Efficacy and Safety of Combination Antiplatelet Therapies in Patients With Symptomatic Intracranial Atherosclerotic Stenosis
Background and Purpose—An optimal strategy for management of symptomatic intracranial atherosclerotic stenosis (ICAS) has not yet been established. We compared the efficacy of 2 combinations of antiplatelets, aspirin plus cilostazol (cilostazol group) verus aspirin plus clopidogrel (clopidogrel group), on the progression of ICAS, which is known to be associated with clinical stroke recurrence.
Methods—In this investigator-initiated double-blind trial, 457 patients with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or the basilar artery were randomly allocated into either a cilostazol group or a clopidogrel group. After 7 months of treatment, follow-up MR angiogram and MRI were performed. The primary end point was the progression of ICAS in comparison with stenosis on the baseline MR angiogram. Secondary end points included the occurrence of new ischemic lesions on MRI, composite of cardiovascular events, and major bleeding complications.
Results—Cardiovascular events occurred in 15 of 232 patients (6.4%) in the cilostazol group and 10 of 225 (4.4%) in the clopidogrel group (P=0.312). Cilostazol did not reduce the progression of symptomatic ICAS (20 of 202) compared to clopidogrel (32 of 207) (odds ratio, 0.61; P=0.092), although favorable changes in serum lipoproteins were observed in the cilostazol group. There were no significant differences between the 2 groups with respect to new ischemic lesions (18.7% versus 12.0%; P=0.078) and major hemorrhagic complications (0.9% versus 2.6%; P=0.163).
Conclusions—This trial failed to show significant difference in preventing progression of ICAS and new ischemic lesions between the 2 combination antiplatelet therapies in the patients with symptomatic ICAS.
Management strategies for atherosclerosis of the extracranial arteries have been established. However, little progress has been made for the management of intracranial atherosclerotic stenosis (ICAS), the major vascular cause of stroke in nonwhite populations.1,2 The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial failed to prove benefit of anticoagulation over aspirin for ICAS.3 Although angioplasty and stenting show promise for certain patients, its efficacy has yet to be validated in randomized clinical trials. Antiplatelet therapy is still the most widely used treatment, although ICAS patients treated with aspirin therapy still have a 15% rate of stroke in the first year after initial presentation.3
Our previous study, the Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis (TOSS), showed that cilostazol plus aspirin was superior to aspirin monotherapy in preventing the progression of symptomatic ICAS.4 The addition of cilostazol to aspirin (with or without clopidogrel) therapy was also effective for the prevention of restenosis after coronary stenting, without increasing bleeding complications.5 Because the progression of ICAS is known to be an important predictor of recurrent stroke,6,7 we hypothesized that prevention of the progression of symptomatic ICAS with the cilostazol plus aspirin combination would be effective for the prevention of recurrent ischemic stroke.
Another combination, clopidogrel plus aspirin, showed no beneficial effects in the long-term prevention of ischemic events in 2 recent large trials8,9 and is not routinely recommended in stroke patients. However, this combination significantly reduced recurrent cardiovascular events in the 12 months after acute coronary events or coronary stenting10,11 and was effective in preventing microembolic signals in patients with cerebral or carotid artery stenosis.12,13 Similarly, aspirin plus clopidogrel may improve outcomes in patients with symptomatic ICAS during the first several months after stroke, and could be another good option for the prevention of recurrent ischemic stroke. In the present study (TOSS-2), we compared the efficacy of 2 combination antiplatelet therapies, cilostazol plus aspirin and clopidogrel plus aspirin, in preventing the progression of symptomatic ICAS, with the aim of developing a management strategy for patients with symptomatic ICAS.
Subjects and Methods
Study Design and Participants
This investigator-initiated, randomized, double-blind, multicenter clinical trial was conducted at 20 centers in 4 East Asian countries. The protocol was approved by the ethics committees of all participating centers.
We recruited acute ischemic stroke patients aged 35 years or older with symptomatic ICAS within 2 weeks of symptom onset. Symptomatic ICAS was defined as a significant focal stenosis in the M1 segment of the middle cerebral artery or basilar artery on MRA, relevant to acute lesions of the index stroke identified by diffusion-weighted imaging. The exclusion criteria included the following: (1) nonatherosclerotic vasculopathy, such as arterial dissection or moyamoya disease; (2) thrombolytic therapy for the index stroke; (3) embolic heart disease; (4) significant stenosis of arteries proximal to the symptomatic stenosis; and (5) scheduling for revascularization for the stenosis.
Baseline clinical data and Digital Imaging and Communications in Medicine image files of the candidate patients who gave informed consents were uploaded to the study Web site. Only when eligibility was confirmed by 2 trained reviewers were subjects randomly assigned either to the cilostazol group (100 mg cilostazol twice daily) or to the clopidogrel group (75 mg clopidogrel once daily). The study medications were administrated with aspirin (75–150 mg once daily) to all subjects for 7 months. Statin therapy and aggressive control of atherosclerosis risk factors were strongly recommended.
At baseline, subjects underwent diffusion-weighted imaging, fluid attenuation inversion recovery imaging, 3-dimensional time-of-flight MRA for intracranial vessels, and 3-dimensional contrast-enhanced MRA for extracranial evaluation. Duplex sonographic evaluation of neck vessels was used as an alternative tool for the evaluation of extracranial arteries. Follow-up visits with strict monitoring, including evaluation for possible bleeding complications, were scheduled at 1, 3, 5, and 7 months. High-sensitivity C-reactive protein levels, glycosylated hemoglobin (HbA1c), and lipid profile including apolipoproteins A1 and B were measured at the initial and final visits. To evaluate the progression of ICAS and occurrence of new ischemic lesions, follow-up MRA and fluid attenuation inversion recovery images were obtained at the 7-month follow-up visit or at the time of patient withdrawal.
The primary end point was the progression of symptomatic ICAS in MRA. According to TOSS grading system,4 the severity of stenosis for the middle cerebral arteries and for the basilar artery in each patient were classified into 1 of 5 grades: normal, mild, moderate, severe, and occlusion (Supplemental Figure I, http://stroke.ahajournals.org). After 2 trial training sessions for the grading system, 2 investigators blinded to clinical information and the location of the symptomatic stenosis independently classified the degree of stenosis on MRA. Discrepancies between the 2 reviewers (L.J.H. and P.J.M.) were referred to the third investigator (C.Y.J.) and resolved by consensus between all 3 reviewers. Progression was defined as worsening in the degree of stenosis by 1 grade or more on the follow-up MRA in comparison with the baseline MRA, and regression was defined as improving of the degree of stenosis (Figure 1). Regression in symptomatic ICAS and progression or regression in asymptomatic ICAS were measured as the secondary end points.
Secondary end points included new ischemic lesions, which were defined as any new ischemic lesions apart from the index lesions on follow-up fluid attenuation inversion recovery using slice-to-slice comparison with the baseline diffusion-weighted imaging and fluid attenuation inversion recovery (Supplemental Figure II). Ischemic stroke in symptomatic ICAS, any recurrent stroke, a composite of cardiovascular events (nonfatal stroke, nonfatal MI, and vascular death), and serious hemorrhagic complications (life-threatening or major bleeding) were also analyzed as secondary end points. Life-threatening bleeding and major bleeding were defined as in a previous clinical trial.9
To avoid bias, analysis of MRI and angiographic data were performed by blind investigators using the same display system and Petaview, a noncommercial Digital Imaging and Communications in Medicine viewer program developed by the Asan Medical Center, just after the locking of clinical data.
The previous clinical trial, TOSS,4 showed that symptomatic ICAS progressed in 6.7% of the cilostazol group versus 28.8% in the placebo group. Because data for clopidogrel combination were not available, we assumed progression rate of 20% in the clopidogrel group by expert consensus. Then, the progression rate of cilostazol group was determined to be 10%, a conservative estimation for the difference in progression rate between the 2 groups.
For the sample size to have a statistical power of 80% with a 2-sided significance level of P<0.05, we required 200 subjects per group. Allowing for a dropout rate of 16.7%, we estimated a total sample size of 480.
The analysis plan was prespecified. We performed assessment of clinical events and safety analysis on an intention-to-treat basis with the inclusion of all randomized patients. The primary end point and other MRI-based end points were analyzed using the full analysis set, which included the patients who completed follow-up MRI evaluations.
The adjusted relative risk and confidence interval were controlled for center interaction and computed by the Mantel-Haenszel method. We generated a Kaplan-Meier curve for the time to clinical events and ischemic events in each group, and we used the log rank test to compare the 2 Kaplan-Meier curves. We performed post hoc analysis with the χ2 trend test for trends in changes in the degree of symptomatic stenosis, including progression and regression. We explored the consistency of effects on the primary end point in 10 subgroups without adjustment for multiple comparisons. All reported probability values were 2-sided, and P<0.05 was considered as statistically significant. We used SAS software version 9.1 for statistical analyses.
Between August 2005 and May 2008, 507 potential subjects were registered, of whom 50 were excluded by reviewers as shown in Figure 2. The dropout rate was lower than the initial plan, and recruitment was ceased after randomization of subject 457 by the steering committee because >200 subjects in each group were expected to be included to the final analysis. Three subjects in the cilostazol group were excluded after randomization by the steering committee because of the presence of atrial fibrillation, arterial dissection, or unruptured aneurysm. The full analysis set comprised 202 subjects in the cilostazol group and 207 in the clopidogrel group (Figure 2).
The baseline characteristics of the randomized subjects were similar in both groups, although the mean age was older and hypertension and a family history of stroke were more common in the cilostazol group (Table 1). The severity and location of the symptomatic stenosis were evenly distributed between groups. The inter-rater agreement between the 2 blinded investigators (L.J.M. and P.J.M.) on the severity of the symptomatic stenosis was high (weighted κ=0.77).
The progression of symptomatic stenosis occurred in 20 patients (9.3%) in the cilostazol group and 32 patients (15.5%) in the clopidogrel group (unadjusted P=0.092; Table 2). No difference was seen in the proportion of subjects with progression between centers (P=0.682 by the Breslow-Day test). Overall change in the symptomatic stenosis was significantly favorable (less progression and more regression) in the cilostazol group (P=0.049 by χ2 trend test, post hoc analysis). Although change in the severity of stenosis of asymptomatic arteries was infrequent, overall change in asymptomatic stenosis was also favorable in the cilostazol group (P=0.039 by χ2 trend test, post hoc analysis). Baseline characteristics of the 48 subjects who were not included in the analysis of the primary end point did not differ from those included, with the exception of the initial National Institutes of Health Stroke Scale score (Supplemental Table II).
No significant difference was seen in total cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, and vascular death) between the cilostazol group (15 of 232 subjects; 6.47%) and the clopidogrel group (10 of 225; 4.44%; P=0.312, log rank test for Kaplan-Meier survival analysis; Figure 3). The cilostazol group had 11 nonfatal strokes (10 ischemic strokes and 1 hemorrhagic stroke). In the clopidogrel group, 6 subjects had ischemic strokes, 1 of which was fatal. There were no significant differences in the frequency of new ischemic lesions (on brain MRI) between the cilostazol group (34 of 182; 18.7%) and the clopidogrel group (23 of 191; 12.0%; P=0.078). Also, no difference was seen in the frequency of new ischemic lesions in the territory of the symptomatic ICAS between groups (P=0.321 by χ2 test).
Safety assessment revealed that major hemorrhagic complications were not significantly different between the 2 groups (P=0.163), as shown in Table 2. Gastrointestinal bleeding requiring massive transfusion occurred in 5 patients in the clopidogrel group and 1 patient in the cilostazol group. One subject in the clopidogrel group died after symptomatic hemorrhagic transformation of the presenting stroke. Headache occurred more frequently in the cilostazol group (62 subjects; 26.7%) than in the clopidogrel group (35 subjects; 15.1%). The frequencies of other adverse events were similar in both groups. Laboratory findings, including lipoprotein profiles and C-reactive protein, were similar in both groups at baseline. At follow-up, total cholesterol and apolipoprotein B levels and the apolipoprotein B-to-apolipoprotein A1 ratio were lower and the high-density lipoprotein-cholesterol level was higher in the cilostazol group (Table 3).
We performed subgroup analysis for the progression of symptomatic ICAS (Supplemental Figure III). No significant interaction was seen with the therapeutic effect of either cilostazol or clopidogrel, except for smoking (P=0.013 for the interaction).
In this study, we compared the efficacy of aspirin plus cilostazol with aspirin plus clopidogrel, with the aim of developing a management strategy for symptomatic ICAS using 2 surrogate markers that are thought to be related to clinical outcomes of ICAS, ie, progression of atherosclerosis and new ischemic lesions. This study showed no significant difference between the 2 combination antiplatelet therapies in the rate of progression of ICAS and development of new ischemic lesions. However, there were some findings from this study. The cilostazol group had trends toward less progression of symptomatic ICAS and more regression of asymptomatic ICAS compared to the clopidogrel group, with significant further reduction in levels of apolipoprotein B and the apolipoprotein B-to-apolipoprotein A1 ratio. However, the clopidogrel group showed a tendency toward fewer new ischemic lesions. Thus, interpretation of the results is challenging.
In previous studies, changes in arterial diameters on conventional angiography or changes in flow velocities on transcranial Doppler were used to evaluate the progression of ICAS.6,7 However, both methods have drawbacks as standard methods. The invasiveness with risk of serious complications of conventional angiography limits its use as a standard follow-up method in clinical trials. Transcranial Doppler is easily affected by factors such as blood pressure, hemoglobin level, and acoustic window.14
The MRA is widely used in clinical practice because of safety and high concordance rate with conventional angiography.15 Although its use in monitoring atherosclerotic progression has not been completely established yet, the concordance between outcomes of ICAS as assessed by MRA and transcranial Doppler was high in the TOSS-1 study.4 The distribution of progression and regression of symptomatic and asymptomatic stenosis in the cilostazol arm were also consistent across the TOSS-1 study and the present study. Furthermore, despite blind assessments, progression and regression were mainly observed in symptomatic arteries and rarely in asymptomatic arteries. These findings were consistent with previous reports.6,7 Therefore, we believe that MRA-based evaluation of outcomes of ICAS is reliable and reproducible.
This study showed tendencies toward less progression in symptomatic ICAS and more regression in asymptomatic ICAS in the cilostazol group. These results correlate with the results of coronary studies that showed preventive effects of cilostazol on restenosis after coronary stenting.5,16
Changes in lipoprotein profiles because of cilostazol may be one of the mechanisms of cilostazol effects suppressing atherosclerosis.17,18 Total cholesterol and low-density lipoprotein cholesterol levels were significantly decreased compared with baseline data in both groups, likely related to the extensive use of statins. Interestingly, apolipoprotein B levels and the apolipoprotein B-to-apolipoprotein A1 ratio decreased, and high-density lipoprotein increased, more markedly in the cilostazol group. Apolipoprotein B levels reflect all type of proatherogenic particles, and the apolipoprotein B-to-apolipoprotein A1 ratio is known to be an independent predictor of cardiovascular events.19 These changes in lipoproteins in the cilostazol group are consistent with those in previous studies20,21 and may have played a role in inhibiting the progression of ICAS.
Despite the favorable results of the cilostazol group on atherosclerosis progression, the prevalence of new ischemic lesions tended to be lower in the clopidogrel group than in the cilostazol group. The progression of atherosclerosis develops gradually over periods of months or years, but new ischemic lesions are known to occur mainly in the acute period of stroke.22 New ischemic lesions therefore may not be affected by the progression of atherosclerosis as observed in this study, explaining the lack of cilostazol effects on new ischemic lesions. In ICAS, artery-to-artery embolism is the major cause of ischemic stroke and new ischemic lesions.23 Microembolic signals on transcranial Doppler can be used as a surrogate marker for artery-to-artery embolism. The CARESS and CLAIR studies showed that addition of clopidogrel to aspirin significantly reduced microembolic signals compared with aspirin monotherapy.12,13 Based on these results, the addition of cilostazol to aspirin might have had less favorable effects in the prevention of new ischemic lesions than the addition of clopidogrel. The trend toward lower incidence of recurrent ischemic events in the clopidogrel group is also in agreement with these findings. However, the concerns of bleeding complications discourage the long-term use of the clopidogrel plus aspirin combination for the prevention of recurrent ischemic stroke, as demonstrated in previous clinical trials.9,24
The cilostazol group suggested trends toward improvement in atherosclerotic outcomes but less effect on the prevention of ischemic events. This discrepancy also has been observed in the previous studies; several months of cilostazol administration after coronary stenting reduced restenosis without reducing coronary events.5,25 Suppression of atherosclerosis progression may have limited effects on the prevention of early recurrence in cerebrovascular or coronary heart disease.
Based on a meta-analysis of previous trials, the addition of cilostazol did not increase major bleeding complications compared with placebo.25 The 7-month major bleeding rate in our study was 0.86% with aspirin plus cilostazol, which was comparable in the aspirin arm in WASID trial (1.8% per year). The combination of aspirin plus cilostazol therefore might have the merits of less hemorrhagic events, an improved lipoprotein profile, and the suppression of atherosclerosis, and it could be more useful for long-term therapy for symptomatic ICAS patients than the combination of aspirin plus clopidogrel.
The cardiovascular event rate in this study (5.47% for the first 7 months) was significantly lower than in previous clinical studies. Event rates in the WASID trial were 15% with aspirin in the first 12 months. As the vascular event rate after stroke decreases over time, our 12-month event rates for vascular events would be lower than those in the WASID trial. One reason could be the inclusion of subjects with mild stenosis who would not have been eligible for the WASID trial.26 However, the shorter time from qualifying event to randomization than in the WASID trial (18.0±14.0 days for the aspirin group and 16.0±12.0 days for the warfarin group) can increase the risk of recurrent ischemic stroke in this study.26 Accordingly, the lower rate of cardiovascular events in this study may have been related to the extensive use of statins,27 as well as the frequent monitoring schedule with aggressive control of risk factors. The use of dual antiplatelet therapy in our study also may have contributed to the lower event rate.
Our study has several limitations. First, we used a radiological surrogate marker rather than clinical events as the major end points of this study. The findings of this study require testing with a much larger sample size and longer follow-up period evaluating clinical events. Second, the progression of symptomatic ICAS was observed in the cilostazol group as expected; however, in the clopidogrel group, the incidence was less than expected at 15.5%, resulting in an underpowered result for the study. If the study had been powered for a smaller difference, then it may have turned out positive for cilostazol regarding the primary end point. Third, because our study was based on MRI surrogate end points, we could not evaluate subjects who did not undergo follow-up MRI scanning. This gives the possibility of bias, although no difference was seen in the characteristics of dropout patients between groups. Most of the dropouts occurred in the beginning of the study, and withdrawals were mostly attributable to headache or exclusion criteria violation, both of which are unrelated to the end points.
This trial failed to show a significant difference in preventing progression of ICAS and new ischemic lesions between the 2 combination antiplatelet therapies in patients with symptomatic ICAS. However, the favorable changes in progression of ICAS, lipoprotein profiles, and a trend toward lesser hemorrhagic complication in the aspirin plus cilostazol group suggest the possibility of its implication as a long-term therapy in symptomatic ICAS. Larger clinical trials will further elucidate the long-term benefits of combination antiplatelet therapies.
Sources of Funding
Korea Otsuka Pharmaceutical (KOP) Company, Korea Otsuka International Asia, and Arab Co Ltd provided financial support for this study. They played no role in protocol development, data collection, analysis, or manuscript preparation. Data collection, verification, and statistical analyses were performed at the biostatistical division of the Clinical Research Center of the Asan Medical Center (Seoul), and at the Department of Preventive Medicine of the University of Ulsan, College of Medicine (Seoul).
S.U. Kwon served on the editorial board of the Korean edition of Lancet Neurology, which is sponsored by Chongkeundang Pharmaceutical company and MD faculty, which is sponsored by MSD Korea, and served as principal investigator of 2 investigator-initiated multicenter clinical trials sponsored by Otsuka Pharmaceutical company, and received funds from Ministry of Health, Welfare, and Family Affairs, Republic of Korea (A060171), and honoraria from MSD, Astrazeneka, Pfizer, BMS, Sanof-Aventis, Janssen, Handok, Norvatis, Korea Otsuka, Donga and Boryeung Pharmaceutical Companies, and SK Chemicals. The honoraria did not exceed $3000 US per year per company.
K.S. Hong is involved in the design and/or as a site investigator of multicenter clinical trials sponsored by Korea Otsuka, Boryung, and Norvartis Korea, and received lecture honoraria from Sanofi-Aventis (modest).
J.M. Park served on the editorial board of MD faculty sponsored by MSD Korea and received research grants from Eisai Korea, Janssen Korea, Sanofi-Aventis, and Pfizer, and honoraria from MSD, Astrazeneca, Pfizer, Sanof-Aventis, Norvatis, and Korea Otsuka. The honoraria did not exceed $3000 US per year per company.
D.W. Kang received honoraria from Korea Otsuka. The honoraria did not exceed $3000 US per year per company.
Y.J. Cho is involved in the design and is a site investigator of multicenter clinical trials sponsored by SK Chemical, Korea Otsuka, Sanofi-Aventis Korea, and Novartis Korea, and received honoraria from Astrazeneka and Pfizer. The honoraria did not exceed $1000 US per year per company.
K.H. Yu served on the editorial board of the Korean edition of Lancet Neurology, which is sponsored by Chongkeundang Pharmaceutical company and received funds from Ministry of Health, Welfare, and Family Affairs, and Republic of Korea, and honoraria from MSD, Astrazeneka, Pfizer, BMS, Sanof-Aventis, Janssen, Norvatis, Korea Otsuka, and Daewoong Pharmaceutical Companies. The honoraria did not exceed $3000 US per year per company.
S.H. Lee served on the editorial board of the Korean edition of Lancet Neurology, which is sponsored by Chongkeundang Pharmaceutical company, received consultation fees from Sanofi-Aventis Korea, received funds from Sanofi-Aventis Korea, and received honoraria from Sanof-Aventis Korea and Korea Otsuka. The honoraria did not exceeding $3000 US per year per company.
B.C. Lee served as principal investigator of 3 multicenter clinical trials sponsored by Norvatis, Servier, and Beringher-Ingelheim, received funds from Ministry of Health, Welfare, and Family Affairs, Republic of Korea (A060171), and received honoraria from Beringher-Ingelheim, Astrazeneka, Pfizer, and BMS. The honoraria did not exceed $3000 US per year per company.
H.Y. Kim served as a coinvestigator of multicenter clinical trials sponsored by Otsuka Pharmaceutical, Eisai, Novartis, and Sanofi-Aventis. He received funds from National Research Foundation of Korea, and consulting fees or honoraria from Astrazeneka, Sanofi-Aventis, Eisai, Handok, and Otsuka that did not exceed $3000 US per year per company.
J.S. Kim served as a speaker or chairman in symposia sponsored by Korea Otzuka company and received travel fees and honoraria that did not exceed $3000 US.
G.M. Kim received honoraria from MSD, Astrazeneka, Pfizer, Norvatis, Korea Otsuka, Donga, Boryeung Pharmaceutical Companies, and SK Chemicals. The honoraria did not exceed $3000 US per year per company. G.M. Kim served on the editorial board of the Korean edition of Lancet Neurology, which is sponsored by Chongkeundang Pharmaceutical.
H.J. Bae received lecture honoraria from Korea Otsuka that did not exceed $3000 US.
K.B. Lee provided consultancy service for Korea Otsuka and received honoraria from Astra-Zeneka, Pfizer, Sanofi-Aventis, Norvatis, Korea Otsuka, Jeil, Beyer, and Boeringer-Ingelheim Pharmaceutical Companies. The honoraria did not exceed $3000 US per year per company.
Louis Caplan, MD, was the Guest Editor for this paper.
The online-only Data Supplement is available at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.609370/-/DC1.
- Received November 22, 2010.
- Accepted April 8, 2011.
- © 2011 American Heart Association, Inc.
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