Sarpogrelate Versus Aspirin in Secondary Prevention of Cerebral Infarction: Differential Efficacy in Diabetes?
Subgroup Analysis From S-ACCESS
Background and Purpose—The results of the Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS), a randomized double-blind study of sarpogrelate (selective 5-HT2A receptor antagonist) versus aspirin in 1510 Japanese patients, have been reported. But S-ACCESS failed to demonstrate noninferiority of sarpogrelate to aspirin for preventing the recurrence of cerebral infarction. Here we compare the characteristics of sarpogrelate and aspirin in various subgroups.
Methods—Subgroups were predefined from patients’ baseline characteristics. Hazard ratio (HR) and 95% confidence interval (CI) for sarpogrelate versus aspirin were calculated for primary (cerebral infarction) and secondary (serious vascular events) end points. Interactions between treatment effects and subgroup variables were examined by post hoc analysis.
Results—No significant difference in outcome between sarpogrelate and aspirin was found across multiple predefined subgroups. In post hoc analysis, a qualitative treatment interaction with diabetes mellitus was detected (P=0.166 for recurrence of cerebral infarction; P=0.098 for serious vascular events). HR for the recurrence of cerebral infarction with sarpogrelate versus that with aspirin was 0.87 (95% CI: 0.48 to 1.60) in diabetic patients and 1.51 (95% CI: 0.98 to 2.31) in nondiabetic patients. For serious vascular events, the corresponding HRs were 0.73 (95% CI: 0.42 to 1.25) and 1.28 (95% CI: 0.89 to 1.83).
Conclusions—No specific baseline characteristic resulting in a significant difference between the effects of sarpogrelate and aspirin was identified. Aspirin was superior in most subgroups, except diabetics. Sarpogrelate may be a useful treatment option for Japanese patients with diabetes.
Aspirin is a first-line agent for secondary prevention of cerebral infarction, but is insufficiently effective in specific populations, such as patients who are postoperative or smokers, or who have diabetes, hyperlipidemia, or unstable angina.1
Sarpogrelate is an antiplatelet agent having a selective antagonistic effect on 5-HT2A receptors. The Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS), a randomized double-blind study in 1510 Japanese patients, failed to demonstrate noninferiority of sarpogrelate to aspirin for preventing the recurrence of cerebral infarction. However, the incidence of bleeding events was significantly lower with sarpogrelate than with aspirin.2
Because aspirin has some significant disadvantages, it seemed worthwhile to evaluate sarpogrelate, which has pleiotropic actions, not only antiplatelet activity.3 Here, to examine the characteristic effects of sarpogrelate compared with aspirin, we analyzed S-ACCESS subgroups predefined according to patients’ baseline characteristics. We also assessed the consistency of the treatment effects by examining interactions.
The study design of S-ACCESS has been reported.2 Briefly, patients with cerebral infarction were randomly assigned to receive sarpogrelate (100 mg × TID, group S) or aspirin (81 mg/d, group A) on a double-blind basis. Mean duration of follow-up was 1.59 years (SD 0.88, maximum 3.37 years). The primary end point was recurrence of cerebral infarction. Clusters of serious vascular events (stroke, acute coronary syndrome, or vascular event–related death) were selected as secondary end points.
Analyses of predefined subgroups based on baseline characteristics (age, sex, presence or absence of complications [hypertension, dyslipidemia, and diabetes mellitus], first episode versus recurrence, and type of cerebral infarction) were performed for the primary and secondary end points of S-ACCESS. The complications were judged by the investigators. To assess whether the treatment effects differ among subgroup, treatment interaction for baseline characteristics was examined by post hoc analysis.
Hazard ratio (HR) and its 95% confidence interval (CI) in group S versus group A were calculated, and the log-rank test was performed, using a 2-tailed significance level of 5%. Interaction was evaluated by a test of homogeneity across strata based on the log-rank test, using a 2-tailed significance level of 20%. All analyses were conducted with SAS version 9.1 software (SAS Institute).
In S-ACCESS, 1510 patients were randomly assigned to either group S or group A; the 2 groups were well matched.2
HR and 95% CI of primary and secondary outcomes are shown in the Table. No significant difference was found between groups in any subgroup. Although in most populations the hazard of group S was higher than that of group A, in diabetics the hazard was reversed for both primary and secondary end points.
The interaction test detected heterogeneity of treatment effects only in the subgroup with diabetes mellitus (P=0.166 for recurrence of cerebral infarction; P=0.098 for occurrence of serious vascular events; Table). The Figure shows the event rates of each treatment in diabetic and nondiabetic patients. HR for the recurrence of cerebral infarction with sarpogrelate versus aspirin was 0.87 (95% CI: 0.48 to 1.60) in diabetic patients and 1.51 (95% CI: 0.98 to 2.31) in nondiabetic patients. For serious vascular events, the corresponding HRs were 0.73 (95% CI: 0.42 to 1.25) and 1.28 (95% CI: 0.89 to 1.83). A qualitative interaction was observed between treatment effect and diabetes mellitus. With regard to bleeding complication, the event rates in diabetic patients were 25/199 (12.6%) in group S and 34/222 (15.3%) in group A (P=0.50), whereas those in nondiabetic patients were 64/551 (11.6%) and 97/535 (18.1%), respectively (P<0.01). A total of 21 intracerebral hemorrhages occurred; for diabetic patients 1 in group S and 2 in group A, and for nondiabetic patients, 8 and 10, respectively.
This subgroup analysis of S-ACCESS did not identify any statistically significant difference between the effects of sarpogrelate and aspirin, though sarpogrelate tended to be inferior to aspirin, except in diabetics. Although the American Diabetes Association recommends aspirin for primary and secondary prevention in type 2 diabetic patients with cardiovascular risk factors,4 aspirin did not reduce primary cardiovascular events in Japanese diabetics.5 The treatment effect of aspirin may vary between diabetic and nondiabetic patients.6 Our results are thus consistent with clinical studies.
Our results reveal a unique feature of sarpogrelate: its hazard in diabetic patients is at as low a level as in nondiabetic patients. This finding may be attributable to the protective effect of sarpogrelate against vascular endothelial dysfunction.3 In addition, sarpogrelate was associated with fewer bleeding complications than aspirin even in diabetic patients in this study. Bleeding complication, including intracerebral hemorrhage, during antithrombotic therapy might be more common in Japanese than in Western patients.7 Given that sarpogrelate prevented secondary vascular events specifically in diabetic patients, this drug could have a role in the clinical arsenal, at least for Japanese patients.
There are limitations in our interaction analysis. First, the treatment heterogeneity for diabetes mellitus was found by post hoc analysis. Second, the finding that the effects of the 2 drugs differed between diabetic and nondiabetic patients does not necessarily mean that sarpogrelate has higher efficacy than aspirin in diabetic patients because the difference between the two drugs in diabetics was not statistically significant.
In conclusion, no specific subgroup showing a statistically significant difference between the effects of sarpogrelate and aspirin was identified. Aspirin was superior for most subgroups of patients, except diabetics. Sarpogrelate may be a useful treatment option for Japanese patients with diabetes.
Y. Shinohara, Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital; H. Tohgi, Iwate Medical University; Y. Fukuuchi, Ashikaga Red Cross Hospital; S. Uchiyama, Tokyo Women’s Medical University School of Medicine; T. Yamaguchi, National Cardiovascular Center; and S. Kobayashi, Shimane University Hospital.
E. Otomo, Yokufukai Geriatric Hospital; F. Gotoh, Keio University.
Safety Monitoring Committee
S. Hirai, Gunma University; K. Hayashi; Gunma University; and M. Fujishima; Kyusyu University.
Efficacy End Point Committee
T. Sawada, Aino Hospital; A. Terashi, Nippon Medical School; and S. Handa, Tokai University Tokyo Hospital.
K. Kondo, Mitsubishi Tanabe Pharma Corp; K. Nishimaru; Fukuoka University.
Investigators and Institutions
H. Kamiyama, Asahikawa Red Cross Hospital; K. Itoh and T. Shimizu, Bibai Rosai Hospital; S. Kuroda, Hokkaido University Hospital; T. Sohma, Sapporo City General Hospital; S. Goto and T. Kawamoto, Miyanomori Memorial Hospital; J. Nakagawara, Nakamura Memorial Hospital; S. Konno, T. Murata, and Y. Ishibashi, Iwate Medical University Hospital; K. Tamura and T. Kikuchi, Iwate Prefectural Central Hospital; H. Nomura, Kohnan Hospital; K. Hisanaga, Miyagi National Hospital; M. Suzuki, Sendai East Neurosurgical Hospital; H. Narikawa, Naruko Public Hospital; A. Suzuki, Y. Hirata, and K. Nagata, Research Institute for Brain and Blood Vessels Akita; H. Ishiguro, Akita Red Cross Hospital; I. Kimura, H. Seki, and T. Tsuda, Yamagata National Hospital; N. Yoshimura and Y. Ishida, Takeda General Hospital; K. Yamane, Ohta Atami Hospital; J. Asari, Southern Tohoku Fukushima Hospital; H. Miura, Tokyo Medical University Kasumigaura Hospital; S. Komatsumoto, Ashikaga Red Cross Hospital; Y. Ishikawa, Ohtawara Red Cross Hospital; K. Arai, Sano Citizens Heartful Hospital; K. Okamoto, Gunma University Hospital; M. Amari, Geriatrics Research Institute and Hospital; B. Mihara, Mihara Memorial Hospital Institute of Brain and Blood Vessels; K. Shimazu, Saitama Medical School Hospital; R. Hirose, Kitasato Institute Medical Center Hospital; T. Shimizu, Saiseikai Kurihashi Hospital; I. Kamitsukasa, Chiba Rosai Hospital; M. Takasaki and T. Iwamoto, Tokyo Medical University Hospital; S. Orimo, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers; T. Kamiya, Nippon Medical School Hospital; K. Takahashi, Tokyo Medical Center; M. Kobari, Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital; H. Yamaguchi and S. Okubo, Tama-Hokubu Medical Center; M. Hagiwara and K. Hirabayashi, Tokyo Metropolitan Ebara Hospital; F. Sakai, Kitasato University Hospital; M. Nagayama, Tokai University Hospital; H. Sugihara, and Y. Takahashi, St. Marianna University School of Medicine Hospital; Y. Kitagawa, Tokai University Oiso Hospital; N. Furuhashi, Kitasato University East Hospital; M. Yamamoto, Yokohama Stroke and Brain Center; T. Tsuchida and T. Tamura, Niigata Prefectural Central Hospital; M. Takado, Kouseiren Takaoka Hospital; S. Minami, Nanto Municipal Hospital; Y. Tsuchiya, Fukui Saiseikai Hospital; K. Kashihara, Fukui Prefectural Hospital; H. Makishita, Hokushin General Hospital; S. Nakagawa, J.A. Azumi General Hospital; R. Waki and K. Kimura, Shizuoka Hospital; I. Fujishima, Seirei Mikatahara General Hospital; T. Shimizu, Seirei Hamamatsu General Hospital; S. Kojima, Shizuoka Medical Center; S. Okuda, Nagoya Medical Center; C. Mabuchi and J. Ochiai, Nagoya Ekisaikai Hospital; A. Kimura and T. Toriyama, Nagoya Kyoritsu Hospital; K. Ojika, Nagoya City University Hospital; T. Inagaki, Nagoya City Koseiin Geriatric Hospital; T. Sakakibara, Chubu Rosai Hospital; I. Aiba, Higashi Nagoya Hospital; S. Imai, Daiyukai General Hospital; S. Mitake, Tosei General Hospital; H. Yamamoto, Fujita Health University Hospital; Y. Naito and Y. Narita, Mie University Hospital; S. Masuzugawa and M. Asahi, Suzuka General Hospital; A. Taniguchi, Matsusaka Chuo General Hospital; S. Nakayama, Matsusaka City Hospital; S. Matsumoto, Kitano Hospital; H. Etani, Osaka National Hospital; T. Miyashita, Yodogawa Christian Hospital; M. Matsumoto and K. Kitagawa, Osaka University Hospital; R. Fukunaga and Y. Okazaki, Osaka Rosai Hospital; H. Naritomi and K. Minematsu, National Cardiovascular Center; E. Takeuchi and J. Deguchi, Osaka Medical College Hospital; H. Tanabe, Shiroyama Hospital; R. Fukunaga, Hoshigaoka Koseinenkin Hospital; H. Kusaka, Kansai Medical University; Y. Seike, Bobath Memorial Hospital; S. Nishimura, Tesseikai Hospital; S. Nakao, Kobe City General Hospital; Y. Nishimura, Nishi-Kobe Medical Center; Y. Shimizu, Matsue Red Cross Hospital; H. Bokura, Shimane University Hospital; K. Sasaki, Hamada Medical Center; M. Kitani, Masuda Red Cross Hospital; K. Okada, Ohda Municipal Hospital; Y. Hayashi, T. Murakami and Y. Manabe, Okayama Medical Center; K. Abe, Okayama University Hospital; T. Tsuji and K. Kashihara, Okayama Kyokuto Hospital; Y. Kanehisa, K. Hiragushi, and S. Yamaguchi, Kure Kyosai Hospital; M. Tsuha and T. Takasago, Saiseikai Yamaguchi General Hospital; M. Suzuki, Yamaguchi University Hospital; T. Fukusako and S. Abiko, Ube Industries Central Hospital; T. Yamada, Aso Iizuka Hospital; T. Soejima and Y. Aiko, Moji Rosai Hospital; T. Ishitsuka, Kyushu Rosai Hospital; M. Tsujimura and T. Toba, Kitakyushu City Yahata Hospital; S. Sadoshima, Nippon Steel Yawata Memorial Hospital; Y. Akaike, Shin Yukuhashi Hospital; K. Yamasaki, Saiseikai Fukuoka General Hospital; S. Ezaki, Nagao Hospital; K. Irie, K. Kishikawa, H. Nakane, T. Takenoyama, and N. Sasagasako, Fukuoka-higashi Medical Center; T. Masuda, Komonji Hospital; Y. Sasaki and K. Fukuyama, Fukuoka Wajiro Hospital; M. Hirooka, Shiroishi Kyoritsu Hospital; H. Nakane, J. Kitayama, and K. Irie, Ureshino Medical Center; N. Ohno, Kumamoto Rosai Hospital; S. Imamura, Kumamoto Saishunso National Hospital; Y. Hokezu, Oita Prefectural Hospital; H. Matsumoto, Ohkatsu Hospital; and R. Hamada, Kyushu Cardiovascular Center.
Sources of Funding
Mitsubishi Tanabe Pharma Corp was the main source of funding for this study and provided the study medication. The sponsor cooperated in the work of the steering committee: study design, data collection, and statistical analysis.
- Received March 30, 2009.
- Accepted May 8, 2009.
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