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Abstract
Background Omeprazole is a common proton pump inhibitor that interferes with the hepatic activation of clopidogrel and potentially reduces its platelet-inhibitory effect. Omeprazole has been shown to increase P2Y12 levels and adverse cardiovascular outcomes in patients treated with drug-eluting stents. However, omeprazole use among patients treated with flow-diverting stents for intracranial aneurysms has not been evaluated.
Methods All patients with placement of a flow-diverting device for treatment of an intracranial aneurysm at a tertiary institution from January 1, 2014, to December 31, 2018, were retrospectively analyzed. Inclusion criteria included documented clopidogrel administration, available P2Y12 levels, and thorough documentation of administration of other medications, including omeprazole.
Results A total of 138 patients met the inclusion criteria. Sixteen patients (12%) were receiving omeprazole and clopidogrel at treatment. P2Y12 reactivity was significantly greater in the omeprazole cohort (mean P2Y12 level, 250 P2Y12 reaction units (PRU)) than in the control cohort (mean P2Y12 level, 112PRU) (P<0.001). Furthermore, a greater proportion of patients had a P2Y12 level >180 PRU in the omeprazole cohort (14 of 16 [88%] vs 24 of 122 [20%]; P<0.001; OR [95% CI], 29 [6–134]).
Conclusion Omeprazole was associated with a significant increase in the mean P2Y12 reactivity level among patients with intracranial aneurysms treated with flow-diverting devices who received clopidogrel. However, receipt of omeprazole was not associated with an increased risk of ischemic events or stent stenosis. For neuroendovascular patients who are treated with a flow diverter while receiving clopidogrel, alternative gastrointestinal medication regimens should be considered.
- aneurysm
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Introduction
Flow-diverting devices (FDDs) are a common approach to the treatment of intracranial aneurysms. FDDs allow for the treatment of previously untreatable complex aneurysms (eg, fusiform, giant, and wide-neck aneurysms) that are not amenable to conventional coiling or clipping.1–3
Recent meta-analyses have reported that thromboembolic complications are the most commonly cited complication associated with this procedure.3 4 Both ischemic and hemorrhagic complications play a significant role in the morbidity and mortality associated with this procedure, accounting for 4.1% and 2.9% of complications, respectively.4 Patients routinely receive a regimen of dual anti-platelet therapy (DAPT) for 6 to 12 months after this procedure. Although platelet function testing is commonly used to help guide selection of antiplatelet medication, its use has not been shown to result in a statistically significant decrease in thromboembolic complications. There is a complex, incompletely understood relationship between antiplatelet therapy and thromboembolic events after FDD placement.5 6 Therefore, it is imperative to assess factors that might affect the extent of platelet inhibition.
Proton pump inhibitors are prescribed for the empirical treatment of gastroesophageal reflux disease.7 Dual antiplatelet medications can increase the risk of gastrointestinal bleeding in this population.8 9 Proton pump inhibitors inhibit hepatic cytochrome P450 enzymes and this effect may contribute to attenuation of platelet inhibition by clopidogrel.10–12 Omeprazole is a more potent cytochrome P450 inhibitor than other proton pump inhibitors and has been documented to cause the most attenuation of clopidogrel.11 Clopidogrel plus omeprazole has been studied in patients with acute coronary syndrome following percutaneous catheter intervention. This drug regimen has been reported to cause an increase in P2Y12 reactivity levels,13 which may lead to adverse cardiovascular outcomes in patients treated with drug-eluting stents after cardiac catheterization.10–12 The neuroendovascular literature on this association is limited, particularly with respect to FDDs, for which platelet inhibition is very important.
Therefore, this study assesses whether omeprazole administered in combination with clopidogrel significantly affects platelet function (P2Y12 levels) in patients with an intracranial aneurysm. It also assesses the clinical risk and complications associated with this medication interaction in patients who undergo FDD placement.
Methods
All patients who had an aneurysm treated by placement of an FDD at a single large tertiary facility from January 1, 2014, to December 31, 2018, were retrospectively analyzed. The institutional review board of St. Joseph’s Hospital and Medical Center (Phoenix, AZ) approved the study protocol and waived the need for patient consent because of the retrospective nature of the study. All patients were prescribed clopidogrel (75 mg daily) and aspirin (81 mg or 325 mg daily) for 6 months after the operation and had their P2Y12 levels monitored before the index procedure (often measured within 3 days of the procedure) and, typically, at 6- month follow-up. Some patients had P2Y12 levels determined between the index procedure and 6-month follow-up if bleeding concerns arose. Patients without clopidogrel were excluded from the analysis. Patients were divided into two groups on the basis of concurrent omeprazole use during the 6-month follow-up period. All patients in the omeprazole group had omeprazole daily during the 6-month period, and 11 of the 16 patients in the omeprazole group were receiving omeprazole prior to the procedure. The P2Y12 levels of the five patients without omeprazole use prior to the procedure were excluded in the main analysis, and only the P2Y12 levels determined while patients were receiving omeprazole were analyzed. However, in a separate analysis, the mean P2Y12 levels of these five patients were analyzed to compare the values when receiving vs not receiving omeprazole. There were patients with very short courses of omeprazole for stress ulcer prevention following the procedure. However, none of these patients had P2Y12 levels in the immediate postprocedure period, and by the 6-month follow-up P2Y12 level, they had not received omeprazole for almost 6 months. Patients were placed on a regimen of omeprazole by their primary care physicians without the knowledge of the neuroendovascular department. Clinical measures, including average P2Y12 levels during therapy, and complications and outcomes, such as the incidence of ischemic stroke, intracranial bleed, vessel dissection, device stenosis, and device failure, were compared between the two groups.
Statistical analysis was performed with SPSS Statistical Windows, version 26 (IBM Corp., Armonk, New York). Patient characteristics and demographics were reported as mean values with SD and percentages. The Fisher exact test was used to compare categorical characteristics and outcomes for the various treatment groups, and the independent samples t-test was used to compare continuous variables. A P-value<0.05 was defined as significant.
Results
Out of 216 patients treated with an FDD, 138 patients met the study inclusion criteria. Of these patients, 16 (12%) also received omeprazole at some point during the 6-month postoperative period. The mean (±SD) age of patients who received omeprazole (69±10 years) was significantly higher than the age of those who did not receive omeprazole (57±14 years; P=0.001). Patients in both groups were similar for sex, rupture status, tobacco use, history of hypertension, cardiovascular disease, aneurysm type, aneurysm location, aneurysm diameter, and last follow-up time (P≥0.41). These demographics are reported in table 1.
Demographic and clinical characteristics of 138 patients with flow-diverting devices for treatment of intracranial aneurysms who received clopidogrel with vs without concomitant omeprazole
The mean P2Y12 level for patients receiving omeprazole plus clopidogrel was 250.1 P2Y12 reaction units, which was significantly higher than the mean P2Y12 level among patients without exposure to omeprazole (112.3 P2Y12 reaction units; P<0.001) (table 1). In addition, a greater proportion of patients in the omeprazole group had a P2Y12 level greater than 180 P2Y12 reaction units, which is a potential threshold for clopidogrel resistance (14 of 16 patients [88%] vs 24 of 122 patients [20%]; P<0.001). The rates of ischemic stroke (P>0.99), intracranial bleed (P>0.99), vessel dissection (P=0.40), device stenosis (P=0.80), and occurrence of an O’Kelly–Marotta grade of D (P=0.08) were similar between the two groups, as shown in table 2.
Risk factors, complications, and outcomes among 138 patients treated with flow-diverting devices for intracranial aneurysms who received clopidogrel with vs without concomitant omeprazole
Five of the 16 patients (31%) in the omeprazole cohort who were not receiving omeprazole prior to the procedure had a significant difference in mean P2Y12 levels when receiving omeprazole (243±59 PRU) vs not receiving the medication (106±30 PRU) (P=0.002).
Discussion
In the present study we found that patients with FDDs who received omeprazole had a higher mean P2Y12 level than those who did not receive omeprazole. Furthermore, in patients without omeprazole use prior to the procedure, the mean P2Y12 level was higher with concurrent omeprazole administration on follow-up. This finding provides evidence that omeprazole use reduces the effect of clopidogrel in neuroendovascular patients, a finding similar to earlier reports involving cardiovascular patients.10–12 However, higher P2Y12 levels were not associated with an increase in cerebrovascular events, such as stroke or intracranial hemorrhage, among these patients.
The findings in this study are consistent with, and extend those from, earlier reports in the cardiovascular literature. Several earlier studies have shown an increase in P2Y12 levels. However, there is mixed evidence as to whether this increase is associated with clinically relevant cardiovascular outcomes.11 Early retrospective observational studies suggested an association between DAPT and the concomitant use of omeprazole with higher rates of cardiovascular events after acute coronary syndrome.14–16 These observational studies are limited by inherent bias, and all of these studies had small sample sizes; thus, it is difficult to infer whether this pharmacodynamic effect has clinical relevance.17
Several randomized clinical trials, including the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) in 2009, the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial in 2013, and the Clopidogrel for Reduction of Events During Observation (CREDO) trial in 2013 have assessed the cardiovascular complications related to the use of DAPT with or without omeprazole.18 19 All three trials reported no significantly increased rate of cardiovascular events, which is reaffirmed by a meta-analysis of nearly 157 000 patients.20 These data agree with our finding that, although P2Y12 levels were significantly elevated among patients who received omeprazole, there were no clinically relevant neurovascular complications. Our finding suggests that, although omeprazole hinders clopidogrel’s antiplatelet activity, the effect may not be large enough to promote thromboembolic complications after FDD placement. In addition, although this study did not find any increased risk of intracranial bleed, ischemic stroke, or vessel stenosis in the omeprazole cohort, the sample size was small (n=16). Therefore, this study may have lacked the power to demonstrate clinically significant adverse events. In the future, large randomized control trials further assessing the safety and efficacy of omeprazole administered concomitantly with DAPT after FDD placement are necessary. The current study is the first, to our knowledge, to evaluate this effect in neuroendovascular patients.
One risk associated with the placement of any intravascular stent is the development of stent stenosis, which is thought to be a result of the wound healing cascade that occurs within the blood vessel lumen as a result of vascular injury associated with stent placement.21 Mühl-Benninghaus et al report a 30% rate of device lumen stenosis at 2 to 4 months of follow-up and an 11% rate at long-term follow-up (>9 months) among patients who underwent FDD placement.22 Other studies report stenosis rates of between 9.8% and 38%, with differences likely attributable to variable stenosis definitions.23 24 The current study reports an overall rate of device stenosis of 22.4%, which is similar between the two groups. This finding provides further evidence that the interaction between omeprazole and clopidogrel does not lead to negative clinical outcomes.
In the current study, although omeprazole was associated with a significant increase in the P2Y12 levels of patients receiving clopidogrel after FDD placement, such patients did not experience an increased risk of complications such as stroke, bleeding, or device stenosis. Although these findings are encouraging, the limited power of this study with a small sample size and its retrospective nature (the omeprazole group relied on patients reporting the use of omeprazole and may not have captured all patients) do not allow for strong evidence that omeprazole therapy is safe in these patients. Furthermore, fibrinogen light aggregometry-based assessment of platelet function in the setting of P2Y12 inhibitors has some limitations. The previous literature has suggested that blood fibrinogen levels affect the P2Y12 assay, and correcting for this effect is likely necessary when assessing the clopidogrel antiplatelet effect.25 Additional studies are needed to evaluate this medication interaction in a larger patient population before the development of guidelines in this area.
Our analysis found no significant differences in demographics between the omeprazole group and the no-omeprazole group, except for greater mean age in the omeprazole group (P=0.001). This result is consistent with the current literature because advanced age is an important risk factor for gastrointestinal bleeding.8 9 11 Patients with advanced age typically receive a regimen of omeprazole with DAPT because there is a greater benefit-to-risk ratio. The American Heart Association currently recommends the use of omeprazole with DAPT in patients with multiple risk factors for gastrointestinal bleeding.26 However, the US Food and Drug Administration has more stringent guidelines and recommends strongly against the use of omeprazole for patients receiving clopidogrel. There are currently no strong neurovascular guidelines for treatment after FDD placement. Patients in this study were given a regimen of omeprazole by their primary care physicians, and judicious screening of medication administration for these patients is necessary before and after placement of an FDD.
Conclusion
Omeprazole therapy was associated with a significant increase in the P2Y12 reactivity levels in our cohort of intracranial aneurysm patients treated with an FDD who also received clopidogrel. However, receipt of omeprazole was not associated with an increased risk of ischemic events, hemorrhagic events, or device stenosis. Nonetheless, given the significant association between receipt of omeprazole and decreased efficacy of clopidogrel, neuroendovascular patients with an FDD for an intracranial aneurysm should not be administered omeprazole and clopidogrel concomitantly. Further research is necessary to evaluate whether the pharmacodynamic interaction between clopidogrel and omeprazole is associated with neurovascular complications.
Data availability statement
No additional data are available to share.
Ethics statements
Patient consent for publication
Acknowledgments
Andre A Wakim is currently a medical student at Creighton University School of Medicine, Phoenix Health Sciences Campus, Phoenix, Arizona. The authors thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.
References
Footnotes
Contributors All authors made substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work; drafted the work or revised it critically for important intellectual content; provided final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests Dr. AFD is a consultant for Medtronic, Stryker, Koswire, Penumbra, and Cerenovus. Drs. FCA and AFD are on the editorial board for the Journal of NeuroInterventional Surgery.
Provenance and peer review Not commissioned; externally peer reviewed.