DNA was extracted from whole blood and genotyping for the CYP2C19*2, *3 and *17 alleles was performed using polymerase chain reaction based TaqMan® allelic discrimination assays (Life Technologies, CA, USA). Genotype results were reviewed by a pathologist and uploaded into the “Molecular Genetics” laboratory section of the EHR (typically within 24–48 h) for all patients tested. CYP2C19 genotype results were categorized into one of the following clopidogrel metabolizer phenotypes: ultrarapid (UM; *17/*17), rapid (RM; *1/*17), normal (NM; *1/*1), intermediate (IM; *1/*2, *1/*3, *2/*17, or *3/*17) or poor metabolizer (PM; *2/*2, *2/*3, or *3/*3) [12]. In addition to the genotype result, the laboratory report included a brief description of clopidogrel clinical pharmacology, the relevance of each tested allele on clopidogrel's active metabolite levels and antiplatelet effects, and an interpretation of the genotype result that aligned with 2013 CPIC guideline recommendations (e.g., this patient has one or two copies of the *2 or *3 allele, which is associated with decreased effectiveness of clopidogrel and an increased risk of adverse cardiovascular events; alternative therapy may be considered, if clinically indicated) [18]. During the study period (2014–21), no active or passive alerts were available in the EHR to inform clinicians that the genotype test result was available when a P2Y12 inhibitor was ordered, and there was not a standardized protocol for how or when to change P2Y12 inhibitor therapy in response to genotype results. The P2Y12 inhibitor prescribing decision was made at the discretion of the treating physician.
2.3. Data collection
Data was retrospectively collected via manual abstraction from the UNC Medical Center EHR (Epic) using a standardized and secure REDCap electronic data capture tool hosted at UNC [19]. Data collected included demographics, clinical characteristics, CYP2C19 genotype, CYP2C19 metabolizer phenotype, procedure details, medication use at hospital discharge and follow-up appointments and clinical outcomes at designated follow-up periods post-procedure. P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) and dose was recorded at several time points including at the initial (pre-procedure) consultation, upon admission and at discharge for the index procedure and at each follow-up outpatient or inpatient visit within 1 year (365 days) of the index procedure. Generally, outpatient follow-up and imaging occurred at 3 months and 6 months post-procedure, at which times the necessity of continuing DAPT was evaluated. Patients in this real-world study were followed until documented discontinuation of P2Y12 inhibitor therapy, a major thromboembolic or bleeding complication or 365 days, whichever came first. A switch in P2Y12 inhibitor therapy was recorded if the initial medication prescribed differed from the P2Y12 inhibitor documented at the last follow-up encounter.
Thromboembolic events and clinically significant bleeding events were identified via the EHR from provider-reported diagnoses. A thromboembolic event was defined as a physician-diagnosed ischemic stroke or transient ischemic attack (TIA) in the EHR during or after the flow diversion procedure. This included documented evidence of thrombosis during follow-up magnetic resonance imaging (3 months post-procedure) and angiography (6 months post-procedure). To identify thromboembolic and bleeding events outside of scheduled post-procedure follow-up imaging, all EHR hospitalizations and encounters over the 12-month follow-up period were evaluated for physician-diagnosed clinical events. Bleeding events were considered clinically significant if they were classified as moderate or severe/life-threatening per the Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding criteria [20]. GUSTO severe or life-threatening bleeding is defined as either intracranial hemorrhage or bleeding resulting in hemodynamic compromise necessitating intervention. GUSTO moderate bleeding is defined as bleeding requiring transfusion, but not resulting in hemodynamic compromise. All thromboembolic and bleeding events identified through EHR review were independently verified by a physician. For patients that experienced thromboembolic or clinically significant bleeding events, time to event occurrence from the index procedure (in days) was collected. P2Y12 inhibitor, aspirin and anticoagulant use were also evaluated at the time of event.
2.4. Data analysis
Data were presented as mean ± standard deviation, median (interquartile range), or count (%) unless otherwise indicated. Baseline characteristics were reported for the full cohort using descriptive statistics. Analyses were performed using SAS-JMP 17.0.0 (SAS Institute, NC, USA). P-values <0.05 were considered statistically significant.
To evaluate the feasibility of using CYP2C19 genotype to guide antiplatelet therapy selection in patients undergoing intracranial aneurysm repair with a flow diversion procedure (primary objective), the proportion of patients that received a CYP2C19 genotype test (tested vs. non-tested) and the antiplatelet therapy prescribed (clopidogrel 75 mg once daily vs. alternative therapy) were reported. Alternative therapy was defined as ticagrelor (90 mg twice daily), prasugrel (10 mg daily), or high-dose clopidogrel (75 mg twice or three-times daily), consistent with prior real-world studies evaluating implementation of genotype-guided antiplatelet therapy in the setting of PCI [21]. Due to low prevalence of prasugrel and high-dose clopidogrel use, these were combined with ticagrelor into a single alternative therapy group for analysis. While P2Y12 inhibitor use was collected at multiple time points, the primary medication end point utilized for analysis was the P2Y12 inhibitor documented at the last follow-up encounter after any changes in therapy. In patients who underwent genotyping, the proportion of patients prescribed clopidogrel versus alternative therapy was first compared across the five CYP2C19 metabolizer phenotype groups (PM, IM, NM, RM, UM). Then, CYP2C19 metabolizer phenotypes were dichotomized into either IM/PMs or NM/RM/UMs (based on CPIC guideline recommendations [12]) and the frequency of each antiplatelet therapy strategy (clopidogrel vs. alternative therapy) was compared across the two CYP2C19 groups. Proportions were compared across groups using a χ2 test or Fisher's exact test, as appropriate. To determine whether clinical or patient-specific factors were associated with P2Y12 inhibitor prescribing, demographic and clinical factors were also compared across antiplatelet therapy groups.
To explore the association between CYP2C19 metabolizer phenotype and antiplatelet therapy selection on major thromboembolic and bleeding outcomes (secondary objective), the frequency of incident thromboembolic (ischemic stroke or TIA) and clinically significant bleeding (GUSTO moderate or severe/life-threatening) events over 12 months of follow-up was compared across the following P2Y12 inhibitor therapy by CYP2C19 status groups: clopidogrel IM/PM, clopidogrel NM/RM/UM and alternative therapy regardless of CYP2C19 phenotype. Because CYP2C19 no function alleles do not impact the clinical effectiveness of prasugrel or ticagrelor [12] and the limited number of NM/RM/UMs prescribed alternative therapy, all patients on alternative therapy were combined into a single reference group. The proportion of patients experiencing a clinical event were compared across the three antiplatelet therapy-CYP2C19 status groups using a χ2 test or Fisher's exact test, as appropriate. Given the small sample size and low number of clinical events, the results of this secondary objective were considered exploratory.
3. Results
3.1. Study population characteristics
A total of 112 patients were included in the analysis. The baseline study population characteristics are summarized in Table 1. Overall, the mean age was 54.5 years, 81.0% were female, 25.0% identified as Black or African American and 7.1% identified as Hispanic or Latino. At initial consultation, 12 (10.8%) patients were already receiving chronic maintenance therapy with clopidogrel 75 mg daily. The prevalence of patients with history of a prior hemorrhagic stroke and prior ischemic stroke was 38.4% and 11.6%, respectively. Patients with history of myocardial infarction (6.3%), prior coronary revascularization (3.6%) and peripheral arterial disease (0%) were less common. Hypertension (59.8%), dyslipidemia (25.0%) and diabetes mellitus (12.5%) were the most prevalent comorbidities. The most commonly prescribed medications at discharge were aspirin (99.1%), statins (33.9%), proton pump inhibitors (26.8%), beta-blockers (22.3%), angiotensin converting enzyme (ACE) inhibitors (19.6%) and angiotensin receptor blockers (ARBs) (19.6%).
Table 1.
Study population characteristics at baseline.
| Patient characteristic | N = 112 | |
|---|---|---|
| Age, y (SD) | 54.5 (14.3) | |
| Female sex, n (%) | 91 (81.0) | |
| Race/ethnicity, n (%) | White | 67 (59.8) |
| Black or African American | 28 (25.0) | |
| Asian | 2 (1.8) | |
| Hispanic or Latino | 8 (7.1) | |
| American Indian or Alaska Native | 6 (5.4) | |
| Unknown | 1 (0.9) | |
| Family history of IA, n (%) | 10 (9.0) | |
| BMI, kg/m2 (IQR) | 28.0 (23.8–34.0) | |
| Current smoking, n (%) | 29 (25.9) | |
| Hypertension, n (%) | 67 (59.8) | |
| Diabetes mellitus, n (%) | 14 (12.5) | |
| Dyslipidemia, n (%) | 28 (25.0) | |
| Chronic renal failure, n (%) | 0 (0) | |
| Atrial fibrillation, n (%) | 5 (4.5) | |
| History of IA repair, n (%) | Flow diversion | 2 (1.8) |
| Coiling w/ or w/o stent | 42 (37.5) | |
| Surgical clipping | 9 (8.0) | |
| History of coronary revascularization, n (%) | 4 (3.6) | |
| History of MI, n (%) | 7 (6.3) | |
| History of ischemic stroke/TIA, n (%) | 13 (11.6) | |
| History of hemorrhagic stroke, n (%) | 43 (38.4) | |
| Chronic P2Y12 inhibitor (clopidogrel), n (%) | 12 (10.8) | |
| Chronic ASA, n (%) | 32 (28.8) | |
| Treated aneurysm characteristic | ||
|---|---|---|
| Location, n (%) | Anterior circulation | 91 (81.3) |
| Posterior circulation | 21 (18.8) | |
| Shape, n (%) | Saccular | 87 (77.7) |
| Fusiform | 7 (6.3) | |
| Blister | 3 (2.7) | |
| Dissection | 14 (12.5) | |
| Other | 3 (2.7) | |
| Maximal diameter, mm (IQR)a | 6.5 (4–10) | |
| Previously coiled aneurysm, n (%) | 33 (29.5) | |
| Presentation with subarachnoid hemorrhage, n (%) | 8 (7.1) | |
| Multiple aneurysms treated, n (%) | 11 (9.8) | |
Data are presented as mean ± SD, median (IQR) or count (%).
Aneurysm size was documented in the EHR in 100 of the 112 patients.
ASA: Aspirin; IA: Intracranial aneurysm; MI: Myocardial infarction; TIA: Transient ischemic attack.
Nearly all patients underwent flow diversion stenting with a PED (107, 95.6%); though two patients were treated with a PED plus coils and three patients were treated with a SE-FD. Eight (7.1%) patients presented with acute SAH as their clinical indication for flow diversion stenting and 11 (9.8%) patients had multiple aneurysms treated during the index procedure. Most treated aneurysms had a saccular morphology (77%), though fusiform (6.3%), blister (2.7%) and dissecting (12.5%) aneurysms were also treated. Among patients with documented aneurysm size, 22% had large (maximal diameter >10 mm) aneurysms and 4% had giant (maximal diameter >25 mm) aneurysms. Anterior circulation aneurysms were common (81.3%), with a total of 52.7% treated aneurysms classified as ophthalmic aneurysms.
3.2. CYP2C19 genotype
CYP2C19 genotype testing was performed on 110 (98.2%) patients; genotype test results were available in the EHR a median of one (IQR 1–2) day following test ordering. Of the 110 genotyped patients, 106 (97.2%) had genotype results prior to the index procedure and 85 (77.3%) had genotype results available prior to P2Y12 inhibitor initiation for the index procedure (Table 2). Genotype results were available a median of 26 (IQR 10–48) days prior to the index procedure. CYP2C19 genotype results are summarized in Figure 1A. Each metabolizer phenotype was represented in the following proportions: PM (6, 5.5%), IM (22, 20.0%), NM (53, 48.2%), RM (26, 23.6%), UM (3, 2.7%). After consolidating into a dichotomous variable, 28 (25.5%) were IM/PMs and 82 (74.5%) were NM/RM/UMs.
Table 2.
CYP2C19 Genotyping and P2Y12 Inhibitor Selection.
| Parameter | ||
|---|---|---|
| CYP2C19 genotype in EHR, n | 110a | |
| Genotype available prior to index procedure, n (%) | 106 (97.2) | |
| Genotype available prior to P2Y12i initiation, n (%) | 85 (77.3) | |
| Time on P2Y12i before procedure, d (IQR) | 7 (6–9.5) | |
| P2Y12i switching, n (%) | 3 (2.7)b | |
| P2Y12i, n (%)a | Clopidogrel 75 mg daily | 87 (79.1) |
| Clopidogrel 75 mg BID | 1 (0.9) | |
| Ticagrelor 90 mg BID | 20 (18.1) | |
| Prasugrel 10 mg daily | 2 (1.8) | |
Data presented as count (%).
Overall, 110 of 112 (98.2%) patients in the study population had a genotype available in EHR.
One patient received cangrelor during the flow diversion procedure and then was switched to ticagrelor prior to discharge. One patient was on prasugrel prior to the index procedure and then was switched to ticagrelor prior to discharge. One patient was on clopidogrel prior to the index procedure and then was switched to ticagrelor 4 days after the procedure; EHR documentation indicated that the switch occurred because the patient was a RM.
BID: Twice daily; P2Y12i: P2Y12 inhibitor.
Figure 1.
CYP2C19 metabolizer phenotype and P2Y12 inhibitor selection. (A) The distribution of CYP2C19 phenotype status of the 110 patients that underwent genotyping is presented: PM (n = 6; 5%), IM (n = 22; 20%), NM (n = 53; 48%), RM (n = 26; 24%), UM (n = 3; 3%). Genotype combinations for each metabolizer phenotype include PM (homozygous *2 or *3), IM (heterozygous *2 or *3), NM (*1/*1), RM (*1/*17), or UM (*17/*17). (B) The distribution of selected P2Y12 inhibitor therapy (clopidogrel 75 mg daily or alternative therapy) by CYP2C19 phenotype status. Alternative therapy includes prasugrel, ticagrelor, or high dose clopidogrel.
IM: Intermediate metabolizer; NM: Normal metabolizer; PM: Poor metabolizer; RM: Rapid metabolizer; UM: Ultrarapid metabolizer.
3.3. Antiplatelet therapy selection
All 112 patients received a P2Y12 inhibitor prior to flow diversion, with a median duration of therapy seven (IQR 6–9.5) days before the index procedure. The exact date of P2Y12 inhibitor initiation was unavailable in four patients. Out of the 110 patients that were genotyped, clopidogrel 75 mg daily was used in 87 (79.1%) patients compared with alternative therapy in 23 (20.9%). In patients prescribed alternative therapy, 20 were prescribed ticagrelor 90 mg twice daily, two were prescribed prasugrel 10 mg daily and one was prescribed clopidogrel 75 mg twice daily (Table 2). There were very low rates of P2Y12 inhibitor switching (2.7%) between the agent initially prescribed and the agent recorded at last follow-up. The circumstances surrounding the three patients with a switch in P2Y12 inhibitor therapy are described in Table 2.
Antiplatelet therapy selection significantly differed across CYP2C19 metabolizer phenotype groups (Supplementary Table S1). Overall, alternative therapy was prescribed more frequently in IM/PMs compared with non-IM/PMs (57.1 vs. 8.5%, respectively, p < 0.0001). In PMs, only one out of six patients received clopidogrel (16.7%), while the remaining five were treated with alternative therapy (83.3%). In IMs, 50% (11 out of 22) of patients received alternative therapy. NMs were rarely treated with alternative therapy (1, 1.9%), while RMs and UMs appeared to exhibit higher rates of alternative therapy (Supplementary Table S1 & Figure 1B). Within the non-IM/PMs, RM/UMs (6, 20.7%) were prescribed alternative therapy more frequently than NMs (1, 1.9%) (p = 0.007).
With the exception of CYP2C19 status, no demographic or clinical factors significantly differed between patients prescribed clopidogrel versus alternative therapy (Supplementary Table S2). Several patient characteristics including obesity (body mass index >30 kg/m2), hypertension, history of ischemic stroke or TIA, statin use at discharge and aneurysm maximal diameter >10 mm were numerically higher, but not significantly different, in patients prescribed clopidogrel.
3.4. Thromboembolic & bleeding complications
The median follow-up time to a clinical event or last documented visit on a P2Y12 inhibitor within 12 months was 175 (IQR 86–359) days. A summary of the treatment outcomes during follow-up in the overall study population is provided in Supplementary Table S3. During the follow-up period, a total of 22 (19.6%) patients experienced a thromboembolic or clinically significant bleeding event. The median time to event was 4.5 (IQR 0–39) days from the index procedure. Overall, 13 (11.6%) patients experienced a thromboembolic event (8 ischemic stroke, 5 TIA) and 11 (9.8%) patients experienced a clinically significant bleeding event. Of the 13 thromboembolic events, six occurred on the day of the procedure and seven occurred a median of 15 (IQR 3–22) days after the procedure. Of the 11 hemorrhagic events, two occurred on the day of the procedure and nine occurred a median of 37 (IQR 6–51) days after the procedure.
The proportion of patients experiencing thromboembolic or clinically significant bleeding events during the follow-up period did not differ significantly across the P2Y12 inhibitor by CYP2C19 status groups (clopidogrel IM/PM, clopidogrel NM/RM/UM and alternative therapy) (Table 3). Numerically, the highest rate of thromboembolic complications occurred in clopidogrel-treated IM/PMs (3 out of 12, 25%) compared with clopidogrel-treated NM/RM/UMs (7 out of 75, 9.3%) and patients treated with alternative therapy regardless of CYP2C19 status (3 out of 23, 13.0%); however, the number of events were low and this difference was not statistically significant (p = 0.352). The rates of bleeding events did not differ across the three groups (8.3 vs. 10.7 vs. 8.7%, respectively; p = 0.942), though the number of events in each group also were low.
Table 3.
Rates of complications across P2Y12 inhibitor strategy.
| Clopidogrel IM/PM | Clopidogrel NM/RM/UM | Alternative therapy | p-value | |
|---|---|---|---|---|
| Thromboembolic event | 3 (25.0) | 7 (9.3) | 3 (13.0) | 0.352 |
| Bleeding event | 1 (8.3) | 8 (10.7) | 2 (8.7) | 0.942 |
| Any event | 3 (25.0) | 14 (18.7) | 5 (21.7) | 0.859 |
Data presented as count (%). Alternative therapy includes ticagrelor, prasugrel, or high dose clopidogrel (75 mg twice daily). Thromboembolic events include ischemic stroke or TIA. Clinically significant bleeding events include moderate or severe bleeding per GUSTO criteria. One patient in the clopidogrel IM/PM group and one patient in the clopidogrel NM/RM/UM group experienced a simultaneous thromboembolic and bleeding event, explaining the discrepancy in event totals.
IM: Intermediate metabolizer; PM: Poor metabolizer.
4. Discussion
Although thromboembolic complications are a major source of morbidity and mortality following percutaneous neurointerventional procedures, CYP2C19 genotype-guided antiplatelet therapy has not been well-studied in patients undergoing a neurointerventional procedure. The current investigation demonstrates the feasibility of ordering and using clinical CYP2C19 genotype results to guide selection of P2Y12 inhibitor therapy in patients undergoing intracranial aneurysm repair with a flow diversion stent at an institution that previously implemented genotype-guided antiplatelet therapy in patients undergoing a PCI procedure. We observed a high rate of pre-emptive genotype testing, which was demonstrated by the high proportion of patients with CYP2C19 results available in the EHR prior to the flow diversion procedure. Additionally, alternative therapy such as ticagrelor was prescribed more frequently than clopidogrel in IM/PMs, compared with NM/RM/UMs, indicating that providers utilized the genotype results to guide treatment decisions. These findings in a real-world clinical setting will inform larger multicenter studies that evaluate the impact of CYP2C19 genotype-guided antiplatelet therapy selection on clinical outcomes in neurointerventional procedure patients.
Due to the first-line use of clopidogrel as the preferred P2Y12 inhibitor, the feasibility of using CYP2C19 genotyping to inform prescribing in the setting of neurointerventional procedures is dependent on the availability of results prior to or very soon after initiation of antiplatelet therapy. Because UIAs were the primary indication for flow diversion stenting in this patient population, providers at our institution were able to implement a pre-emptive genotyping strategy via neurointerventional radiologists routinely ordering the genotype test during the pre-procedure outpatient clinical workup. This stands in contrast to CYP2C19 genotyping for other indications like PCI or ischemic stroke, where genotype is reactively obtained at the time of procedure and will require frequent P2Y12 inhibitor switching following return of results unless the institution has a point-of-care rapid turnaround test available [15,22]. This is a clinically important distinction because the need to frequently switch agents in reaction to genotype results could serve as a barrier to consistent and sustainable implementation of this precision medicine strategy in clinical practice [23]. In the current investigation, virtually all patients had genotype results available in the EHR prior to their procedure, approximately 75% had results available prior to documented P2Y12 inhibitor initiation and <5% of patients underwent a P2Y12 inhibitor switch. This finding suggests that, in some cases, NM status was assumed and providers initiated clopidogrel 75 mg daily in the absence of genotype information. This was also necessary for patients presenting emergently with SAH or high-risk aneurysm morphology who typically underwent genotyping post-procedure.
The 2022 CPIC guideline update for CYP2C19 genotype and clopidogrel therapy includes a moderate strength recommendation to avoid clopidogrel in PMs and to consider alternative treatment (e.g., ticagrelor) in IMs and PMs receiving DAPT for neurovascular indications [12]. In alignment with this recommendation, alternative therapy was used more frequently than clopidogrel in IM/PMs compared with NM/RM/UMs in the study population. Until recently, there was limited prospective evidence for the use of alternative P2Y12 inhibitors in CYP2C19 IM/PMs outside the setting of acute coronary syndrome and PCI. The current CPIC recommendation for neurovascular indications is mainly informed by a large randomized controlled trial demonstrating decreased risk of recurrent stroke in CYP2C19 IMs and PMs randomly assigned to ticagrelor versus clopidogrel after minor ischemic stroke or TIA [14]. Although the US FDA issued a boxed warning regarding clopidogrel's diminished antiplatelet effects in CYP2C19 PMs in 2010, the 2013 CPIC guidelines focused on acute coronary syndrome and PCI indications for clopidogrel given insufficient evidence in other indications [18]. Therefore, it is notable that clinicians at our institution were implementing this precision medicine strategy in intracranial aneurysm repair patients between 2014 and 2021. Of note, we observed that approximately 50% of IMs were prescribed alternative therapy, which is consistent with the proportion of IMs prescribed alternative therapy (48%) at early adopter institutions of CYP2C19 testing for PCI [15]. Among patients without a CYP2C19 no function allele in our study population, we also observed that RMs and UMs were prescribed alternative therapy more frequently than NMs; this was presumably due to clinician concerns about higher bleeding risk with clopidogrel in RMs and UMs. This finding was not anticipated and further demonstrates that genotype results were being used by providers when selecting P2Y12 inhibitor therapy. While a growing body of evidence now suggests that RM/UM status does not increase bleeding risk with clopidogrel in ACS/PCI patients, this evidence emerged after the study period [24]. In addition, current CPIC guidelines have “no recommendation” for UMs and RMs in the setting of neurovascular indications due to lack of outcomes evidence [12]. Future studies evaluating the clinical impact of the increased function *17 allele on bleeding outcomes following a neurointerventional procedure are needed.
Our findings add to an emerging body of evidence supporting the use of precision medicine strategies to guide antiplatelet therapy selection in neurointerventional procedures. Platelet function testing (PFT), a dynamic measure of on-treatment platelet reactivity, is being used clinically to identify clopidogrel non-responders and guide antiplatelet medication optimization in the setting of neurointerventional procedures [25]. In a retrospective cohort of 402 patients undergoing flow diversion stenting, the rate of thromboembolic complications was significantly lower in clopidogrel non-responders switched to ticagrelor compared with those who continued clopidogrel (2.7% vs. 24.4%, respectively; p = 0.004) [26]. An analysis of institutions that utilize PFT before neurointerventional procedures report widely variable strategies for managing clopidogrel non-responders, which often result in procedures being delayed or rescheduled while DAPT regimens are adjusted [27]. Although PFT captures the influence of multiple factors on platelet reactivity, CYP2C19 genotype testing only needs to be completed once, does not require the patient to be stabilized on P2Y12 inhibitor therapy and thus allows for pre-emptive testing prior to initiation of antiplatelet therapy. However, in intracranial aneurysm repair and more specifically flow diversion stenting, there remains limited outcomes evidence evaluating the impact of CYP2C19 genotyping to guide P2Y12 inhibitor prescribing to prevent thromboembolic complications. In a retrospective study of 215 Chinese patients undergoing intracranial aneurysm repair with stent-assisted coiling, clopidogrel-treated IM/PMs exhibited significantly higher risk of periprocedural ischemic events compared with NMs [28]. Similar results were reported in two cohorts of Chinese patients undergoing carotid artery stenting and treatment with clopidogrel [29,30]. In contrast, CYP2C19 no function alleles were not associated with higher risk of ischemic events in either a cohort of 379 Chinese patients undergoing intracranial aneurysm repair with intracranial stents or a cohort of 123 Spanish patients undergoing various percutaneous neurointerventional procedures [31,32].
Though exploratory in nature, we report for the first time thromboembolic complications in a USA population of patients undergoing a neurointerventional procedure and clinical CYP2C19 genotype testing. Although the rate of thromboembolic events did not differ significantly between P2Y12 inhibitor strategies (clopidogrel IM/PM, clopidogrel NM/RM/UM and alternative therapy), there was a trend toward a higher event rate in IM/PMs treated with clopidogrel following flow diversion stenting. With a notable proportion of patients having a history of hemorrhagic stroke (most often due to aneurysm rupture) and multiple patients presenting with acute SAH, it is important to highlight that clinically significant bleeding rates were not different between groups. Although these findings support the feasibility and potential utility of genotype-guided antiplatelet therapy in patients undergoing intracranial aneurysm repair with flow diversion stenting, larger clinical outcome studies are needed.
It is important to acknowledge several limitations in this study. As a retrospective cohort study without a standardized protocol for treatment decisions based on genotype results, we cannot attribute causality to the observed associations between CYP2C19 phenotype results reported in the EHR and prescribing decisions. Because of incomplete documentation in the EHR on whether genotype results were used, it is difficult to interpret provider rationale for therapeutic decisions. However, the retrospective nature of this analysis does provide insight into prescribing practices in a real-world clinical setting. Second, the data presented illustrate CYP2C19 genotype-guided antiplatelet therapy selection at a single academic institution and a small number of prescribers with access to in-house CYP2C19 genotype testing, which limit the generalizability of these results to other institutions, prescribers and neurointerventional procedure clinical settings. Future qualitative studies evaluating clinician perspectives on CYP2C19 testing for neurovascular indications across diverse clinical settings are needed. Third, while symptomatic thromboembolic and bleeding complications were well documented in the EHR, silent ischemic events and minor bleeding were not captured. Also, some patients underwent a second flow diversion procedure within the study period, which may have influenced P2Y12 inhibitor prescribing or increased the risk of complications. Finally, due to the relative low frequency of intracranial aneurysm repair procedures, our study was limited in sample size and not based on an a priori sample size calculation designed to evaluate clinical outcomes. Therefore, comparison of clinical outcome rates across groups was exploratory and should be interpreted with caution. Studies in larger populations are needed to draw conclusions on the effectiveness and safety of genotype-guided antiplatelet therapy in patients undergoing intracranial aneurysm treatment.
5. Conclusion
In summary, this analysis indicates that clinical implementation of a CYP2C19 genotype-guided antiplatelet therapy selection algorithm is feasible in patients undergoing intracranial aneurysm repair and sets the foundation for future multicenter studies to evaluate the impact of genotype-guided antiplatelet therapy selection on clinical outcomes in neurointerventional procedures.
Supplementary Material
Funding Statement
The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Award Number UM1TR004406.
Supplemental material
Supplemental data for this article can be accessed at https://doi.org/10.1080/14622416.2024.2406213
Author contributions
LP Fox, GA Stouffer, S Solander and CR Lee designed the study. LP Fox, A Nguyen, S Reed, D Shastri and N Quig conducted data collection, LP Fox, KR Tunehag and CR Lee completed the data analysis. LP Fox and CR Lee wrote the manuscript. S Solander and CR Lee supervised the project. All authors contributed to critically reviewing the article and approved the submitted version.
Financial disclosure
The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Award Number UM1TR004406. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
No funded writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The study was approved by the UNC Institutional Review Board (study 22-0582). Due to the retrospective nature of the study, the requirement for informed consent was waived.
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