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Abstract
Background Patients with cervical carotid and intracranial stenting are routinely premedicated with antithrombotic agents, clopidogrel and aspirin (ASA), and intraprocedurally with heparin. The levels of antithrombotic therapy necessary for these neurovascular therapies have yet to be well defined.
Method A retrospective review of 52 patients who underwent neurovascular stenting procedures was carried out. Measurements obtained intraoperatively included: activating clotting time, antiplatelet inhibition (from Accumetrics) recorded as ASA reaction units (ARU), P2Y12 reaction units (PRU), baseline (BASE), and percentage inhibition. Percentage P2Y12 platelet inhibition <20% and ARU >550 were defined as suboptimal clopidogrel and ASA responses, respectively.
Results 52 patients (mean age 62.6 years) underwent stent implantation for wide necked aneurysms (28, 54%), symptomatic intracranial stenosis (13, 25%) and cervical carotid stenosis (11, 21%). Mean ARU assays were 463.0±84.7. The response was suboptimal in seven patients. For clopidogrel, the mean BASE, PRU and percentage inhibition were 374.0±54.9, 279.5±78.5 and 30.7%±22.6%, respectively. 19 patients (36.5%; p<0.01) showed suboptimal responses for percentage inhibition. Multivariate analysis showed that body weight (82.0±11 vs 73.6±14 kg; p =0.04) and body mass index were significant predictors (OR 1.18, 95% CI 1.01 to 1.18; p =0.003) in the suboptimal group. One case of intraprocedural thrombosis (2%) was observed in the suboptimal group and no cases were seen in the therapeutic group.
Conclusion Data obtained in this study suggest a suboptimal clopidogrel response in patients with greater body weight and body mass index. Adjusted dosing according to weight may help achieve adequate therapeutic platelet inhibition and reactivity while decreasing thromboembolic complications.
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Introduction
For cervical carotid and intracranial stenting, patients are routinely premedicated with antithrombotic agents, clopidogrel and aspirin (ASA), and intraprocedurally with heparin. These antithrombotic agents have been chosen because large clinical trials showed that they reduced the risk of recurrent cardiovascular events in patients with coronary artery disease.1 There are no current guidelines for prevention of stent thrombosis or thromboembolic events for neuroendovascular procedures. Rather, the most current American Heart Association guidelines recommend dual antiplatelet therapy for 1 month following bare metal coronary stents and up to 6–12 months for drug eluting stents.2
Despite this antithrombotic treatment regimen, a proportion of patients still manifest thrombotic events. There has been growing evidence on the individual variability in the response to antiplatelet treatment.3–6 Various studies report relative antiplatelet non-response rates ranging from 5% to more than 30% for clopidogrel and from 5% to 60% for ASA.7 8 The mechanism for non-responsiveness has yet to be well defined but it is likely to be associated with alterations in genetic, pharmacokinetic and platelet properties. For example, the US Food and Drug Administration recently changed the black box warning for clopidogrel to note that mutations in the CYP2C19 gene are associated with poor drug metabolization and an increased risk of cardiovascular adverse events and stent thrombosis.9
The gold standard for measuring platelet resistance involves light transmittance aggregometry but simpler point-of-care tests that can be performed in the angiography suite, such as the VerifyNow-P2Y12 assay (Accumetrics, San Diego, California, USA), are more routinely used as studies have shown that both of these modalities produce similar results.10 11 Given the importance of platelet inhibition, our aim was to evaluate our experiences using this point-of-care test and to determine the prevalence of ASA and clopidogrel resistance as well as to identify predictors of inadequate platelet inhibition.
Methods
Consecutive patients who were pretreated with ASA and clopidrogel prior to neurovascular stenting procedures and had platelet function assay numbers were included in the study. Inclusion criteria were neurovascular stenting patients (cervical carotid or intracranial) treated with ASA and clopidogrel and who had point-of-care testing. An exclusion criterion was an allergy to ASA or clopidogrel or any other contraindication to ASA or clopidogrel. All patients received a loading dose of 600 mg of clopidrogel at least 12 h before the intervention and continued with 75 mg/day. In the three ruptured aneurysm cases, clopidogrel therapy was initiated on the day of intervention. In addition, patients were given 81 mg of ASA the day prior to the intervention and were continued at the same dose daily.
Data were collected on age, gender, height, weight, diabetes, smoking, proton pump inhibition, procedure type, and clinical and angiographic outcome at discharge and follow-up. Platelet activity was measured using the VerifyNow system (Accumetrics Inc) that tests platelet activity over 3 min and uses the combination of adenosine diphosphate and prostaglandin E1 to directly measure the effects of clopidogrel on the P2Y12 receptor. Measurements obtained intraoperatively included activating clotting time, Accumetrics' antiplatelet inhibition, recorded as ASA reaction units (ARU), P2Y12 reaction units (PRU), and baseline and percentage inhibition. Discharge and follow-up functioning, according to the modified Ranking Scale (mRS), and Glasgow Outcome Score (GOS) were evaluated. Percentage P2Y12 platelet inhibition <20% and ARU >550 were defined as suboptimal clopidogrel and ASA responses, respectively. If clopidogrel inhibition was between 10% and 19%, patients were re-bolused with 300 mg of Plavix. Patients with inhibition less than 10% were re-bolused with 600 mg of clopidogrel.
Patient characteristics, diagnosis and intraoperative measurements are summarized for the entire population and the responder groups in table 1. The population was dichotomized according to the percentage platelet inhibition criteria. Suboptimal responders were patients whose per cent inhibition was below 20% whereas patients with a per cent inhibition above 20% were considered optimal responders. Univariate analysis was used to assess differences in response for each outcome observed. Wilcoxon–Mann–Whitney tests were used for continuous variables; a χ2or Fisher's exact test was used to test for associations between categorical variables.
Patient demographics, diagnosis and intraoperative measurements evaluated according to platelet inhibition per cent
Assuming a categorical variable that denotes a responder versus a non-responder as aforementioned, multiple regression analysis was used to evaluate the relationship between the outcome P2Y12 reaction units while controlling for weight, age and gender, diabetes, smoking and proton pump inhibition status. Multivariate logistic regression analysis was used to determine whether platelet inhibition (optimal versus non-optimal responder) was associated with a patient's characteristics. Regression ordinal model for the analysis of repeated ordinal response outcomes (mRS, GOS) was used to evaluate associations between patient functioning and inhibition response while adjusting for patient characteristics. All analysis was conducted using SAS V.9.1 for Windows (SAS Institute Inc).
Results
From 2007 to 2009, 52 consecutive patients (20 men, 32 women) underwent neurovascular stenting procedures and were included in the study. Twenty-four patients (46%) had intracranial stenosis and 11 (21%) were in the cervical carotid artery. Twenty-eight (54%) had stent implantation for wide necked intracranial aneurysms, three (10%) of which were ruptured.
Table 1 describes the findings of univariate analysis for the patient characteristics, diagnosis and intraoperative measurements for the suboptimal versus the optimal responders. Differences in response were observed for age (p=0.05), weight in kilograms (p=0.02), body mass index (BMI) (p=0.006) and per cent inhibition (p<0.001). Overall, the mean ARU assays were 463±84.7 with a target inhibition range of 550. The response was suboptimal in seven patients. For clopidogrel, mean baseline, PRU and percentage inhibition were 374±55, 279.5±78.5 and 30.75%±22.5%, respectively. Nineteen patients (37%; p<0.01) showed suboptimal response for percentage inhibition. Multivariate analysis showed greater body weight (82.0±11 vs 73.6±14 kg; p=0.04) and PRU result (335.65±48 vs 241.3±72.3; p<0.01) in the suboptimal group. One case of intraprocedural thrombosis (2%) was observed among suboptimal responders, and no cases were seen in the therapeutic group.
Multiple regression analysis modeled P2Y12 and found the responder variable to be the only significant predictor (t=4.48, p<0.001). Multivariate logistic regression of the outcome variable pertaining to responders (optimal vs suboptimal) showed that weight was a significant predictor (OR 1.06, 95% CI 1.0 to 1.12; p=0.04), age was borderline significant (OR 1.05, 95% CI 0.99 to 1.12; p =0.07) while gender was not significant (OR 3.36, 95% CI 0.78 to 14.54; p=0.10). A similar model showed that BMI was also a significant predictor of response (OR 1.18, 95% CI 1.01 to 1.18; p =0.003) (figure 1). A patient's smoking, diabetes and proton pump inhibition status were found to be non-significant in these models (p>0.05).
Patient inhibition per cent (PIP) by body mass index (BMI) for each patient. Broken lines represent the thresholds for suboptimal (<20%) and optimal (>20%) responders, and the threshold for overweight (BMI >25). Of the 19 patients with a suboptimal response (PIP <20%), 16 were considered obese according to the BMI (>25).
A patient's functioning at discharge and follow-up according to the mRS and GOS are summarized in table 2. The average follow-up was 12 months (range 0–34 months). The per cent of patients with good function (mRS ≤2) from discharge to follow-up improved (84.2% to 88.9%) in the suboptimal group while it declined slightly among optimal responders (97% to 93.9%). Function (mRS and GOS) was further evaluated with an ordinal repeated measures (discharge and follow-up) model adjusting for response (table 2). No significant differences were observed in mRS (OR 1.55, CI 0.54 to 4.44; p=0.41) and GOS (OR 1.19, CI 0.25 to 5.67; p=0.83) according to the platelet inhibition response. This suggests that while the odds of suboptimal responders having poorer outcomes is 1.55 (mRS) and 1.19 (GOS) times the odds of optimal responders having poorer outcomes, these observations were not statistically significant. There were no clinical thromboembolic events reported at follow-up.
Suboptimal and optimal responders according to the modified Ranking Scale and Glasgow Outcome Score at discharge and follow-up
Illustrative case
A patient presented with a 1 year history of memory loss and two syncopal episodes. The patient did not have a history of diabetes and was not taking proton pump inhibitors (PPIs). The patient had a history of smoking tobacco in the distant past but had not smoked for many years. The patient's neurological examination was normal except for some mild short term memory loss. Carotid duplex showed 50–60% stenosis of the left cervical internal carotid artery with CT angiogram demonstrating approximately a 70% stenosis. Informed consent was obtained for performing a cervical and cerebral angiogram with angioplasty and stenting of the left internal carotid artery stenosis. The patient was loaded with 600 mg of clopidogrel the day prior to the procedure and was started on 81 mg of ASA daily. A 7 French Arrow-Flex Sheath (Arrow International, Diegem, Belgium) was introduced into the left common carotid artery and angiography confirmed a 70% stenosis of the left internal carotid artery origin. The patient was given 6000 units of intravenous heparin yielding an activating clotting time of 229 s. This was followed by an additional 1000 units of intravenous heparin. Point-of-care testing with the Accumetrics' VerifyNow system showed an ARU of 459 and yielded 0% clopidogrel platelet inhibition. The test was repeated and resulted once again in 0% clopidogrel platelet inhibition. Under road map guidance, a 5 mm Angioguard (Cordis, Bridgewater, New Jersey, USA) distal protection device was navigated past the stenotic lesion and deployed in the distal left cervical internal carotid artery. A 6 mm × 20 mm Precise stent (Cordis) was deployed across the stenotic lesion followed by angioplasty with a 6 mm×20 mm Sterling balloon (Cordis) to a nominal pressure of 6 atmospheres. The distal protection device was removed and contained no debris. Final angiography revealed no residual stenosis. Immediately following the procedure, the patient was noted to be confused and aphasic with a right hemiplegia. Emergent CT scan did not show intracranial hemorrhage. The patient was reloaded with 600 mg of clopidogrel and also loaded with 0.25 mg/kg of intravenous Abciximab followed by an infusion of 10 μg/min for 12 h. Over the course of the next 4 days, the patient's aphasia steadily improved and the right hemiplegia improved to 4/5 in the upper extremity and 5/5 in the lower extremity. The patient was discharged to an acute rehabilitation facility where the patient's neurologic function continued to improve over approximately 2 weeks. The patient was maintained on clopidogrel 75 mg daily for 6 weeks and ASA 81 mg daily indefinitely.
Discussion
Adverse thrombotic events following stenting procedures are multifactorial but in part can be attributed to platelets.12 Achieving platelet inhibition is an essential part of managing patients who need this intervention. Following a large meta-analysis of 287 randomized studies, low dose ASA demonstrated a 25–30% reduction of cardiovascular events, including myocardial infarction and stroke.13 However, ASA has been proven to be insufficient as it only inhibits the cyclooxygenase pathway.14 Clopidogrel has a similar effect on the adenosine diphosphate P2Y12 receptor. Dual antiplatelet therapy is the current standard of care because it demonstrates the highest reduction of ischemic events status post percutaneous coronary intervention.15 16 Despite its proven benefit, recent data indicate that individual patients show significantly different responses to ASA and clopidogrel.7 8 This implies that some patients may be resistant or unresponsive.
The definition of clopidogrel resistance varies in the cardiology literature. Godino et al compared VerifyNow to flow cytometry and found a cut-off value of ≤15% inhibition to represent resistance.17 Another study by Lee et al looked at patients undergoing drug eluting stent implantation for acute coronary syndrome and found that <20% inhibition on the VerifyNow assay was an independent predictor for stent thrombosis and coronary death.18
In the present study, our interest was primarily to identify whether thromboembolic complications were more likely to occur in those patients whose platelet inhibition was suboptimal. We chose <20% inhibition for clopidogrel resistance based on the study from Lee et al18 because the thromboembolic events we were interested in were similar in theory to their interest in stent thrombosis. Although 37% of patients in our study had a suboptimal clopidogrel response, only one patient from this group had a thromboembolic event. No patients with ≥20% inhibition had such events. Multivariate analysis showed a suboptimal clopidogrel response in patients with greater body weight and BMI.
The neurointerventional literature is limited in respect to antiplatelet therapy resistance in patients undergoing cervical carotid or intracranial stenting.19–22 Much of our rationale for treating these patients with dual antiplatelet therapy and determining their responsiveness to these treatments with the VerifyNow assay is largely extrapolated from the cardiac literature. A recent study by Pandya et al, investigating clopidogrel, ASA dose and duration in patients undergoing neurointerventional procedures found that almost two-thirds of patients did not achieve adequate platelet inhibition with clopidogrel premedication.19 In this study, clopidogrel resistance was defined as ≤50% and ASA resistance as ≥550 ARU.
In another study by Müller-Schunk et al, one-third of patients were considered clopidrogel non-responders and they found a significant relationship in that adverse events were only found in the non-responder group.20 Prabhakaran et al found that in their cohort of 76 patients undergoing cerebrovascular stenting, 52% were clopidrogel resistant and that age older than 55 years and diabetes were inversely related to per cent platelet inhibition.21
Two previous studies looked at platelet aggregation in overweight patients.23 24 Angiolillo et al23 assessed 300 mg loading dosing while Sibbing et al24 assessed 600 mg loading dose prior to percutaneous coronary intervention (PCI). According to the results of these studies, the outcomes of overweight patients after PCI were inferior to the outcomes of normal weight patients. Specifically, Angiolillo et al used light transmittance aggregometry in 48 patients undergoing PCI and showed that 59% of overweight patients had a suboptimal platelet response. Sibbing et al showed that in 402 patients undergoing PCI, being overweight (BMI >25) was the only independent predictor for increased adenosine diphosphate induced platelet aggregation. In both of these studies, the loading dose did not inhibit platelet aggregation in overweight patients to the same extent as in normal weight patients. In the present study, we similarly found that overweight patients (greater body weight and BMI) were more likely to have a suboptimal clopidogrel response when compared with normal weight patients. The relationship between obesity and platelet inhibition is complex and might be related to insufficient dosage of drug or adipose tissue induced inflammation. The higher degree of suboptimal clopidrogel response observed in overweight patients in this study may be due to the differences in the metabolic rate of clopidogrel among these individuals. Clopidogrel is a prodrug that undergoes hepatic biotransformation and requires metabolism via several cytochrome CYP450 isoenzymes in order to exert its antiplatelet effects. One cytochrome enzyme, CYP3A4, has been observed to be reduced in overweight individuals and this may explain the lower response in these patients.25 26 It is hypothesized that interference in these activation steps is the primary cause of clopidogrel non-responsiveness.
In a recently published study investigating the effect of insulin treatment on platelet dysfunction in diabetic patients, obesity was an independent predictor of platelet aggregation.27 In the present study, however, we found no association with diabetes.
Proton pump inhibitors (PPIs), often used with patients taking ASA and clopidogrel, are metabolized in the cytochrome P450 system. Two retrospective cohort studies investigating the clinical effectiveness of clopidogrel taken in combination with PPIs both demonstrated that taking clopidogrel together with PPIs resulted in an increased risk of rehospitalization for acute coronary syndrome.28 29 Preliminary results, however, of a randomized double blinded trial of omeprazole versus placebo in patients taking clopidogrel plus ASA were in direct conflict with these studies and instead, showed no indication of a clinically relevant adverse cardiovascular interaction between clopidogrel and PPIs.30 Contradicting findings like these have caused uncertainty regarding administering a PPI concurrent with clopidogrel. Currently, the US Food and Drug Administration and the European Medicines Agency both advise providers to carefully evaluate the need before prescribing a PPI for patients taking clopidogrel.31–33 In the present study, we found no association between PPI status and platelet inhibition.
In a recent study, Bliden et al found that smoking increases clopidogrel platelet inhibition compared with non-smoking.34 By analyzing patients on chronic clopidogrel therapy (n=120) and undergoing elective coronary stenting, Bliden showed significantly lower platelet aggregation in patients smoking ≥0.5 pack/day compared with patients who were non-smokers (p<0.05). In the present study, we found no association between smoking and platelet inhibition.
Limitation
A limitation of the present study is that platelet aggregation was assessed only at a single time point. Lack of baseline values did not allow us to determine the decrease in aggregation achieved with clopidogrel in each patient. However, single measurements of platelet reactivity after treatment were shown to correlate with early outcomes after PCI.35 A large randomized trial is attempting to determine whether adjustment of clopidogrel therapy on the basis of platelet function testing with a point-of-care assay safely improves outcomes after PCI.36
Conclusion
Data obtained in this study suggest a suboptimal clopidogrel response in patients with greater body weight and BMI. The data also suggest that overweight patients may need a higher loading dose of clopidogrel to adequately inhibit platelet activity. Adjusted dosing according to weight may help achieve adequate therapeutic platelet inhibition and reactivity while decreasing thromboembolic complications. Further studies to explore the optimal antithrombotic regimen in overweight patients undergoing neurovascular stenting should be performed to confirm this hypothesis.
Key messages
Therapeutic levels of antiplatelet medications for neuroendovascular procedures are not well defined and may not necessarily be extrapolated from cardiac data.
This study analyzes potential variables contributing to relative antiplatelet therapy resistance in the neurovascular pathology population.
The data from this study suggest a suboptimal antiplatelet therapy response from clopidogrel in patients with greater body weight and BMI.
These results suggest that patients with higher body weight and BMI may require clopidogrel dose adjustment for neuroendovascular therapy.
References
Footnotes
Competing interests MJA is a consultant for Boston Scientific and Codman. AC receives a Cordis Endovascular Fellowship Training Grant and a Boston Scientific Endovascular Neurosurgery Postgraduate Fellow Grant.
Patient consent Obtained.
Provenance and peer review Not commissioned; not externally peer reviewed.