Article Text

Original research
Association of thrombelastographic parameters with post-stenting ischemic events
  1. Bo Wang1,
  2. Xiao-Qing Li1,2,
  3. Ning Ma1,
  4. Dapeng Mo1,
  5. Feng Gao1,
  6. Xuan Sun1,
  7. Xiaotong Xu1,
  8. Lian Liu1,
  9. Ligang Song,
  10. Xin-Gang Li3,
  11. Zhigang Zhao3,
  12. Xingquan Zhao4,
  13. Zhong-Rong Miao1
  1. 1Department of Interventional Neuroradiology, Beijing Tian Tan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (NCRC-ND); Center of Stroke, Beijing Institute for Brain Disorders; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
  2. 2Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an, China
  3. 3Department of Pharmacy, Beijing Tian Tan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (NCRC-ND); Center of Stroke, Beijing Institute for Brain Disorders; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
  4. 4Department of Neurology, Beijing Tian Tan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (NCRC-ND); Center of Stroke, Beijing Institute for Brain Disorders; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
  1. Correspondence to Dr Zhong-Rong Miao, Department of Interventional Neuroradiology, Beijing Tian Tan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases, Center of Stroke, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China; zhongrongm{at}163.com

Abstract

Background and purpose Thrombelastography (TEG) is widely used for the measurement of platelet function. However, few studies have investigated the TEG parameters in patients receiving extracranial or intracranial artery stenting for ischemic cerebrovascular disease. This study sought to describe the association of TEG parameters before the procedure with post-procedural ischemic events after extracranial or intracranial artery stenting.

Methods Patients in whom stenting was performed for extracranial or intracranial artery stenosis (70–99%) were recruited into the study. Blood samples were obtained for TEG to assess platelet function before stenting. The primary endpoint was ischemic stroke or transient ischemic attack in the territory of the stented artery.

Results A total of 218 patients were included in the study. During a mean follow-up period of 132 days (range 98–226 days), 18 (8.3%) primary endpoint events were recorded. Compared with patients without ischemic events, the ADP-induced platelet-fibrin clot strength (MAADP) was significantly higher (41.57±15.10 vs 33.50±13.86, p=0.020) and the ADP inhibition rate (ADP%) was significantly lower in patients with ischemic events (39.54±23.15 vs 55.29±24.43, p=0.009). Multivariate analysis identified MAADP and ADP% as significant independent predictors of subsequent ischemic events with HRs of 1.036 and 0.965, respectively. From receiver operating characteristic curve analysis, MAADP >49.95 mm had the best predictive value of ischemic events.

Conclusions Our study suggests that TEG parameters MAADP and ADP% are associated with subsequent ischemic events in patients with extracranial or intracranial stents.

Clinical trial number NCT01925872.

  • Angioplasty
  • Atherosclerosis
  • Platelets
  • Stenosis
  • Stent

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Introduction

Stroke is the leading cause of death in China.1 Percutaneous transluminal angioplasty and stenting is an important means of prevention and treatment of ischemic stroke.2–4 In order to better prevent the ischemic events after stent placement, clopidogrel and aspirin are widely prescribed in combination as dual antiplatelet therapy in patients undergoing neuroendovascular stenting.5 ,6 However, it has been estimated that about one-fifth of patients treated with clopidogrel do not respond adequately to the drug during treatment.7 ,8 Although clopidogrel resistance has been associated with thromboembolic complications in patients after coronary stent placement, it has not been well studied in patients who have undergone neuroendovascular stenting.

Thrombelastography (TEG) is widely used for the measurement of platelet function. However, few studies have investigated TEG parameters in patients receiving extracranial or intracranial artery stenting for ischemic cerebrovascular disease. This study sought to describe the association of TEG parameters with subsequent ischemic events after extracranial or intracranial artery stenting.

Methods

Study design

This study was an institutional review board-approved prospective cohort study.

Study population

All patients who underwent stenting for extracranial or intracranial artery stenosis were consecutively enrolled in the study from May 2013 to September 2013 in Beijing Tian Tan Hospital.The inclusion criteria were: (1) symptomatic or asymptomatic extracranial artery stenosis (common carotid artery, extracranial segment of the internal carotid artery, subclavian artery, innominate artery or extracranial segment of the vertebral artery) 70–99%, and symptomatic and refractory intracranial artery stenosis (intracranial segment of the internal carotid artery, middle cerebral artery stem, intracranial segment of the vertebral artery or basilar artery) 70–99%. The degree of stenosis was confirmed by a normal distal vessel bed on digital subtraction angiography. The symptomatic lesion was defined as that causing the primary or recurrent ischemic stroke or transient ischemic attack (TIA) in the target arterial territory which occurred within 90 days. Refractory lesions were defined as those where the symptom recurred despite treatment with at least one antiplatelet drug; for patients with asymptomatic extracranial lesions, only those with target territory area hypoperfusion confirmed by CT perfusion were enrolled; (2) no evidence of cardioembolism, including atrial fibrillation or recent myocardial infarction within 1 month; (3) age ≥30 years; (4) two or more atherosclerotic risk factors including hypertension, hypercholesterolemia, diabetes mellitus, cigarette smoking, and obesity; (5) informed consent given by the patients and their relative.

Exclusion criteria were: (1) contraindications to extracranial or intracranial artery stenting; (2) known allergy or contraindication to aspirin, clopidogrel, heparin, nitinol, and local or general anesthesia; (3) active peptic ulcer disease, bleeding tendency, severe liver or kidney impairment; (4) comorbid conditions that may limit survival to less than 1 year; (5) enrollment in another study that would conflict with the current study.

Medication regimen

Clopidogrel (75 mg/day) plus aspirin (100 mg or 300 mg/day) were started at least 5 days before the procedure. If patients had not been on dual antiplatelet therapy for 5 days prior to the procedure, a 300 mg loading dose of aspirin plus 300 mg clopidogrel were given; if aspirin or clopidogrel had not been taken for 5 days prior to the procedure, 300 mg of aspirin or clopidogrel alone was given.

Platelet function testing

Blood samples were obtained for TEG to assess their platelet function before stenting. Platelet function testing was carried out using the TEG Hemostasis System (Haemoscope Corporation, Niles, Illinois, USA). The TEG Hemostasis Analyzer with automated analytical software provides quantitative and qualitative measurements of the physical properties of a clot.9 ,10 Venous blood samples were obtained from patients in a fasting state on the first day of enrollment. The following TEG parameters were tested: maximum amplitude (MA), arachidonic acid inhibition rate (AA%), ADP-induced platelet-fibrin clot strength (MAADP), and ADP inhibition rate (ADP%).11

Study endpoints

The primary endpoint was ischemic stroke or TIA in the territory of the stented artery. Secondary endpoints included coronary ischemic events, death, and severe bleeding complications. The occurrence of adverse events were identified on the follow-up visit to the clinic at 30, 60, 90 days and thereafter; patients who did not attend their follow-up visit were contacted by telephone for the above information. Patient records including electronic source documents were obtained and reviewed by two physicians blinded to the study who adjudicated events. Based on the presence or absence of ischemic events during follow-up, patients were divided into the ischemic events group (IEG) and the control group (CG).

Statistical analysis

Categorical variables were expressed as number (%) and continuous variables were expressed as mean±SD, with p<0.05 considered statistically significant. The Fisher exact test and Mann–Whitney rank sum test were used for comparison of categorical and continuous variables between groups. Univariate and multivariate Cox regression analysis was used to evaluate the significance of variables concerning ischemic events occurring during the follow-up period. A receiver operator curve analysis was used to determine the ability of TEG to predict ischemic events. All data were analyzed using SPSS V.13.0 software.

Results

Demographics and procedural characteristics

A total of 218 patients were recruited; 210 (96.3%) patients received clopidogrel (75 mg/day) plus aspirin (100 mg/day or 300 mg/day) at least 5 days before the procedure, 1 patient (0.5%) received a loading dose of 300 mg aspirin plus 300 mg of clopidogrel, 6 patients (2.8%) received a 300 mg loading dose of aspirin alone, and 1 patient (0.5%) received a 300 mg loading dose of clopidogrel alone. During a mean follow-up period of 132 days (range 98–226 days), 18 (8.3%) primary endpoint events were recorded (9 (4.1%) TIA and 9 (4.1%) ischemic stroke). The nine ischemic events occurred within 7 days of stenting and the rest occurred after 7 days. Five other adverse events occurred in the study period: two patients died of cerebral hemorrhage related to hyperperfusion, two patients had mucocutaneous hemorrhage, and one patient developed deep venous thrombosis (see online supplementary table S1).

Patient demographics and procedural characteristics are shown in table 1. No significant difference was found in the diagnosis, number and site of the stents between the two groups, nor were there any significant differences in age, gender, risk factors, and hematological data between the two groups.

Table 1

Comparsion of demographics, procedural characteristics, and TEG parameters between the ischemic events group (IEG) and the control group (CG)

Association of TEG changes with subsequent ischemic events

The MAADP was significantly higher (41.57±15.10 vs 33.50±13.86, p=0.020) and the ADP% was significantly lower (39.54±23.15 vs 55.29±24.43, p=0.009) in patients with ischemic events than in those without ischemic events (table 1).

Quartile analysis showed a lower incidence of ischemic events in the lower quartiles and a higher incidence of ischemic events in the higher quartiles of MAADP (see online supplementary figure S1). On ADP inhibition rate analysis, higher quartiles were associated with a lower incidence of ischemic events and a higher incidence of ischemic events was associated with lower quartiles (see online supplementary figure S2).

On univariate Cox regression analysis, MAADP and ADP% were identified as significant independent predictors of subsequent ischemic events with HR 1.039 (95% CI 1.003 to 1.076, p=0.032) and HR 0.975 (95% CI 0.955 to 0.995, p=0.016), respectively (see online supplementary table S2). On multivariate Cox regression analysis, MAADP and ADP% were identified as significant independent predictors of subsequent ischemic events with HR 0.889 (95% CI 0.809 to 0.977, p=0.015) and HR 0.909 (95% CI 0.858 to 0.963, p=0.001), respectively. Receiver operating characteristic curve analysis showed that MAADP and ADP% had good predictive value of ischemic events: area under the curve (AUC) 0.654 (95% CI 0.520 to 0.789), p=0.030; and AUC 0.304 (95% CI 0.171 to 0.437), p=0.006, respectively (figure 1). After adjustment for risk factors and analysis of the sensitivity and specificity of different MAADP tangent points, a cut-off point of MAADP 49.95 mm was identified with a specificity of 91.0%. The proportion of patients with MAADP >49.95 mm was 11.0% (24/218). The incidence of ischemic events in patients with MAADP >49.95 mm was markedly higher than in patients with MAADP ≤49.95 mm (20.8% vs 6.7%, p=0.018). The occurrence of ischemic events over time was depicted on Kaplan–Meier event–time curves, which also demonstrated the association of events with platelet function parameters by a cut-off point of MAADP 49.95 mm (figure 2).

Figure 1

Receiver operating characteristic curve. ADP%: AUC 0.304 (95% CI 0.171 to 0.437), p=0.006; MAADP: AUC 0.654 (95% CI 0.520 to 0.789), p=0.030. ADP%, ADP inhibition rate; AUC, area under the curve; MAADP, ADP-induced platelet-fibrin clot strength.

Figure 2

Survival functions. The graph shows the association between events and platelet function parameters using a MAADP cut-off point of 49.95 mm. MAADP, ADP-induced platelet-fibrin clot strength.

Discussion

A dual antiplatelet regimen including clopidogrel and aspirin is widely used for patients undergoing neuroendovascular stenting. However, some patients show resistance to clopidogrel or aspirin and impaired inhibition of platelet aggregation.12 It has been estimated that 4.2–31.0% of patients treated with clopidogrel do not achieve an appropriate level of efficacy of platelet activity,13–15 and aspirin resistance accounts for 7.8–32.0% of patients with recurrent events.16 ,17 Many platelet function tests have been used to define the responsiveness of patients with cardiovascular disease to clopidogrel or aspirin.16 Different tests have provided wide-ranging figures for the prevalence of clopidogrel resistance, suggesting poor correlation between currently available platelet function tests.18 Some platelet function test parameters are related to recurrent ischemic events although usage of aspirin which is regarded as aspirin resistance.19 ,20

Recently, TEG has been widely used in the assessment of platelet function.21 ,22 However, few studies have investigated TEG parameters in patients undergoing extracranial or intracranial artery stenting for ischemic cerebrovascular disease. In this study, ADP% was significantly lower and MAADP was significantly higher in patients with ischemic events. Our receiver operating characteristic curve analysis suggested that MAADP >49.95 mm was significantly associated with ischemic events after neurovascular stenting with a specificity of 91.0%. This is similar to that observed in a previous study in which MAADP >47 mm was significantly associated with the short-term and long-term clinical outcomes after percutaneous coronary intervention (PCI).23 Based on this finding, we suggest MAADP may be a predictor for ischemic events after extracranial or intracranial artery stenting.

In this study, using MAADP 49.95 mm as the cut-off point, 11.0% of the patients had MAADP >49.95 mm. This shows the difference in adopting a distinct diagnostic standard to estimate the incidence of clopidogrel resistance. Similarly, Nordeen et al reported that 21.0% of patients undergoing neuroendovascular procedures were resistant to clopidogrel using <20% inhibition on P2Y12 platelet function testing as the criterion.24 Tang et al reported that CYP2C19 loss of function genotypes with the *2 and/or *3 allele were associated with higher residual platelet reactivity; MAADP >47 mm was an independent predictor of major adverse cardiovascular events for patients with acute coronary syndrome undergoing PCI at 6 months measured by TEG.25

This study showed no hematological parameters to be related to recurrent ischemic events. Fong et al reported that patients with elevated HbA1c had a significantly increased likelihood of having biochemical aspirin resistance.26 Other studies have shown that C-reactive protein is correlated with greater surface involvement by embolic materials in the protection filters during the carotid artery stenting procedure.27 ,28 Further studies are necessary to validate these controversies.

The SAMMPRIS study showed that ischemic stroke within 30 days after intervention was partly due to thrombosis, which was found in 1.4% of all the patients undergoing angioplasty and stenting.29 An incidence of thrombosis ranging from 0.5% to 0.8% was found in previous studies on carotid artery stenting.30 ,31 The complication of acute or subacute thrombosis may be related to non-response to dual antiplatelet therapy with aspirin and clopidogrel. Similarly, clopidogrel resistance is associated with a poor prognosis after neurovascular stenting.32 ,33 Given the poor prognosis of stent thrombosis and the uncertainties surrounding treatment, TEG may help to screen out potential antiplatelet non-responders who would be likely develop acute or subacute thrombosis after the endovascular treatment.

We suggest that, before undergoing neuroendovascular stenting, TEG testing should be conducted to evaluate patients for platelet responsiveness to antiplatelet drugs in order to identify high-risk patients sufficiently early to intervene.

Limitations of the study

There were some limitations in this study. First, the sample size was small and the incidence of ischemic events was low, so there is concern about the statistical significance as the number of events needs to be substantially larger to make the TEG parameters significant. Second, we only studied the Asian population so it is uncertain whether TEG testing has the same sensitivity in other ethnic groups. Before the findings can be accepted, similar studies across the world are needed to evaluate the productivity of TEG parameters in other groups of people. Third, this study did not focus on the mechanism of complications. We will try to improve this in a future study.

Conclusion

Our study suggests that MAADP and ADP% in TEG analysis are associated with subsequent ischemic events in patients with extracranial or intracranial artery stents. The quantitative assessment of MAADP measured by TEG may be used as a powerful tool to derive a personalized antiplatelet treatment plan for patients to reduce secondary ischemic events.

Acknowledgments

We thank Dr Lin-Feng Zhang, Department of Epidemiology, The Cardiovascular Institute, Fu Wai Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College, and the National Center for Cardiovascular Disease Control and Research, Beijing, China for the statistical analysis.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • BW and X-QL contributed equally to this article.

  • ZZ, XZ, and Z-RM contributed equally to this article.

  • Contributors XZ, Z-RM: conceived and designed the experiments. BW, X-QL, NM, DM, FG, XS, XX, LL, LS: performed the experiments. BW, X-QL, NM, Z-RM: analyzed the data. BW, X-QL, NM, DM, FG, XS, XX, LL, LS, X-GL, ZZ, XZ, Z-RM: contributed reagents/materials/analysis tools. BW, X-QL, NM: wrote the paper. ZZ, XZ, Z-RM: supervised the quality of the study.

  • Funding Beijing High-level personnel funds, Contract grant number: 2013-2-19 to Z-RM; National Natural Science Foundation of China, Contract grant number: 81371290 to Z-RM; Beijing Municipal Science and Technology Commission, Contract grant number: D111107003111007 to X-QZ; Clinical and Basic Medical Cooperation Project of Capital Medical University, Contract grant number: 13JL40 to NM.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the institutional ethics committee at Beijing Tian Tan Hospital.

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

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