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Original Article
A Markov model to compare the long-term effect of aspirin, clopidogrel and clopidogrel plus aspirin on prevention of recurrent ischemic stroke due to intracranial artery stenosis Jinqiu Yang, Lukui Chen1, Naveen Chitkara2, Qiang Xu3 Medical College, The Wang Yanan Institute for Studies in Economics, Xiamen University, Fujian, 1Department of Neurosurgery, Zhongda Hospital, Southeast University, Nanjing, 2Department of Neurosurgery, NASA Neuro Care, Jalandhar, Punjab, India, 3 Guangdong Landau Biotechnology Co. Ltd., Guangzhou, China
Abstract
Address for correspondence: Prof. Lukui Chen, Department of Neurosurgery, Zhongda Hospital Southeast University, Nanjing, China. E-mail: [email protected] Received : 17-07-2013 Review completed : 09-09-2013 Accepted : 31-01-2014
Background: Given the importance of intracranial stenosis as a cause of recurrent ischemic stroke and the lack of evidence supporting a clear choice for prevention of recurrent ischemic events, a computer simulation model for prognostic prediction could be used to improve decision making. Aims: The aim of the following study is to compare the long-term effect of aspirin, clopidogrel and clopidogrel plus aspirin for prevention of recurrent stroke due to atherosclerotic intracranial artery stenosis. Setting and Design: The cohort consisted of 206 patients from 2006 to 2011. Materials and Methods: A two-state Markov model was used to predict the prognosis of patients with stroke or transient ischemic attack (TIA) caused by angiographically verified 50-99% stenosis of a major intracranial artery to receive aspirin, clopidogrel, or dual therapy. Statistical Analysis: Two tests were used: Pearson Chi-square test or Fisher’s exact test (for percentages) and Kruskal Wallis test (for rank order data). Results: In the 10-year Markov cohort analysis, 36.24% of patients who were treated with clopidogrel plus aspirin developed to recurrent stroke while the probability for patients in the aspirin group and clopidogrel group was 42.60% and 48.39% respectively. Patients with clopidogrel plus aspirin had the highest quality-adjusted life years, followed by aspirin and clopidogrel. Conclusion: To prevent recurrent stroke in patients with intracranial artery stenosis, especially in those patients with a history of TIA or coronary artery disease, medical therapy with clopidogrel plus aspirin should be considered in preference to aspirin alone. Key words: Aspirin, clopidogrel, Markov model, recurrent ischemic stroke
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48
Introduction Atherosclerotic stenosis of a major intracranial artery is an important cause of stroke, especially in Asians, Africans and Hispanics.[1-5] The risk of recurrent stroke in patients with intracranial atherosclerotic stenosis may be as high as 15% per year.[6,7] Given the importance of intracranial stenosis as a cause of recurrent ischemic Neurology India | Jan-Feb 2014 | Vol 62 | Issue 1
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stroke and the lack of evidence supporting a clear choice for prevention of recurrent ischemic events,[8] a computer simulation model for prognostic prediction could be used to improve decision making. In this study, we conducted a Markov cohort analysis to predict the prognosis in patients with atherosclerotic intracranial artery stenosis after treated with clopidogrel plus aspirin, aspirin or clopidogrel alone for prevention of recurrent stroke.
Materials and Methods Data source The study protocol was approved by the institutional review board. Data collection and analysis were supervised by the operation committee. It was retrospective cohort analysis. The inclusion criteria included initial non-disabling ischemic stroke confirmed by magnetic resonance imaging (MRI) and transient ischemic attack (TIA) within 48 h of onset, which was attributable to angiographically verified 50-99% stenosis of a major intracranial artery (carotid, middle cerebral, vertebral, or basilar) confirmed by digital subtraction angiography, a modified Ranking scale of 3 or less (indicating a non-disabling stroke) and an age of at least 40 years. Exclusion criteria included a contraindication to aspirin or clopidogrel therapy, any antiplatelet agents taken before initial stroke, any stents placed before initial stroke, non-atherosclerotic stenosis of an intracranial artery, a cardiac source of embolism and a co-existing condition that limited survival to 60-year-old and patients with history of TIA or coronary artery diseases (CAD) were run separately to examine the influence on preferred strategy. Statistical analysis Baseline features of the three groups (Group A: Aspirin; Group C: Clopidogrel; Group D: Clopidogrel plus aspirin) were compared with the use of a one-way 49
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analysis of variance (for means), Pearson Chi-square test or Fisher’s exact test (for percentages) and Kruskal Wallis test (for rank order data). All reported P values are two-sided, with Bonferroni’s method to adjust the minimum achieved P value to account for the multiple tests; P < 0.05 was considered statistically significant. Statistical analysis was performed using the SPSS software system (SPSS for Windows, Version 17.0, SPSS Inc., Chicago, IL).
Results Baseline analysis A total of remained 206 patients had been finally analyzed. Most of the baseline characteristics had no significant difference among the three treatment groups except for patients with history of CAD and history of post-extracranial internal carotid artery (ICA) or vertebral artery (VA) stent [Table 1]. Multivariant analysis showed that Group D (61.91%) had significantly more patients with history of CAD than Group A (3.70%) and Group C (20.97%) (P < 0.05); Group C had significantly more patients with history of CAD than Group A (P < 0.05). Group D (23.81%) also had significantly more patients with history of post-extracranial ICA or VA stent than Group A (2.47%) (P < 0.05); there is no significant difference between Group A (2.47%) and Group C (9.68%), Group C (9.68%) and Group D (23.81%) (P > 0.05). In the 10-year Markov cohort analysis, the possibility of recurrent stroke was 36.24% for patients in clopidogrel plus aspirin group, compared with 42.60% in the aspirin group and 48.39% in the clopidogrel group.
Patients with clopidogrel plus aspirin gain the highest QALYs (8.24 years), followed by aspirin (7.89 years) and clopidogrel (7.56 years). Sensitivity analysis Table 2 lists the results of sensitivity analysis. On average, when the baseline value of transition probability increased by 25%, the QALYs decreased by 0.38, 0.49 and 0.46 for patients in Group D, Group C and Group A respectively. Alternatively, the decreased transition probability resulted in an increased QALYs of 0.40, 0.53 and 0.45 for the above three groups. When we took a look at patients who were >60-year-old, the QALYs fell slightly to 8.20, 7.07 and 7.40 for Group D, Group C and Group A respectively. In addition, simulation of the model for patients with history of TIA or CAD widened the differences among the three groups. The results showed that the additional QALYs gained with clopidogrel plus aspirin compared to aspirin alone ranged from 3.89 to 7.35 while the difference between clopidogrel plus aspirin and clopidogrel alone ranged from 0.52 to 1.73. Likewise, the benefits gained with clopidogrel compared to aspirin ranged from 2.69 to 6.53. As a result, clopidogrel plus aspirin gained the highest QALYs when using most plausible scenarios in our analysis.
Discussion Intracranial stenosis is one of the most common causes of recurrent stroke world-wide.[4,5] Even in patients with minor stroke or TIA, intracranial stenosis has a high early risk of recurrent stroke.[11] Patients at greatest risk for recurrent stroke secondary to intracranial stenosis are
Table 1: Baseline characteristics of the patients
Characteristic Age-year (x±s) Male sex-no. (%) History of extra stenosis-no. (%) History of TIA-no. (%) History of lacunar infarct-no. (%) History of hypertension-no. (%) History of coronary artery diseases-no. (%) History of diabetes mellitus-no. (%) History of peripheral vascular disease-no. (%) History of post-extracranial ICA or VA stent-no. (%) Affected stenotic artery-no. (%) ICA Middle cerebral artery VA Basilar artery Multiple arteries* Percent stenosis of affected artery-no. (%) 50-69 70-99 100 Follow-up-m (x±s)
Group A (n=81)
Group C (n=62)
Group D (n=63)
P
65.30±13.01 57 (70.37) 24 (29.63) 9 (11.11) 43 (53.09) 62 (76.54) 3 (3.70) 32 (39.51) 4 (4.94) 2 (2.47)
66.98±13.24 41 (66.13) 22 (35.48) 13 (20.97) 40 (64.52) 51 (82.26) 13 (20.97) 22 (35.48) 5 (8.06) 6 (9.68)
70.06±11.55 38 (60.32) 28 (44.44) 16 (25.40) 37 (58.73) 48 (76.19) 39 (61.91) 25 (39.68) 10 (15.87) 15 (23.81)
0.08 0.45 0.18 0.08 0.39 0.65 0.00 0.86 0.07 0.00
25 (30.86) 34 (41.98) 12 (14.81) 10 (12.35) 3 (3.70)
20 (32.26) 25 (40.32) 6 (9.68) 11 (17.74) 4 (6.45)
21 (33.33) 24 (38.10) 12 (19.05) 6 (9.52) 5 (7.94)
0.95 0.90 0.33 0.38 0.54
45 (55.56) 22 (27.16) 14 (17.28) (26.69±13.30)
27 (43.55) 33 (53.23) 2 (3.23) (23.35±10.58)
20 (31.75) 36 (57.14) 7 (11.11) (25.38±13.21)
0.11
0.29
*The affected arteries were a combination of the left and right vertebral arteries. TIA - Transient ischemic attack, ICA - Internal carotid artery, VA - Vertebral artery
50
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Table 2: Results of sensitivity analysis
Variable Transition probability (%) Baseline value −25 +25 Patients who were >60 years −25 +25 Patients with history of TIA −25 +25 Patients with history of CAD −25 +25 Quality-adjusted life years (%) Baseline value −25 +25 Patients who were >60 years −25 +25 Patients with history of TIA −25 +25 Patients with history of CAD −25 +25 Probability for recurrent stroke after 10 years (%) Baseline value −25 +25 Patients who were >60 years −25 +25 Patients with history of TIA −25 +25 Patients with history of CAD −25 +25
Group A Group C Group D 0.054 0.041 0.068 0.069 0.052 0.086 0.217 0.163 0.271 0.513 0.385 0.641
0.064 0.048 0.080 0.080 0.060 0.100 0.076 0.057 0.095 0.038 0.029 0.048
0.044 0.033 0.055 0.045 0.034 0.056 0.032 0.024 0.040 0.021 0.016 0.026
7.89 8.34 7.43 7.40 7.96 6.90 4.21 5.10 3.53 1.95 2.58 1.56
7.56 8.09 7.07 7.07 7.69 6.51 7.19 7.79 6.65 8.45 8.79 8.09
8.24 8.64 7.86 8.20 8.60 7.82 8.68 8.99 8.38 9.11 9.31 8.91
42.60 34.21 50.55 51.08 41.37 59.31 91.34 83.12 95.76 99.92 99.23 100
48.39 38.85 56.56 56.56 46.14 65.13 54.64 44.39 63.15 32.12 25.49 38.85
36.24 28.51 43.20 36.90 29.24 43.80 27.76 21.57 33.52 19.12 14.90 23.16
TIA - Transient ischemic attack, CAD - Coronary artery diseases
those with both high-grade stenosis and hemodynamic compromise.[12] In patients with intracranial stenosis, anticoagulation with warfarin or low-molecular-weight heparin, associated with significantly higher rates of adverse events, was no better than aspirin in reducing risk of recurrent stroke[13] or improving disability.[14] Despite medical therapy with aspirin, among patients with >70% stenosis, approximately 23% had a recurrent ipsilateral ischemic stroke over the next 12 months.[13,15] Combination treatment with cilostazol and aspirin did not show any clinical benefit compared with aspirin and placebo.[16] In the management of atherothrombosis with clopidogrel in high-risk patients (MATCH) study,[17] the combination of clopidogrel and aspirin was no more effective than clopidogrel alone in preventing recurrent ischemic events in patients with stroke, but data in the acute setting suggest this combination might be more effective than aspirin alone for the prevention of early Neurology India | Jan-Feb 2014 | Vol 62 | Issue 1
recurrent stroke and TIA.[18,19] In the clopidogrel and aspirin for reduction of emboli in symptomatic carotid stenosis trial,[18] combination therapy with clopidogrel and aspirin was more effective than aspirin alone in reducing asymptomatic embolization. In patients with intracranial stenosis, the presence of microembolic signals is associated with risk of early recurrent TIA, stroke[20] and new silent cerebral infarctions.[21] In the clopidogrel plus aspirin versus aspirin alone for reducing embolization in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR) study,[22] combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing the proportion of patients with at least one microembolic signal in a population of patients who have cerebral or carotid artery stenosis, most of whom had stenosis of the intracranial carotid artery. A consensus conferences dedicated to intracranial atherosclerotic disease (ICAD) were considered timely due to their importance.[1,23,24] Recently, the large clinical and observational studies[12-16,23,25-28] were completed. Patients who have had a stroke or TIA attributed to stenosis (50-99%) of a major intracranial artery face a 12-14% risk of subsequent stroke during the 2-year period after the initial ischemic event, despite treatment with antithrombotic medications. The annual risk of subsequent stroke may exceed 20% in high-risk groups. The medical treatment of patients with symptomatic ICAD is directed toward: (1) Prevention of intraluminal thrombo-embolism; (2) plaque stabilization and regression; and (3) management of atherogenic risk factors. Aspirin monotherapy, the combination of aspirin and extended release dipyridamole and clopidogrel monotherapy are all acceptable options in patients with non-cardioembolic ischemic stroke and TIA. Daily treatment with statin had been recommended for patients with a recent stroke or TIA which could reduce the incidence of fatal or non-fatal stroke, whether patients met their low-density lipoprotein goal or not. There was no ischemic stroke, brain hemorrhage, or death from other vascular causes after treatment with statin. When combined with dual antiplatelet therapy, there would be more effective for the prevention of recurrent vascular events.[29,30] However, some issues regarding medical management cannot be addressed by clinical trials due to practical and logistical considerations. The results of our Markov model have important implications for prevention of recurrent stroke in patients with intracranial artery stenosis: Dual therapy with clopidogrel plus aspirin seemed to have the best long-term effect in reducing rates of recurrent ischemic events, especially in those patients with a history of TIA or CAD. The sensitivity analysis yielded robust results, which demonstrated that clopidogrel plus aspirin was the optimal strategy on prevention of recurrent ischemic stroke. 51
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Conclusion Patients of intracranial artery stenosis with history of TIA, CAD, or extracranial artery stenosis should be treated aggressively. Medical therapy with clopidogrel plus aspirin should be considered in preference to aspirin alone especially for those patients with a history of TIA or CAD. It seems that 100 mg of aspirin and 75 mg of clopidogrel per day is reliably safe for Chinese patients in this study. Future randomized controlled trails should help to further refine clinical decision making for patients with this condition.
Acknowledgments
16.
17.
18.
19.
There is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
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How to cite this article: Yang J, Chen L, Chitkara N, Xu Q. A Markov model to compare the long-term effect of aspirin, clopidogrel and clopidogrel plus aspirin on prevention of recurrent ischemic stroke due to intracranial artery stenosis. Neurol India 2014;62:48-52. Source of Support: National Science and Technology Major Project of Key Drug Innovation and Development (2011ZX09307-303-03), Conflict of Interest: None declared.
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Original Article
A Markov model to compare the long-term effect of aspirin, clopidogrel and clopidogrel plus aspirin on prevention of recurrent ischemic stroke due to intracranial artery stenosis Jinqiu Yang, Lukui Chen1, Naveen Chitkara2, Qiang Xu3 Medical College, The Wang Yanan Institute for Studies in Economics, Xiamen University, Fujian, 1Department of Neurosurgery, Zhongda Hospital, Southeast University, Nanjing, 2Department of Neurosurgery, NASA Neuro Care, Jalandhar, Punjab, India, 3 Guangdong Landau Biotechnology Co. Ltd., Guangzhou, China
Abstract
Address for correspondence: Prof. Lukui Chen, Department of Neurosurgery, Zhongda Hospital Southeast University, Nanjing, China. E-mail: [email protected] Received : 17-07-2013 Review completed : 09-09-2013 Accepted : 31-01-2014
Background: Given the importance of intracranial stenosis as a cause of recurrent ischemic stroke and the lack of evidence supporting a clear choice for prevention of recurrent ischemic events, a computer simulation model for prognostic prediction could be used to improve decision making. Aims: The aim of the following study is to compare the long-term effect of aspirin, clopidogrel and clopidogrel plus aspirin for prevention of recurrent stroke due to atherosclerotic intracranial artery stenosis. Setting and Design: The cohort consisted of 206 patients from 2006 to 2011. Materials and Methods: A two-state Markov model was used to predict the prognosis of patients with stroke or transient ischemic attack (TIA) caused by angiographically verified 50-99% stenosis of a major intracranial artery to receive aspirin, clopidogrel, or dual therapy. Statistical Analysis: Two tests were used: Pearson Chi-square test or Fisher’s exact test (for percentages) and Kruskal Wallis test (for rank order data). Results: In the 10-year Markov cohort analysis, 36.24% of patients who were treated with clopidogrel plus aspirin developed to recurrent stroke while the probability for patients in the aspirin group and clopidogrel group was 42.60% and 48.39% respectively. Patients with clopidogrel plus aspirin had the highest quality-adjusted life years, followed by aspirin and clopidogrel. Conclusion: To prevent recurrent stroke in patients with intracranial artery stenosis, especially in those patients with a history of TIA or coronary artery disease, medical therapy with clopidogrel plus aspirin should be considered in preference to aspirin alone. Key words: Aspirin, clopidogrel, Markov model, recurrent ischemic stroke
Access this article online Quick Response Code:
Website: www.neurologyindia.com PMID: *** DOI: 10.4103/0028-3886.128290
48
Introduction Atherosclerotic stenosis of a major intracranial artery is an important cause of stroke, especially in Asians, Africans and Hispanics.[1-5] The risk of recurrent stroke in patients with intracranial atherosclerotic stenosis may be as high as 15% per year.[6,7] Given the importance of intracranial stenosis as a cause of recurrent ischemic Neurology India | Jan-Feb 2014 | Vol 62 | Issue 1
[Downloaded free from http://www.neurologyindia.com on Thursday, March 13, 2014, IP: 202.177.173.189] || Click here to download free Android application for thi journal Yang, et al.: Comparison of treatments for prevention of recurrent ischemic stroke
stroke and the lack of evidence supporting a clear choice for prevention of recurrent ischemic events,[8] a computer simulation model for prognostic prediction could be used to improve decision making. In this study, we conducted a Markov cohort analysis to predict the prognosis in patients with atherosclerotic intracranial artery stenosis after treated with clopidogrel plus aspirin, aspirin or clopidogrel alone for prevention of recurrent stroke.
Materials and Methods Data source The study protocol was approved by the institutional review board. Data collection and analysis were supervised by the operation committee. It was retrospective cohort analysis. The inclusion criteria included initial non-disabling ischemic stroke confirmed by magnetic resonance imaging (MRI) and transient ischemic attack (TIA) within 48 h of onset, which was attributable to angiographically verified 50-99% stenosis of a major intracranial artery (carotid, middle cerebral, vertebral, or basilar) confirmed by digital subtraction angiography, a modified Ranking scale of 3 or less (indicating a non-disabling stroke) and an age of at least 40 years. Exclusion criteria included a contraindication to aspirin or clopidogrel therapy, any antiplatelet agents taken before initial stroke, any stents placed before initial stroke, non-atherosclerotic stenosis of an intracranial artery, a cardiac source of embolism and a co-existing condition that limited survival to 60-year-old and patients with history of TIA or coronary artery diseases (CAD) were run separately to examine the influence on preferred strategy. Statistical analysis Baseline features of the three groups (Group A: Aspirin; Group C: Clopidogrel; Group D: Clopidogrel plus aspirin) were compared with the use of a one-way 49
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analysis of variance (for means), Pearson Chi-square test or Fisher’s exact test (for percentages) and Kruskal Wallis test (for rank order data). All reported P values are two-sided, with Bonferroni’s method to adjust the minimum achieved P value to account for the multiple tests; P < 0.05 was considered statistically significant. Statistical analysis was performed using the SPSS software system (SPSS for Windows, Version 17.0, SPSS Inc., Chicago, IL).
Results Baseline analysis A total of remained 206 patients had been finally analyzed. Most of the baseline characteristics had no significant difference among the three treatment groups except for patients with history of CAD and history of post-extracranial internal carotid artery (ICA) or vertebral artery (VA) stent [Table 1]. Multivariant analysis showed that Group D (61.91%) had significantly more patients with history of CAD than Group A (3.70%) and Group C (20.97%) (P < 0.05); Group C had significantly more patients with history of CAD than Group A (P < 0.05). Group D (23.81%) also had significantly more patients with history of post-extracranial ICA or VA stent than Group A (2.47%) (P < 0.05); there is no significant difference between Group A (2.47%) and Group C (9.68%), Group C (9.68%) and Group D (23.81%) (P > 0.05). In the 10-year Markov cohort analysis, the possibility of recurrent stroke was 36.24% for patients in clopidogrel plus aspirin group, compared with 42.60% in the aspirin group and 48.39% in the clopidogrel group.
Patients with clopidogrel plus aspirin gain the highest QALYs (8.24 years), followed by aspirin (7.89 years) and clopidogrel (7.56 years). Sensitivity analysis Table 2 lists the results of sensitivity analysis. On average, when the baseline value of transition probability increased by 25%, the QALYs decreased by 0.38, 0.49 and 0.46 for patients in Group D, Group C and Group A respectively. Alternatively, the decreased transition probability resulted in an increased QALYs of 0.40, 0.53 and 0.45 for the above three groups. When we took a look at patients who were >60-year-old, the QALYs fell slightly to 8.20, 7.07 and 7.40 for Group D, Group C and Group A respectively. In addition, simulation of the model for patients with history of TIA or CAD widened the differences among the three groups. The results showed that the additional QALYs gained with clopidogrel plus aspirin compared to aspirin alone ranged from 3.89 to 7.35 while the difference between clopidogrel plus aspirin and clopidogrel alone ranged from 0.52 to 1.73. Likewise, the benefits gained with clopidogrel compared to aspirin ranged from 2.69 to 6.53. As a result, clopidogrel plus aspirin gained the highest QALYs when using most plausible scenarios in our analysis.
Discussion Intracranial stenosis is one of the most common causes of recurrent stroke world-wide.[4,5] Even in patients with minor stroke or TIA, intracranial stenosis has a high early risk of recurrent stroke.[11] Patients at greatest risk for recurrent stroke secondary to intracranial stenosis are
Table 1: Baseline characteristics of the patients
Characteristic Age-year (x±s) Male sex-no. (%) History of extra stenosis-no. (%) History of TIA-no. (%) History of lacunar infarct-no. (%) History of hypertension-no. (%) History of coronary artery diseases-no. (%) History of diabetes mellitus-no. (%) History of peripheral vascular disease-no. (%) History of post-extracranial ICA or VA stent-no. (%) Affected stenotic artery-no. (%) ICA Middle cerebral artery VA Basilar artery Multiple arteries* Percent stenosis of affected artery-no. (%) 50-69 70-99 100 Follow-up-m (x±s)
Group A (n=81)
Group C (n=62)
Group D (n=63)
P
65.30±13.01 57 (70.37) 24 (29.63) 9 (11.11) 43 (53.09) 62 (76.54) 3 (3.70) 32 (39.51) 4 (4.94) 2 (2.47)
66.98±13.24 41 (66.13) 22 (35.48) 13 (20.97) 40 (64.52) 51 (82.26) 13 (20.97) 22 (35.48) 5 (8.06) 6 (9.68)
70.06±11.55 38 (60.32) 28 (44.44) 16 (25.40) 37 (58.73) 48 (76.19) 39 (61.91) 25 (39.68) 10 (15.87) 15 (23.81)
0.08 0.45 0.18 0.08 0.39 0.65 0.00 0.86 0.07 0.00
25 (30.86) 34 (41.98) 12 (14.81) 10 (12.35) 3 (3.70)
20 (32.26) 25 (40.32) 6 (9.68) 11 (17.74) 4 (6.45)
21 (33.33) 24 (38.10) 12 (19.05) 6 (9.52) 5 (7.94)
0.95 0.90 0.33 0.38 0.54
45 (55.56) 22 (27.16) 14 (17.28) (26.69±13.30)
27 (43.55) 33 (53.23) 2 (3.23) (23.35±10.58)
20 (31.75) 36 (57.14) 7 (11.11) (25.38±13.21)
0.11
0.29
*The affected arteries were a combination of the left and right vertebral arteries. TIA - Transient ischemic attack, ICA - Internal carotid artery, VA - Vertebral artery
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Table 2: Results of sensitivity analysis
Variable Transition probability (%) Baseline value −25 +25 Patients who were >60 years −25 +25 Patients with history of TIA −25 +25 Patients with history of CAD −25 +25 Quality-adjusted life years (%) Baseline value −25 +25 Patients who were >60 years −25 +25 Patients with history of TIA −25 +25 Patients with history of CAD −25 +25 Probability for recurrent stroke after 10 years (%) Baseline value −25 +25 Patients who were >60 years −25 +25 Patients with history of TIA −25 +25 Patients with history of CAD −25 +25
Group A Group C Group D 0.054 0.041 0.068 0.069 0.052 0.086 0.217 0.163 0.271 0.513 0.385 0.641
0.064 0.048 0.080 0.080 0.060 0.100 0.076 0.057 0.095 0.038 0.029 0.048
0.044 0.033 0.055 0.045 0.034 0.056 0.032 0.024 0.040 0.021 0.016 0.026
7.89 8.34 7.43 7.40 7.96 6.90 4.21 5.10 3.53 1.95 2.58 1.56
7.56 8.09 7.07 7.07 7.69 6.51 7.19 7.79 6.65 8.45 8.79 8.09
8.24 8.64 7.86 8.20 8.60 7.82 8.68 8.99 8.38 9.11 9.31 8.91
42.60 34.21 50.55 51.08 41.37 59.31 91.34 83.12 95.76 99.92 99.23 100
48.39 38.85 56.56 56.56 46.14 65.13 54.64 44.39 63.15 32.12 25.49 38.85
36.24 28.51 43.20 36.90 29.24 43.80 27.76 21.57 33.52 19.12 14.90 23.16
TIA - Transient ischemic attack, CAD - Coronary artery diseases
those with both high-grade stenosis and hemodynamic compromise.[12] In patients with intracranial stenosis, anticoagulation with warfarin or low-molecular-weight heparin, associated with significantly higher rates of adverse events, was no better than aspirin in reducing risk of recurrent stroke[13] or improving disability.[14] Despite medical therapy with aspirin, among patients with >70% stenosis, approximately 23% had a recurrent ipsilateral ischemic stroke over the next 12 months.[13,15] Combination treatment with cilostazol and aspirin did not show any clinical benefit compared with aspirin and placebo.[16] In the management of atherothrombosis with clopidogrel in high-risk patients (MATCH) study,[17] the combination of clopidogrel and aspirin was no more effective than clopidogrel alone in preventing recurrent ischemic events in patients with stroke, but data in the acute setting suggest this combination might be more effective than aspirin alone for the prevention of early Neurology India | Jan-Feb 2014 | Vol 62 | Issue 1
recurrent stroke and TIA.[18,19] In the clopidogrel and aspirin for reduction of emboli in symptomatic carotid stenosis trial,[18] combination therapy with clopidogrel and aspirin was more effective than aspirin alone in reducing asymptomatic embolization. In patients with intracranial stenosis, the presence of microembolic signals is associated with risk of early recurrent TIA, stroke[20] and new silent cerebral infarctions.[21] In the clopidogrel plus aspirin versus aspirin alone for reducing embolization in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR) study,[22] combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing the proportion of patients with at least one microembolic signal in a population of patients who have cerebral or carotid artery stenosis, most of whom had stenosis of the intracranial carotid artery. A consensus conferences dedicated to intracranial atherosclerotic disease (ICAD) were considered timely due to their importance.[1,23,24] Recently, the large clinical and observational studies[12-16,23,25-28] were completed. Patients who have had a stroke or TIA attributed to stenosis (50-99%) of a major intracranial artery face a 12-14% risk of subsequent stroke during the 2-year period after the initial ischemic event, despite treatment with antithrombotic medications. The annual risk of subsequent stroke may exceed 20% in high-risk groups. The medical treatment of patients with symptomatic ICAD is directed toward: (1) Prevention of intraluminal thrombo-embolism; (2) plaque stabilization and regression; and (3) management of atherogenic risk factors. Aspirin monotherapy, the combination of aspirin and extended release dipyridamole and clopidogrel monotherapy are all acceptable options in patients with non-cardioembolic ischemic stroke and TIA. Daily treatment with statin had been recommended for patients with a recent stroke or TIA which could reduce the incidence of fatal or non-fatal stroke, whether patients met their low-density lipoprotein goal or not. There was no ischemic stroke, brain hemorrhage, or death from other vascular causes after treatment with statin. When combined with dual antiplatelet therapy, there would be more effective for the prevention of recurrent vascular events.[29,30] However, some issues regarding medical management cannot be addressed by clinical trials due to practical and logistical considerations. The results of our Markov model have important implications for prevention of recurrent stroke in patients with intracranial artery stenosis: Dual therapy with clopidogrel plus aspirin seemed to have the best long-term effect in reducing rates of recurrent ischemic events, especially in those patients with a history of TIA or CAD. The sensitivity analysis yielded robust results, which demonstrated that clopidogrel plus aspirin was the optimal strategy on prevention of recurrent ischemic stroke. 51
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Conclusion Patients of intracranial artery stenosis with history of TIA, CAD, or extracranial artery stenosis should be treated aggressively. Medical therapy with clopidogrel plus aspirin should be considered in preference to aspirin alone especially for those patients with a history of TIA or CAD. It seems that 100 mg of aspirin and 75 mg of clopidogrel per day is reliably safe for Chinese patients in this study. Future randomized controlled trails should help to further refine clinical decision making for patients with this condition.
Acknowledgments
16.
17.
18.
19.
There is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
20.
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How to cite this article: Yang J, Chen L, Chitkara N, Xu Q. A Markov model to compare the long-term effect of aspirin, clopidogrel and clopidogrel plus aspirin on prevention of recurrent ischemic stroke due to intracranial artery stenosis. Neurol India 2014;62:48-52. Source of Support: National Science and Technology Major Project of Key Drug Innovation and Development (2011ZX09307-303-03), Conflict of Interest: None declared.
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