Safety Evaluation of Substituting Clopidogrel for Ticlopidine in Japanese Patients with Ischemic Stroke—Hiroshima Ticlopidine, Clopidogrel Safe Exchange Trial Tatsuo Kohriyama, MD, PhD,* Chie Mihara, MD, PhD,† Takakazu Yokoyama, MD, PhD,† Tsuyoshi Torii, MD, PhD,‡ Atsuo Yamada, MD, PhD,‡ Kazuhiro Takamatsu, MD,x Taisei Ota, MD,x Kouichi Noda, MD, PhD,jj Satoshi Kataoka, MD, PhD,{ Hijiri Ito, MD, PhD,# Eiichi Nomura, MD, PhD,** Toshiho Ohtsuki, MD, DMSc,* Shiro Aoki, MD, PhD,* Tomohisa Nezu, MD,* Ikuko Takeda, MD,* Tomoya Mukai, MD,* Naohisa Hosomi, MD, PhD,* and Masayasu Matsumoto, MD, PhD*
Background: Clopidogrel is sometimes substituted for ticlopidine when cerebrovascular or cardiovascular patients develop hematologic abnormalities after ticlopidine treatment. However, the adverse event rate after the substitution to clopidogrel remains undetermined. Therefore, in this study, we aimed to define the risk of adverse events after substituting clopidogrel for ticlopidine without a washout period. Methods: We prospectively enrolled patients older than 20 years who had a history of noncardioembolic strokes, including transient ischemic attacks, were treated with ticlopidine for at least 6 months. This study was conducted from August 26, 2008, when the first patient was enrolled, to January 16, 2012, the date of the last patient examination, at 8 active stroke centers in Hiroshima, Japan. We excluded patients who had severe disabilities, evidence of cardioembolic stroke, or history of a bleeding event. Each patient received clopidogrel (either 50 mg or 75 mg) once a day in place of ticlopidine without a washout period. Follow-up exams were scheduled within 12 months after the medication substitution. The primary end point of this study was adverse events of interest, including clinically significant reduced blood cell counts, hepatic dysfunction, bleeding, and other serious side effects. Results: In this study, 110 patients were enrolled and analyzed in an intent-to-treat manner (modified intent to treat). Within the scheduled follow-up periods, 9 primary end point events were observed in separate patients. The primary end point events were observed at a rate of 8.4% per year (Kaplan–Meier method). At the time of enrolment, 16 patients met the exclusion criteria, of which 8 recovered from their abnormal hematologic results to the institutional normal limit after the substitution of ticlopidine for clopidogrel (57.4% per year). Conclusions: The adverse
From the Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima; †Department of Neurosurgery, Yokoyama Hospital, Kure; ‡Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure; xDepartment of Neurology, Brain Attack Center Ota Memorial Hospital, Fukuyama; jjDepartment of Neurology, National Hospital Organization Higashihiroshima Medical Center, Higashihiroshima; {Department of Neurology, Chugoku Rousai Hospital, Kure; #Department of Neurology, Mifukai Vihara Hananosato Hospital, Miyoshi; and **Department of Neurology, Suiseikai Kajikawa Hospital, Hiroshima, Japan.
Received November 25, 2013; revision received December 9, 2013; accepted December 16, 2013. This study was partially supported by Sanofi K.K., Tokyo, Japan. Address correspondence to Naohisa Hosomi, MD, PhD, FAHA, Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail: nhosomi@ hiroshima-u.ac.jp. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.025
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event rates after the substitution of ticlopidine for clopidogrel is similar to the adverse event rates of patients who were initially treated with clopidogrel. The substitution of clopidogrel for ticlopidine should be considered for patients who develop hematologic abnormalities from ticlopidine treatment. Key Words: Ischemic stroke—clopidogrel—ticlopidine—safety event. Ó 2014 by National Stroke Association
Introduction In Japan, before the approval of clopidogrel in 2006, ticlopidine had a long history of use for the secondary prevention of noncardioembolic ischemic stroke. Ticlopidine is still used to prevent noncardioembolic ischemic stroke in patients who do not exhibit adverse events from this medication in Japan. Additionally, ticlopidine is listed in the Japanese guidelines for the management of stroke and is recommended to prevent the recurrence of noncardioembolic ischemic stroke (grade B).1 Previous reports indicate that ticlopidine can cause serious adverse events, including agranulocytosis, thrombotic thrombocytopenic purpura, or hepatic dysfunction.2 Moreover, hepatic disorders caused by ticlopidine are observed more frequently in the Japanese than in other ethnicities.3 The onset of hepatotoxicity is variable and ranges from 1 week to 6 months, although in most patients the onset occurs between 2 and 12 weeks after initiation of ticlopidine treatment. Nevertheless, adverse events can occur after several years of ticlopidine treatment. Clopidogrel is also a thienopyridine antiplatelet agent. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events study, clopidogrel reduced the relative risk of ischemic stroke, myocardial infarction, or vascular death by 8.7% in 19,185 patients, with a mean follow-up time of 1.91 years.4 Treatment with clopidogrel results in a lower cumulative incidence of adverse events than ticlopidine.5 Therefore, substitution of clopidogrel for ticlopidine might be effective when an adverse event is observed in cerebrovascular or cardiovascular patients treated with ticlopidine. However, the rate of adverse events after switching to clopidogrel is currently unknown. In the clopidogrel trial in patients with elective percutaneous coronary intervention for stable angina and old myocardial infarction (CLEAN) trial, the adverse events after treatment with clopidogrel or after switching from ticlopidine to clopidogrel at 12 weeks were evaluated.6 The CLEAN trial revealed that in patients initially treated with clopidogrel, the adverse event rate was observed in 19 of 158 patients (12.0%) after a 52-week follow-up time. Among the patients whose medication was switched to clopidogrel from ticlopidine after 12 weeks of treatment, adverse events were observed in 8 of 143 patients (5.6%) 40 weeks after the substitution. These rates are in agreement with the adverse event rate (12 of 158 patients [7.6%]) that is observed between 13 and 52 weeks after
initiation of clopidogrel treatment. Therefore, in this study, we aimed to investigate the rate of adverse events in patients with noncardioembolic strokes who were first treated with ticlopidine for at least 6 months and then were switched to clopidogrel treatment.
Materials and Methods Patients We prospectively enrolled patients (older than 20 years) who had a history of noncardioembolic strokes, including transient ischemic attack, with evidence of ischemic lesions observed by brain computed tomography or magnetic resonance imaging and who were treated with ticlopidine for at least 6 months. Diagnosis of the stroke subtype was determined at the patients’ discharges based on the Trial of Org 10172 in Acute Stroke Treatment criteria.7 This study was conducted from August 26, 2008, when the first patient enrolled, to January 16, 2012, the date of the last patient visit, at 8 active stroke centers in Hiroshima, Japan. We excluded patients who had a severe disability, evidence or cause of cardioembolic stroke, or history of a bleeding event. In addition, patients were excluded when they exhibited reduced blood cell counts (white blood cells, neutrophils, or platelets), renal dysfunction, history of allergy to medications, or hepatic dysfunction determined by the following liver function tests: aspartate aminotransferase, alanine transaminase, g-glutamyltranspeptitase, alkaline phosphatase, lactate dehydrogenase, or total bilirubin (Table 1). The patients who enrolled in this study provided their informed consent to participate. Our protocol was approved by the ethics review committee of each hospital according to the guidelines of the national government based on the 1964 Helsinki Declaration.
Study Design Each patient was switched to 50 or 75 mg of clopidogrel once a day instead of ticlopidine with no washout period. Follow-up examinations were performed at 1, 3, 6, and 12 months after the medication change. The primary end points of this study were the occurrence of specific adverse events, including clinically significant reduced blood cell counts, hepatic dysfunction, bleeding, and other serious side effects (Table 2). Those laboratory value criteria were decided based on the notice released in June
SAFETY EVALUATION OF SUBSTITUTING CLOPIDOGREL FOR TICLOPIDINE
Table 1. The exclusion criteria Component class Reduced blood cell counts Hepatic dysfunction
Definition White blood cells , 3000/mm3 Neutrophils , 1500/mm3 Platelets , 100,000/mm3 AST $ 50 IU/L or 1.25 3 upper INL ALT $ 50 IU/L or 1.25 3 upper INL g-GTP $ 1.5 3 upper INL ALP $ 1.25 3 upper INL LDH $ 1.5 3 upper INL Total bilirubin $ 1.6 mg/dL
Renal dysfunction History of allergy to medication Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; g-GTP, g-glutamyltranspeptitase; INL, institutional normal limit; LDH, lactate dehydrogenase.
1992 by Ministry of Health, Labour, and Welfare of Japan. The secondary end points included recurrent ischemic stroke and a major adverse cardiac or cerebrovascular event.
The data are expressed as the medians (minimum and maximum) for continuous variables and as the freTable 2. Primary end points Component class Reduced blood cell counts Hepatic dysfunction
Bleeding
Serious side effects
quencies and percentages for discrete variables. The cumulative incidence of the first adverse event of interest and the recovery from the exclusion criteria were estimated using the Kaplan–Meier method. The differences in categorical variables among the groups were examined using Fisher exact test. The statistical analyses were performed using JMP software version 10.0 for Macintosh (SAS, Cary, NC). All the analyses were 2 tailed, and a value of P less than .05 was considered statistically significant.
Results Of the 111 patients enrolled in this study, 1 patient did not return to his hospital and did not undergo a follow-up examination. Therefore, this patient was excluded from the analysis. The analysis was performed using results from the remaining 110 patients in an intent-to-treat manner (modified intent to treat). The participant characteristics are presented in Table 3. The median age of the participants was 74 years. The ischemic stroke profiles of the participants included 42.7% who had a largeartery atherosclerosis stroke, 46.4% who had a smallTable 3. Participant characteristics Factors
Statistical Analyses
Definition White blood cells , 3000/mm3 Neutrophils , 1500/mm3 Platelets , 100,000/mm3 AST $ 100 IU/L or 2.5 3 upper INL ALT $ 100 IU/L or 2.5 3 upper INL g-GTP $ 150 IU/L or 4 3 upper INL ALP $ 2.5 3 upper INL Total bilirubin $ 3.0 mg/dL Icterus Symptomatic intracranial bleeding Bleeding requiring hospitalization for treatment Any cause of death Any cause of hospitalization Irreversible impairment
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; g-GTP, g-glutamyltranspeptitase; INL, institutional normal limit; LDH, lactate dehydrogenase.
3
N 5 110
Median age, y (range) 74 (53, 100) Female, n (%) 41 (37.3) Hypertension, n (%) 78 (70.9) Diabetes mellitus, n (%) 18 (16.4) Dyslipidemia, n (%) 41 (37.3) Smoking, n (%) 30 (27.3) Alcohol consumption, n (%) 40 (36.4) Ischemic stroke profiles (TOAST classification) Large-artery atherosclerosis 47 (42.7) stroke, n (%) 51 (46.4) Small-vessel occlusion stroke, n (%) Stroke of other determined 5 (4.5) etiology, n (%) 2 (1.8) Stroke of undetermined etiology, n (%) Transient ischemic attack, 5 (4.5) n (%) Latest incident Incipience, n (%) 78 (71.6) Recurrence, n (%) 21 (19.3) Duration after onset Within 1 y, n (%) 5 (4.5) .1 y, n (%) 102 (92.7) Clopidogrel, 25/50/75 (mg), n 5/39/66 Concomitant antithrombotic agent Oral anticoagulant, n (%) 1 (.9) Antiplatelet, n (%) 19 (17.3) Abbreviation: TOAST, Trial of Org 10172 in Acute Stroke Treatment.
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Table 4. Primary end points—modified intent-to-treat population Component class Reduced blood cell counts Hepatic dysfunction
Bleeding Serious side effects Total
Definition
n
White blood cells , 3000/mm3 Neutrophils , 1500/mm3 Total in component AST $ 100 IU/L or 2.5 3 upper INL ALT $ 100 IU/L or 2.5 3 upper INL Icterus Total in component Symptomatic intracranial bleeding Total in component Any cause of hospitalization (cholecystitis and drug eruption) Total in component
1 1 2 1 1 1 3 2 2 2 2 9
Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; INL, institutional normal limit; LDH, lactate dehydrogenase.
0.20 0.18 Cumulative Incidence
vessel occlusion stroke, 4.5% who had a stroke of other determined etiology, 1.8% who had a stroke of undetermined etiology, and 4.5% who had a transient ischemic attack. There were 65 patients who were treated with 200 mg of ticlopidine and 45 patients who were treated with 100 mg of ticlopidine before the medication substitution. Among the patients who were treated with 200 mg of ticlopidine, 52 patients were switched to 75 mg of clopidogrel, and 13 patients were switched to 50 mg of clopidogrel. In the patients initially treated with 100 mg of ticlopidine, 14 patients were switched to 75 mg of clopidogrel, 26 patients were switched to 50 mg of clopidogrel, and 5 patients were switched to 25 mg of clopidogrel. At the time of enrolment, 16 patients met the exclusion criteria and were excluded from the analysis. During the scheduled follow-up periods, primary end point events were observed in 9 different patients (Table 4). A Kaplan–Meier curve was constructed of the cumulative incidence of the first occurrence of an adverse event of interest (Fig 1). Primary end point events were observed at a rate of 8.4% per year using the Kaplan–Meier method. There were 2 patients who developed intracerebral hemorrhages during the follow-up period. Two patients with reduced blood cell counts, 3 patients with hepatic dysfunction, and 1 patient with cholecystitis recovered from their adverse events without discontinuation of clopidogrel. A patient who exhibited drug eruption 16 days after starting 75 mg of clopidogrel recovered after discontinuation for 2 weeks. For the secondary end points, 1 patient developed a recurrence of ischemic stroke and 1 patient exhibited
0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0 0
2
Number at Risk 110 109 106 103
4
6 months 99 98
8
10
12 96
Figure 1. Time to the first adverse event of interest. Kaplan–Meier curve in the modified intent-to-treat population.
myocardial infarction within the scheduled follow-up period. There were 2 major adverse cardiac and cerebrovascular events, which were defined as all-cause mortality, acute myocardial infarction, revascularization, stent thrombosis, or ischemic stroke. This corresponded to a rate of 2.0% per year according to the Kaplan–Meier method. Of the 16 patients who met the exclusion criteria, 1 patient had low neutrophil levels, 2 patients had high aspartate aminotransferase, 5 patients had high alanine transaminase, 10 patients had high g-glutamyltranspeptitase, and 3 patients had high alkaline phosphatase (Table 5). Before the drug substitution, 8 of the patients who met exclusion criteria were treated with 200 mg of ticlopidine, and the other 8 patients were treated with 100 mg of ticlopidine. Eight patients with abnormal hematologic results returned to their institutional normal limits after the switch to clopidogrel (57.4% according to the Kaplan–Meier method, Fig 2). Of these recovered patients, the abnormalities were reversed within 6 (median; range: 1-12) months after the medication substitution. In the 8 patients whose abnormal hematologic results were reversed, 4 patients (50.0%) developed abnormal blood test results after the start of ticlopidine treatment. This result was higher than the patients whose abnormal hematologic results were not reversed (1 of 8 [12.5%], P 5 .28). Additionally, in the present study, the 8 patients who did not recover included a patient with hepatitis C and daily alcohol consumption, a patient with chronic hepatitis, a patient showed low neutrophil caused by phenytoin, and 2 other patients with daily alcohol consumption. Seven of those patients were treated with ticlopidine for more than 3 years; 5 of the 8 patients were treated with 200 mg of ticlopidine and 3 were treated with 100 mg of ticlopidine.
Discussion In this study, each patient was switched to treatment with clopidogrel instead of ticlopidine without a washout period. During the follow-up period, adverse events of interest were observed at a rate of 8.4% per year. Of the
SAFETY EVALUATION OF SUBSTITUTING CLOPIDOGREL FOR TICLOPIDINE
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Table 5. The patients who met exclusion criteria and their recovery Component class
Definition
N
R
NR
Reduced blood cell counts
Neutrophils , 1500/mm3 Total in component AST $ 50 IU/L or 1.25 3 upper INL ALT $ 50 IU/L or 1.25 3 upper INL g-GTP $ 1.5 3 upper INL ALP $ 1.25 3 upper INL Total in component
1 1 2 5 10 3 16 16
0 0 2 2 4 2 8 8
1 1 0 3 6 1 8 8
Hepatic dysfunction
Per participant
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; g-GTP, g-glutamyltranspeptitase; INL, institutional normal limit; NR, not recovered; R, recovered.
patients who exhibited reduced blood cell counts or hepatic dysfunction after the medication substitution, 57.4% recovered to the institutional normal limits after the switch to clopidogrel. In this study, an intent-to-treat analysis was performed on 16 patients who met the exclusion criteria at enrolment because a medication substitution is recommended for patients who develop abnormalities from this medication. The cumulative incidence of Japanese patients treated with clopidogrel that experienced at least 1 adverse event of interest within the first 52 weeks was 4.8% to 23.8%.5,6,8,9 These results are in agreement with our observed adverse event of interest rate of 8.4% per year. Although we cannot directly compare these results because of differences in the study protocols, the adverse event rate appears higher in the patients who were switched from ticlopidine to clopidogrel during the observation period compared with the patients who were treated with clopidogrel or ticlopidine throughout the period.5,6 According to our results, the adverse event rate after abrupt exchange from ticlopidine to clopidogrel was similar to the adverse event rate after initial clopidogrel treatment. Therefore, the adverse event rate after the medication substitution may result from an additive adverse event rate derived from treatment with both ticlopidine and clopidogrel. According to the results of the CLEAN trial, the adverse events of interest rate occurred less frequently when clopidogrel was substituted for ticlopidine (5.6% [8 of 143]
Recovery from excluson criteria
0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0 0 Number at Risk
Figure 2.
16
2 16
4 12
6 months 10
8
10
12 7
Kaplan–Meier curve of the recovery from the exclusion criteria.
for 40 weeks), compared with the rate when clopidogrel was started at the time of enrolment, 12.0% (19 of 158) for 52 weeks. In our study, the adverse events of interest occurred in 8.4% of patients (9 of 110) for the 12-month follow-up period. Both adverse event rates were in the range of the cumulative incidence of clopidogrel for the first year. In the present study, 2 patients developed intracranial hemorrhages during the observation period. One patient was an 81-year-old man who had an ischemic stroke of other determined etiology and was treated with 75 mg of clopidogrel adding 100 mg of aspirin 3 months after the exchange from 200 mg of ticlopidine. He developed an intracranial hemorrhage 6 months after the medication substitution. His blood pressure was 160/60 mm Hg at his most recent examination before the incident. The other patient was a 63-year-old men with an atherothrombotic stroke who was treated with 50 mg of clopidogrel after being treated with 100 mg of ticlopidine. He developed an intracranial hemorrhage 3 months after the medication substitution. His blood pressure was 136/84 mm Hg at his most recent examination before the incident. Both patients were hypertensive. In the Clopidogrel Two Doses Comparative 1-Year Assessment of Safety and Efficacy study, intracranial hemorrhage was observed in .18% of patients.9 The Bleeding with Antithrombotic Therapy Study indicated that both systolic blood pressure of 130 mm Hg or more and diastolic blood pressure of 81 mm Hg or more were independently associated with intracranial hemorrhage even after adjustment for the intracranial hemorrhage predictors.10 Two intracranial hemorrhagic patients exhibited blood pressures greater than 130/81 mm Hg at their most visits before the incidents in the present study. It is important to reduce the blood pressures of such patients to reduce the risk of intracranial hemorrhage. In the Perindopril Protection Against Recurrent Stroke Study trial, the incidence of hemorrhagic stroke was reduced 50% by an average 9 mm Hg reduction in systolic blood pressure and 76% by a 12 mm Hg reduction (absolute rates of .6% per year to .3% per year and .2% per year, respectively).11 Additionally, 1 of 2 intracranial hemorrhagic patients
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had a combined administration of aspirin to clopidogrel. It has been reported that dual antiplatelet therapy increases a risk of intracranial hemorrhage approximately twice.12 Therefore, we should be more careful to use dual antiplatelet therapy in ischemic stroke patients. There were 16 patients with reduced blood cell counts or hepatic dysfunction at the time of enrolment for this study. Of these patients, 8 recovered from their hematologic abnormalities after the switch from ticlopidine to clopidogrel. Generally, it is recommended to change or stop the suspected medication when a hematologic abnormality is observed with treatment. The patients who did not recover from the reduced blood cell counts or hepatic dysfunction might have another underlying cause of their abnormal values. In conclusion, the substitution of ticlopidine to clopidogrel should be considered when patients develop hematologic abnormalities from ticlopidine treatment because our results argue that the adverse event rate after the substitution is similar to the rate of initial treatment with clopidogrel. Additionally, approximately 57.4% of patients may recover from their hematologic abnormalities after the substitution. Acknowledgment: We would like to show our appreciation to all study participants and participating physicians and Ms Hisami Hashida, Ms Chisato Sugimoto, and Ms Eri Kashima for their assistance in the preparation and execution of this study.
3.
4.
5.
6.
7.
8.
9.
10.
11.
References 1. Kern R, Nagayama M, Toyoda K, et al. Comparison of the European and Japanese guidelines for the management of ischemic stroke. Cerebrovasc Dis 2013;35:402-418. 2. Weisberg LA. The efficacy and safety of ticlopidine and aspirin in non-whites: analysis of a patient subgroup
12.
from the Ticlopidine Aspirin Stroke Study. Neurology 1993;43:27-31. Mizushima M, Iwata N, Fujimoto TT, et al. Patient characteristics in ticlopidine hydrochloride-induced liver injury: case-control study. Hepatol Res 2005;33:234-240. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339. Fukuuchi Y, Tohgi H, Okudera T, et al. A randomized, double-blind study comparing the safety and efficacy of clopidogrel versus ticlopidine in Japanese patients with noncardioembolic cerebral infarction. Cerebrovasc Dis 2008;25:40-49. Isshiki T, Kimura T, Ueno T, et al. Clopidogrel trial in patients with elective percutaneous coronary intervention for stable angina and old myocardial infarction (CLEAN). Int Heart J 2012;53:91-101. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41. Shigematsu H, Komori K, Tanemoto K, et al. Clopidogrel for Atherothrombotic Event Management in Patients with Peripheral Arterial Disease (COOPER) study: safety and efficacy of clopidogrel versus ticlopidine in Japanese patients. Ann Vasc Dis 2012;5:364-375. Uchiyama S, Tanahashi N, Minematsu K, et al. Clopidogrel two doses comparative 1-year assessment of safety and efficacy (COMPASS) study in Japanese patients with ischemic stroke. Cerebrovasc Dis 2012;34:229-239. Toyoda K, Yasaka M, Uchiyama S, et al. Blood pressure levels and bleeding events during antithrombotic therapy: the Bleeding with Antithrombotic Therapy (BAT) Study. Stroke 2010;41:1440-1444. Chapman N, Huxley R, Anderson C, et al. Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS trial. Stroke 2004; 35:116-121. Toyoda K, Yasaka M, Iwade K, et al. Dual antithrombotic therapy increases severe bleeding events in patients with stroke and cardiovascular disease: a prospective, multicenter, observational study. Stroke 2008;39:1740-1745.
Background: Clopidogrel is sometimes substituted for ticlopidine when cerebrovascular or cardiovascular patients develop hematologic abnormalities after ticlopidine treatment. However, the adverse event rate after the substitution to clopidogrel remains undetermined. Therefore, in this study, we aimed to define the risk of adverse events after substituting clopidogrel for ticlopidine without a washout period. Methods: We prospectively enrolled patients older than 20 years who had a history of noncardioembolic strokes, including transient ischemic attacks, were treated with ticlopidine for at least 6 months. This study was conducted from August 26, 2008, when the first patient was enrolled, to January 16, 2012, the date of the last patient examination, at 8 active stroke centers in Hiroshima, Japan. We excluded patients who had severe disabilities, evidence of cardioembolic stroke, or history of a bleeding event. Each patient received clopidogrel (either 50 mg or 75 mg) once a day in place of ticlopidine without a washout period. Follow-up exams were scheduled within 12 months after the medication substitution. The primary end point of this study was adverse events of interest, including clinically significant reduced blood cell counts, hepatic dysfunction, bleeding, and other serious side effects. Results: In this study, 110 patients were enrolled and analyzed in an intent-to-treat manner (modified intent to treat). Within the scheduled follow-up periods, 9 primary end point events were observed in separate patients. The primary end point events were observed at a rate of 8.4% per year (Kaplan–Meier method). At the time of enrolment, 16 patients met the exclusion criteria, of which 8 recovered from their abnormal hematologic results to the institutional normal limit after the substitution of ticlopidine for clopidogrel (57.4% per year). Conclusions: The adverse
From the Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima; †Department of Neurosurgery, Yokoyama Hospital, Kure; ‡Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure; xDepartment of Neurology, Brain Attack Center Ota Memorial Hospital, Fukuyama; jjDepartment of Neurology, National Hospital Organization Higashihiroshima Medical Center, Higashihiroshima; {Department of Neurology, Chugoku Rousai Hospital, Kure; #Department of Neurology, Mifukai Vihara Hananosato Hospital, Miyoshi; and **Department of Neurology, Suiseikai Kajikawa Hospital, Hiroshima, Japan.
Received November 25, 2013; revision received December 9, 2013; accepted December 16, 2013. This study was partially supported by Sanofi K.K., Tokyo, Japan. Address correspondence to Naohisa Hosomi, MD, PhD, FAHA, Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail: nhosomi@ hiroshima-u.ac.jp. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.025
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event rates after the substitution of ticlopidine for clopidogrel is similar to the adverse event rates of patients who were initially treated with clopidogrel. The substitution of clopidogrel for ticlopidine should be considered for patients who develop hematologic abnormalities from ticlopidine treatment. Key Words: Ischemic stroke—clopidogrel—ticlopidine—safety event. Ó 2014 by National Stroke Association
Introduction In Japan, before the approval of clopidogrel in 2006, ticlopidine had a long history of use for the secondary prevention of noncardioembolic ischemic stroke. Ticlopidine is still used to prevent noncardioembolic ischemic stroke in patients who do not exhibit adverse events from this medication in Japan. Additionally, ticlopidine is listed in the Japanese guidelines for the management of stroke and is recommended to prevent the recurrence of noncardioembolic ischemic stroke (grade B).1 Previous reports indicate that ticlopidine can cause serious adverse events, including agranulocytosis, thrombotic thrombocytopenic purpura, or hepatic dysfunction.2 Moreover, hepatic disorders caused by ticlopidine are observed more frequently in the Japanese than in other ethnicities.3 The onset of hepatotoxicity is variable and ranges from 1 week to 6 months, although in most patients the onset occurs between 2 and 12 weeks after initiation of ticlopidine treatment. Nevertheless, adverse events can occur after several years of ticlopidine treatment. Clopidogrel is also a thienopyridine antiplatelet agent. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events study, clopidogrel reduced the relative risk of ischemic stroke, myocardial infarction, or vascular death by 8.7% in 19,185 patients, with a mean follow-up time of 1.91 years.4 Treatment with clopidogrel results in a lower cumulative incidence of adverse events than ticlopidine.5 Therefore, substitution of clopidogrel for ticlopidine might be effective when an adverse event is observed in cerebrovascular or cardiovascular patients treated with ticlopidine. However, the rate of adverse events after switching to clopidogrel is currently unknown. In the clopidogrel trial in patients with elective percutaneous coronary intervention for stable angina and old myocardial infarction (CLEAN) trial, the adverse events after treatment with clopidogrel or after switching from ticlopidine to clopidogrel at 12 weeks were evaluated.6 The CLEAN trial revealed that in patients initially treated with clopidogrel, the adverse event rate was observed in 19 of 158 patients (12.0%) after a 52-week follow-up time. Among the patients whose medication was switched to clopidogrel from ticlopidine after 12 weeks of treatment, adverse events were observed in 8 of 143 patients (5.6%) 40 weeks after the substitution. These rates are in agreement with the adverse event rate (12 of 158 patients [7.6%]) that is observed between 13 and 52 weeks after
initiation of clopidogrel treatment. Therefore, in this study, we aimed to investigate the rate of adverse events in patients with noncardioembolic strokes who were first treated with ticlopidine for at least 6 months and then were switched to clopidogrel treatment.
Materials and Methods Patients We prospectively enrolled patients (older than 20 years) who had a history of noncardioembolic strokes, including transient ischemic attack, with evidence of ischemic lesions observed by brain computed tomography or magnetic resonance imaging and who were treated with ticlopidine for at least 6 months. Diagnosis of the stroke subtype was determined at the patients’ discharges based on the Trial of Org 10172 in Acute Stroke Treatment criteria.7 This study was conducted from August 26, 2008, when the first patient enrolled, to January 16, 2012, the date of the last patient visit, at 8 active stroke centers in Hiroshima, Japan. We excluded patients who had a severe disability, evidence or cause of cardioembolic stroke, or history of a bleeding event. In addition, patients were excluded when they exhibited reduced blood cell counts (white blood cells, neutrophils, or platelets), renal dysfunction, history of allergy to medications, or hepatic dysfunction determined by the following liver function tests: aspartate aminotransferase, alanine transaminase, g-glutamyltranspeptitase, alkaline phosphatase, lactate dehydrogenase, or total bilirubin (Table 1). The patients who enrolled in this study provided their informed consent to participate. Our protocol was approved by the ethics review committee of each hospital according to the guidelines of the national government based on the 1964 Helsinki Declaration.
Study Design Each patient was switched to 50 or 75 mg of clopidogrel once a day instead of ticlopidine with no washout period. Follow-up examinations were performed at 1, 3, 6, and 12 months after the medication change. The primary end points of this study were the occurrence of specific adverse events, including clinically significant reduced blood cell counts, hepatic dysfunction, bleeding, and other serious side effects (Table 2). Those laboratory value criteria were decided based on the notice released in June
SAFETY EVALUATION OF SUBSTITUTING CLOPIDOGREL FOR TICLOPIDINE
Table 1. The exclusion criteria Component class Reduced blood cell counts Hepatic dysfunction
Definition White blood cells , 3000/mm3 Neutrophils , 1500/mm3 Platelets , 100,000/mm3 AST $ 50 IU/L or 1.25 3 upper INL ALT $ 50 IU/L or 1.25 3 upper INL g-GTP $ 1.5 3 upper INL ALP $ 1.25 3 upper INL LDH $ 1.5 3 upper INL Total bilirubin $ 1.6 mg/dL
Renal dysfunction History of allergy to medication Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; g-GTP, g-glutamyltranspeptitase; INL, institutional normal limit; LDH, lactate dehydrogenase.
1992 by Ministry of Health, Labour, and Welfare of Japan. The secondary end points included recurrent ischemic stroke and a major adverse cardiac or cerebrovascular event.
The data are expressed as the medians (minimum and maximum) for continuous variables and as the freTable 2. Primary end points Component class Reduced blood cell counts Hepatic dysfunction
Bleeding
Serious side effects
quencies and percentages for discrete variables. The cumulative incidence of the first adverse event of interest and the recovery from the exclusion criteria were estimated using the Kaplan–Meier method. The differences in categorical variables among the groups were examined using Fisher exact test. The statistical analyses were performed using JMP software version 10.0 for Macintosh (SAS, Cary, NC). All the analyses were 2 tailed, and a value of P less than .05 was considered statistically significant.
Results Of the 111 patients enrolled in this study, 1 patient did not return to his hospital and did not undergo a follow-up examination. Therefore, this patient was excluded from the analysis. The analysis was performed using results from the remaining 110 patients in an intent-to-treat manner (modified intent to treat). The participant characteristics are presented in Table 3. The median age of the participants was 74 years. The ischemic stroke profiles of the participants included 42.7% who had a largeartery atherosclerosis stroke, 46.4% who had a smallTable 3. Participant characteristics Factors
Statistical Analyses
Definition White blood cells , 3000/mm3 Neutrophils , 1500/mm3 Platelets , 100,000/mm3 AST $ 100 IU/L or 2.5 3 upper INL ALT $ 100 IU/L or 2.5 3 upper INL g-GTP $ 150 IU/L or 4 3 upper INL ALP $ 2.5 3 upper INL Total bilirubin $ 3.0 mg/dL Icterus Symptomatic intracranial bleeding Bleeding requiring hospitalization for treatment Any cause of death Any cause of hospitalization Irreversible impairment
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; g-GTP, g-glutamyltranspeptitase; INL, institutional normal limit; LDH, lactate dehydrogenase.
3
N 5 110
Median age, y (range) 74 (53, 100) Female, n (%) 41 (37.3) Hypertension, n (%) 78 (70.9) Diabetes mellitus, n (%) 18 (16.4) Dyslipidemia, n (%) 41 (37.3) Smoking, n (%) 30 (27.3) Alcohol consumption, n (%) 40 (36.4) Ischemic stroke profiles (TOAST classification) Large-artery atherosclerosis 47 (42.7) stroke, n (%) 51 (46.4) Small-vessel occlusion stroke, n (%) Stroke of other determined 5 (4.5) etiology, n (%) 2 (1.8) Stroke of undetermined etiology, n (%) Transient ischemic attack, 5 (4.5) n (%) Latest incident Incipience, n (%) 78 (71.6) Recurrence, n (%) 21 (19.3) Duration after onset Within 1 y, n (%) 5 (4.5) .1 y, n (%) 102 (92.7) Clopidogrel, 25/50/75 (mg), n 5/39/66 Concomitant antithrombotic agent Oral anticoagulant, n (%) 1 (.9) Antiplatelet, n (%) 19 (17.3) Abbreviation: TOAST, Trial of Org 10172 in Acute Stroke Treatment.
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Table 4. Primary end points—modified intent-to-treat population Component class Reduced blood cell counts Hepatic dysfunction
Bleeding Serious side effects Total
Definition
n
White blood cells , 3000/mm3 Neutrophils , 1500/mm3 Total in component AST $ 100 IU/L or 2.5 3 upper INL ALT $ 100 IU/L or 2.5 3 upper INL Icterus Total in component Symptomatic intracranial bleeding Total in component Any cause of hospitalization (cholecystitis and drug eruption) Total in component
1 1 2 1 1 1 3 2 2 2 2 9
Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; INL, institutional normal limit; LDH, lactate dehydrogenase.
0.20 0.18 Cumulative Incidence
vessel occlusion stroke, 4.5% who had a stroke of other determined etiology, 1.8% who had a stroke of undetermined etiology, and 4.5% who had a transient ischemic attack. There were 65 patients who were treated with 200 mg of ticlopidine and 45 patients who were treated with 100 mg of ticlopidine before the medication substitution. Among the patients who were treated with 200 mg of ticlopidine, 52 patients were switched to 75 mg of clopidogrel, and 13 patients were switched to 50 mg of clopidogrel. In the patients initially treated with 100 mg of ticlopidine, 14 patients were switched to 75 mg of clopidogrel, 26 patients were switched to 50 mg of clopidogrel, and 5 patients were switched to 25 mg of clopidogrel. At the time of enrolment, 16 patients met the exclusion criteria and were excluded from the analysis. During the scheduled follow-up periods, primary end point events were observed in 9 different patients (Table 4). A Kaplan–Meier curve was constructed of the cumulative incidence of the first occurrence of an adverse event of interest (Fig 1). Primary end point events were observed at a rate of 8.4% per year using the Kaplan–Meier method. There were 2 patients who developed intracerebral hemorrhages during the follow-up period. Two patients with reduced blood cell counts, 3 patients with hepatic dysfunction, and 1 patient with cholecystitis recovered from their adverse events without discontinuation of clopidogrel. A patient who exhibited drug eruption 16 days after starting 75 mg of clopidogrel recovered after discontinuation for 2 weeks. For the secondary end points, 1 patient developed a recurrence of ischemic stroke and 1 patient exhibited
0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0 0
2
Number at Risk 110 109 106 103
4
6 months 99 98
8
10
12 96
Figure 1. Time to the first adverse event of interest. Kaplan–Meier curve in the modified intent-to-treat population.
myocardial infarction within the scheduled follow-up period. There were 2 major adverse cardiac and cerebrovascular events, which were defined as all-cause mortality, acute myocardial infarction, revascularization, stent thrombosis, or ischemic stroke. This corresponded to a rate of 2.0% per year according to the Kaplan–Meier method. Of the 16 patients who met the exclusion criteria, 1 patient had low neutrophil levels, 2 patients had high aspartate aminotransferase, 5 patients had high alanine transaminase, 10 patients had high g-glutamyltranspeptitase, and 3 patients had high alkaline phosphatase (Table 5). Before the drug substitution, 8 of the patients who met exclusion criteria were treated with 200 mg of ticlopidine, and the other 8 patients were treated with 100 mg of ticlopidine. Eight patients with abnormal hematologic results returned to their institutional normal limits after the switch to clopidogrel (57.4% according to the Kaplan–Meier method, Fig 2). Of these recovered patients, the abnormalities were reversed within 6 (median; range: 1-12) months after the medication substitution. In the 8 patients whose abnormal hematologic results were reversed, 4 patients (50.0%) developed abnormal blood test results after the start of ticlopidine treatment. This result was higher than the patients whose abnormal hematologic results were not reversed (1 of 8 [12.5%], P 5 .28). Additionally, in the present study, the 8 patients who did not recover included a patient with hepatitis C and daily alcohol consumption, a patient with chronic hepatitis, a patient showed low neutrophil caused by phenytoin, and 2 other patients with daily alcohol consumption. Seven of those patients were treated with ticlopidine for more than 3 years; 5 of the 8 patients were treated with 200 mg of ticlopidine and 3 were treated with 100 mg of ticlopidine.
Discussion In this study, each patient was switched to treatment with clopidogrel instead of ticlopidine without a washout period. During the follow-up period, adverse events of interest were observed at a rate of 8.4% per year. Of the
SAFETY EVALUATION OF SUBSTITUTING CLOPIDOGREL FOR TICLOPIDINE
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Table 5. The patients who met exclusion criteria and their recovery Component class
Definition
N
R
NR
Reduced blood cell counts
Neutrophils , 1500/mm3 Total in component AST $ 50 IU/L or 1.25 3 upper INL ALT $ 50 IU/L or 1.25 3 upper INL g-GTP $ 1.5 3 upper INL ALP $ 1.25 3 upper INL Total in component
1 1 2 5 10 3 16 16
0 0 2 2 4 2 8 8
1 1 0 3 6 1 8 8
Hepatic dysfunction
Per participant
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; g-GTP, g-glutamyltranspeptitase; INL, institutional normal limit; NR, not recovered; R, recovered.
patients who exhibited reduced blood cell counts or hepatic dysfunction after the medication substitution, 57.4% recovered to the institutional normal limits after the switch to clopidogrel. In this study, an intent-to-treat analysis was performed on 16 patients who met the exclusion criteria at enrolment because a medication substitution is recommended for patients who develop abnormalities from this medication. The cumulative incidence of Japanese patients treated with clopidogrel that experienced at least 1 adverse event of interest within the first 52 weeks was 4.8% to 23.8%.5,6,8,9 These results are in agreement with our observed adverse event of interest rate of 8.4% per year. Although we cannot directly compare these results because of differences in the study protocols, the adverse event rate appears higher in the patients who were switched from ticlopidine to clopidogrel during the observation period compared with the patients who were treated with clopidogrel or ticlopidine throughout the period.5,6 According to our results, the adverse event rate after abrupt exchange from ticlopidine to clopidogrel was similar to the adverse event rate after initial clopidogrel treatment. Therefore, the adverse event rate after the medication substitution may result from an additive adverse event rate derived from treatment with both ticlopidine and clopidogrel. According to the results of the CLEAN trial, the adverse events of interest rate occurred less frequently when clopidogrel was substituted for ticlopidine (5.6% [8 of 143]
Recovery from excluson criteria
0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0 0 Number at Risk
Figure 2.
16
2 16
4 12
6 months 10
8
10
12 7
Kaplan–Meier curve of the recovery from the exclusion criteria.
for 40 weeks), compared with the rate when clopidogrel was started at the time of enrolment, 12.0% (19 of 158) for 52 weeks. In our study, the adverse events of interest occurred in 8.4% of patients (9 of 110) for the 12-month follow-up period. Both adverse event rates were in the range of the cumulative incidence of clopidogrel for the first year. In the present study, 2 patients developed intracranial hemorrhages during the observation period. One patient was an 81-year-old man who had an ischemic stroke of other determined etiology and was treated with 75 mg of clopidogrel adding 100 mg of aspirin 3 months after the exchange from 200 mg of ticlopidine. He developed an intracranial hemorrhage 6 months after the medication substitution. His blood pressure was 160/60 mm Hg at his most recent examination before the incident. The other patient was a 63-year-old men with an atherothrombotic stroke who was treated with 50 mg of clopidogrel after being treated with 100 mg of ticlopidine. He developed an intracranial hemorrhage 3 months after the medication substitution. His blood pressure was 136/84 mm Hg at his most recent examination before the incident. Both patients were hypertensive. In the Clopidogrel Two Doses Comparative 1-Year Assessment of Safety and Efficacy study, intracranial hemorrhage was observed in .18% of patients.9 The Bleeding with Antithrombotic Therapy Study indicated that both systolic blood pressure of 130 mm Hg or more and diastolic blood pressure of 81 mm Hg or more were independently associated with intracranial hemorrhage even after adjustment for the intracranial hemorrhage predictors.10 Two intracranial hemorrhagic patients exhibited blood pressures greater than 130/81 mm Hg at their most visits before the incidents in the present study. It is important to reduce the blood pressures of such patients to reduce the risk of intracranial hemorrhage. In the Perindopril Protection Against Recurrent Stroke Study trial, the incidence of hemorrhagic stroke was reduced 50% by an average 9 mm Hg reduction in systolic blood pressure and 76% by a 12 mm Hg reduction (absolute rates of .6% per year to .3% per year and .2% per year, respectively).11 Additionally, 1 of 2 intracranial hemorrhagic patients
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had a combined administration of aspirin to clopidogrel. It has been reported that dual antiplatelet therapy increases a risk of intracranial hemorrhage approximately twice.12 Therefore, we should be more careful to use dual antiplatelet therapy in ischemic stroke patients. There were 16 patients with reduced blood cell counts or hepatic dysfunction at the time of enrolment for this study. Of these patients, 8 recovered from their hematologic abnormalities after the switch from ticlopidine to clopidogrel. Generally, it is recommended to change or stop the suspected medication when a hematologic abnormality is observed with treatment. The patients who did not recover from the reduced blood cell counts or hepatic dysfunction might have another underlying cause of their abnormal values. In conclusion, the substitution of ticlopidine to clopidogrel should be considered when patients develop hematologic abnormalities from ticlopidine treatment because our results argue that the adverse event rate after the substitution is similar to the rate of initial treatment with clopidogrel. Additionally, approximately 57.4% of patients may recover from their hematologic abnormalities after the substitution. Acknowledgment: We would like to show our appreciation to all study participants and participating physicians and Ms Hisami Hashida, Ms Chisato Sugimoto, and Ms Eri Kashima for their assistance in the preparation and execution of this study.
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