The Phosphodiesterase Inhibitor Cilostazol Induces Regression of Carotid Atherosclerosis in Subjects With Type 2 Diabetes Mellitus
Principal Results of the Diabetic Atherosclerosis Prevention by Cilostazol (DAPC) Study: A Randomized Trial
Background— Antiplatelet drugs are effective in preventing recurrence of atherosclerosis in type 2 diabetic patients. However, the efficacy and usefulness of 2 different antiplatelet drugs, aspirin and cilostazol, in the progression of carotid intima-media thickening are unknown.
Methods and Results— To compare prevention by cilostazol and aspirin of progression of atherosclerosis, we conducted a prospective, randomized, open, blinded end point study in 4 East Asian countries. A total of 329 type 2 diabetic patients suspected of peripheral artery disease were allocated to either an aspirin-treated (81 to 100 mg/d) group or a cilostazol-treated (100 to 200 mg/d) group. The changes in intima-media thickness of the common carotid artery during a 2-year observation period were examined as the primary end point. The regression in maximum left, maximum right, mean left, and mean right common carotid artery intima-media thickness was significantly greater with cilostazol compared with aspirin (−0.088±0.260 versus 0.059±0.275 mm, P<0.001; −0.042±0.274 versus 0.045±0.216 mm, P=0.003; −0.043±0.182 versus 0.028±0.202 mm, P=0.004; and −0.024±0.182 versus 0.048±0.169 mm, P<0.001). In a regression analysis adjusted for possible confounding factors such as lipid levels and hemoglobin A1c, the improvements in common carotid artery intima-media thickness with cilostazol treatment over aspirin treatment remained significant.
Conclusions— Compared with aspirin, cilostazol potently inhibited progression of carotid intima-media thickness, an established surrogate marker of cardiovascular events, in patients with type 2 diabetes mellitus.
Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: C000000215.
Received July 9, 2009; accepted April 12, 2010.
Westernization of lifestyle has led to an explosive increase in the number of diabetic patients in East Asian countries. Diabetes mellitus is often associated with major cardiovascular diseases such as coronary artery disease and ischemic heart disease. In patients with type 2 diabetes mellitus (T2DM), the risk of coronary heart disease is 2- to 4-fold that in the general population, and it has been suggested that diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as nondiabetic patients with previous myocardial infarction.1 These findings suggest that primary prevention of cardiovascular events in diabetic patients should be as aggressive as secondary prevention of such events in nondiabetic patients.1
Clinical Perspective on p 2591
Antiplatelet agents are widely reported to be effective in preventing the recurrence of cardiovascular events. Administration of aspirin, in particular, which blocks thromboxane synthesis by acetylation of platelet cyclooxygenase, is established as a strategy for secondary prevention of cardiovascular events in such patients.2 Clinical guidelines have recommended that individuals with risk factors for coronary heart disease (eg, diabetes mellitus) take aspirin for both primary and secondary prevention,3 although the effects of aspirin on the prevention of cardiovascular events are still controversial.4–6
Cilostazol, a phosphodiesterase III inhibitor with antiplatelet, antithrombotic, and vasodilatory effects, is indicated for the treatment of intermittent claudication in the United States and for the treatment of ischemic signs and symptoms associated with chronic arterial occlusion in Japan. Although some studies have reported that cilostazol may be effective in preventing cardiovascular events in patients with T2DM,7,8 the number of such studies is still relatively small.
We therefore conducted an international, 2-year prospective study to clarify the efficacy and benefits of cilostazol in preventing the progression of atherosclerosis in patients with T2DM and mild atherosclerosis in 4 Asian countries using common carotid artery intima-media thickness (CCA-IMT), a widely used surrogate marker of atherosclerosis, as the primary end point.
Participants and Selection Criteria
The Diabetic Atherosclerosis Prevention by Cilostazol (DAPC) study was an international, prospective, randomized, open, blinded end point study conducted from November 2004 to August 2008 in 20 institutions in East Asia (13 institutions in Japan, 5 institutions in Korea, 1 institution in China, and 1 institution in the Philippines). The study protocol was approved by the ethics review boards of all institutions that participated in this study, and written informed consent was obtained from all patients enrolled. The DAPC study protocol has been described in detail previously.9
Participants eligible for the study were patients with T2DM aged 40 to 85 years at the time of enrollment who were suspected of having peripheral artery disease (PAD) on the basis of an ankle-brachial pressure index of <1.0, poor pulsation bilaterally or substantially weaker pulsation on either side in the case of the popliteal artery or dorsalis pedis artery, and/or clinical symptoms of PAD. Exclusion criteria included type 1 diabetes mellitus or secondary diabetes; age <40 years or ≥86 years; severe PAD rated Fontaine ≥IIb; cerebrovascular disorder rated grade ≥4 on the Modified Rankin Scale; a medical history of angina or myocardial infarction; severe hepatic dysfunction or renal dysfunction (serum creatinine ≥1.5 mg/dL); congestive heart failure; bleeding tendency or active bleeding; severe hematologic abnormality; diagnosed homozygous familial hypercholesterolemia; allergies or a medical history of hypersensitivity to the investigational drugs; and, in the case of women, pregnancy or lactation. Screening of the study subjects was performed consecutively; all the patients that met eligibility criteria were asked if they could participate in the present study, and all of the patients who agreed to participate were registered.
The investigators registered eligible patients in the central office of the study through a Web site for registration on which the patients were randomly assigned to an aspirin group (81 to 100 mg/d) or a cilostazol group (100 to 200 mg/d) with the use of an online allocation system. The treatment period was 2 years. Although the recommended dosage of cilostazol was 200 mg/d, the dose for each subject was titrated in consideration of age, renal function, and other symptoms. In patients on antiplatelet drugs before the study, the previously used antiplatelet drugs were replaced by the allocated test drug without a washout period. Use of the following drugs was prohibited during the study period: sarpogrelate hydrochloride, ticlopidine hydrochloride, dipyridamole, beraprost sodium, limaprost alfadex, and warfarin potassium.
The primary end points of the study were the changes in maximum IMT of the right and left common carotid arteries (maximum CCA-IMT) and mean CCA-IMT from baseline. CCA-IMT was measured by the IMT Evaluation Committee using conventional B-mode images of arteries before breaking of study blindness. The secondary end points were major cardiovascular events (ie, sudden cardiovascular death, new onset or recurrence of cerebral infarction or transient cerebral ischemia, development of angina or acute myocardial ischemia, or exacerbation of PAD) and all-cause mortality.
Periodic evaluation, including measurement of CCA-IMT, was performed at baseline and 1 and 2 years after initiation of the study. Investigators were requested to report discontinuations of or withdrawals from the study, occurrence of major cardiovascular events or other serious adverse events, and changes in dose of the test drug at month 3 of treatment or thereafter to the central office.
Measurement of IMT
Ultrasonographic scans of the carotid artery were performed by expert sonographers who were specifically trained to perform the prescribed study examination. To avoid intersonographer variability, each participant was examined by the same sonographer with the same equipment (high-resolution B-mode ultrasound scanners equipped with a 7.5- to 12-MHz linear transducer, with a limit of detection of <0.1 mm) throughout all of the visits. Scanning of the extracranial common carotid artery, the carotid bulb, and the internal carotid artery in the neck was performed bilaterally in 3 different longitudinal projections (anterior, lateral, and posterior, which approximately corresponded to 60, 90, and 150 degrees for the right carotid artery and 210, 270, and 300 degrees for the left carotid artery marked on Meijer’s Arc) as well as transverse projections, and the site of greatest thickness, including plaque lesions, was sought along the arterial walls.
To avoid interreader variability, all scans were stored electronically and sent to the central office (IMT Evaluation Committee, Osaka, Japan) and read in random order by a single reader (N.K.) unaware of the clinical characteristics of the subjects, using automated digital edge-detection software (Intimascope; MediaCross, Tokyo, Japan). The IMT was measured as the distance between 2 parallel echogenic lines corresponding to the blood-intima and media-adventitia interface on the posterior wall of the artery. Three determinations of IMT were performed at the site of the thickest point: maximum CCA-IMT and 2 adjacent points (1 cm upstream and 1 cm downstream from this site). These 3 determinations were averaged (mean CCA-IMT). Plaques are included when maximum IMT is measured. The greatest value among the 3 maximum or mean IMTs from 3 selected angles was used as the representative value for the individual.
Reproducibility analysis of 122 replicate measurements at baseline yielded absolute mean differences of 0.00±0.03 and 0.01±0.04 mm for maximum CCA-IMT and mean CCA-IMT, respectively. The intraclass correlations were 0.99 and 0.97 for maximum CCA-IMT and mean CCA-IMT, respectively. The primary study outcomes were the absolute changes from baseline to final visit in maximum and mean IMT of the left and right common carotid arteries.
It has been reported that IMT was reduced to 0.033±0.062 mm/y (mean±SD) when aspirin was administered to patients with T2DM for 3 years and to 0.00±0.20 mm/3 y (mean±SD) when cilostazol was administered.8,10 Therefore, in the present 2-year study, registration of at least 408 patients was required to obtain 90% power (305 patients for 80% power) to detect a difference of 0.066 mm in IMT between the 2 groups, assuming a SD of 0.20, 5% dropout, and a 0.05 level of significance. In this study with a primary end point of CCA-IMT, the target number of enrolled patients was set at 400 for the 1-year registration period.
Primary analysis of data was performed with the use of a linear mixed-effects model. Differences between baseline and after 2 years were assessed with paired t test. The level of significance was set at P<0.05.
A total of 329 patients were randomized, with 166 and 163 patients allocated to the aspirin and cilostazol treatment groups, respectively. After exclusion of 14 and 18 patients in the aspirin and cilostazol groups, respectively, 152 and 145 patients (297 patients in total), respectively, were included in the full analysis set (Figure). Table 1 shows the baseline characteristics of the study subjects. Per-protocol analysis was performed in 250 patients, including 134 and 116 patients in the aspirin and cilostazol groups, respectively, who completed the protocol.
Carotid Artery IMT
In patients in the cilostazol group, there was significant improvement in maximum and mean left CCA-IMT during treatment compared with baseline; maximum and mean right CCA-IMT also exhibited a tendency toward improvement. In patients in the aspirin group, however, there was significant increase in the maximum left, maximum right, and mean right CCA-IMT from baseline; mean left CCA-IMT also exhibited a tendency toward increase during treatment.
Statistical comparison of the 2 treatment groups with the use of linear mixed-effects models revealed that cilostazol significantly inhibited the increase in the maximum left and right CCA-IMT and mean left and right CCA-IMT compared with aspirin (Table 2). The degrees of regression in maximum left and right CCA-IMT and mean left and right CCA-IMT were greater with cilostazol than with aspirin. Similar results were obtained with analyses with adjustment for the baseline imbalance of IMT, age, diastolic blood pressure, and administration of statins that possibly affect the treatment effect of the test drugs (Table 2, models 1 to 3). In addition, in a linear mixed-effects model adjusted for possible confounding factors such as lipid levels and hemoglobin A1c, the improvements in maximum and mean right and left CCA-IMTs with cilostazol treatment over aspirin treatment remained significant (data not shown). Thus, comparison of change in CCA-IMT during treatment from baseline between the 2 groups revealed significant differences in all measures, indicating significant improvement in CCA-IMT by cilostazol compared with aspirin. Per-protocol analysis of the primary end point produced findings similar to those of the full analysis set.
Secondary End Points
There were no significant differences between the 2 treatment groups in major cardiovascular events (ie, sudden cardiovascular death, new onset or recurrence of cerebral infarction or transient cerebral ischemia, development of acute myocardial infarction or angina, or exacerbation of PAD or all-cause mortality) (Table I in the online-only Data Supplement).
Table 3 shows changes in serum lipid levels over time from baseline to year 2. Low-density lipoprotein (LDL) cholesterol was significantly improved during treatment in the cilostazol group (from 117±33 to 109±31 mg/dL; P=0.009) but not in the aspirin group. The improvement in LDL cholesterol from baseline tended to be larger in the cilostazol than in the aspirin group, although not to a significant extent (P=0.054).
High-density lipoprotein (HDL) cholesterol improved significantly in the cilostazol (from 51±13 to 57±18 mg/dL; P<0.0001) and aspirin (from 48±12 to 51±13 mg/dL; P=0.002) groups. Increase in HDL cholesterol from baseline to year 2 was significantly larger in the cilostazol than in the aspirin group (P=0.0008).
Improvement of triglyceride level during treatment was significant in the cilostazol group (from 133±80 to 103±48 mg/dL; P<0.0001) but not in the aspirin group (from 143±114 to 149±130 mg/dL; P=0.36). Change in triglyceride level from baseline to year 2 was significantly larger in the cilostazol than in the aspirin group (P=0.0004). However, there were no significant associations between the improvement of serum lipid levels and the changes in IMT during treatment. There were no significant differences between the treatment groups in hemoglobin A1c and blood pressure from baseline to year 2.
During the study, 2 and 0 patients in the aspirin and cilostazol groups, respectively, died, and 4 and 5 cases in the aspirin and cilostazol groups, respectively, experienced serious adverse events requiring discontinuation of study participation (Figure).
Cilostazol, a potent selective inhibitor of type 3 phosphodiesterase that increases cAMP levels in platelets and vascular cells, exhibits antiplatelet effects by a mechanism of action different from that of aspirin and is also a potent antiatherosclerotic agent.8,11,12 The present study involved a randomized trial to evaluate the prevention by cilostazol of progression of carotid IMT in diabetic patients suspected of having PAD, with aspirin-treated patients used as a control group, and found that increase in carotid IMT, the primary end point, was significantly prevented in the cilostazol group compared with the aspirin group. These findings suggest that cilostazol is a more effective antiatherosclerotic agent than aspirin. Furthermore, there was substantial regression in left maximum and mean IMT in the cilostazol group, suggesting that cilostazol has potent antiatherosclerotic effects and can reverse the process of atherosclerosis even in high-risk subjects such as those with diabetes mellitus.
The improvements in serum HDL cholesterol and triglyceride levels were significantly larger in the cilostazol than in the aspirin group, suggesting that cilostazol has beneficial effects on lipid profiles. Although previous studies have reported that cilostazol increases serum HDL cholesterol levels and reduces serum triglyceride levels,13–15 the mechanism of improvement of lipid profiles by cilostazol is still unclear. One possible mechanism is reduction of hepatic triglyceride secretion by potentiating the effect of glucagon to inhibit very-low-density lipoprotein secretion. In addition, it has been shown that increased cAMP promotes the release of lipoprotein lipase from adipocytes, which may explain the reduction of serum triglyceride levels.16
We used surrogate end points for this trial because of many practical constraints, including trial costs and concern about the feasibility of performing long-term intervention. Carotid ultrasound measurements of IMT have been validated against pathological specimens and demonstrated to be strong predictors of cardiovascular events in subjects with and without T2DM.17,18 It has also been shown that changes in carotid IMT over time correlate with rates of future cardiovascular events.19 There have been few previous reports on the effects of antiplatelet agents on progression of changes in carotid IMT in diabetic subjects. One study evaluating the effects of aspirin therapy on carotid IMT found that aspirin attenuated an increase in carotid IMT by 50%.10 On the other hand, 2 studies evaluating the effects of cilostazol therapy on carotid IMT revealed nearly complete prevention of increase in this parameter.8,20 Furthermore, another study reported a significant decrease in carotid IMT after 1 year of cilostazol treatment.21 The results of these studies thus indicate that cilostazol prevents an increase in carotid IMT more strongly than aspirin in diabetic subjects. However, these findings are of limited applicability because they were obtained in a relatively short trial in a small number of subjects, and there have been no large-scale prospective studies of the effects of cilostazol on atherosclerosis. Furthermore, no previous studies have directly compared the effects of cilostazol with those of aspirin. We therefore initiated an international, 2-year prospective follow-up interventional study to clarify the efficacy and usefulness of aspirin and cilostazol in the primary prevention and secondary treatment of diabetic atherosclerosis in Asian patients.
Although the mechanism by which cilostazol treatment potently inhibited the progression of carotid IMT is unclear, several possibilities may be suggested. First, it may be a secondary effect of improvement of risk factors for atherosclerosis. As also was found in several previous studies,13–15 cilostazol treatment significantly decreased serum triglyceride and LDL cholesterol levels and significantly increased HDL cholesterol levels in the present study (Table 3). Thus, the beneficial effect of cilostazol on carotid IMT was considered to be due in part to improvement of lipid profiles. However, no significant associations were observed between the improvement of serum lipid levels and the changes in IMT during treatment. Furthermore, after adjustment for lipid profiles and the administration of statins, a beneficial effect of cilostazol on carotid IMT was still observed. Therefore, other mechanisms must have been operative as well. For example, cilostazol may have prevented the progression of carotid IMT by improving insulin sensitivity because cilostazol reduces insulin resistance and/or abdominal fat accumulation in an animal model of T2DM.22 However, we did not examine whether cilostazol treatment affected insulin sensitivity in this study.
It is also possible that cilostazol directly inhibited the progression of carotid IMT. Type 3 phosphodiesterase is present not only in platelets but also endothelial cells and vascular smooth muscle cells. Cilostazol has an antiatherogenic effect on these vascular cells. Cilostazol inhibited high glucose– and platelet-derived growth factor–induced proliferation of human vascular smooth muscle cells in vitro and virtually abolished neointimal formation in rats subjected to carotid artery injury in vivo.23,24 In addition, it increased nitric oxide production and prevented expression of adhesion molecules.25 Because activation of AMP-activated protein kinase has been believed to prevent glucose-induced endothelial dysfunction,26 AMP-activated protein kinase activation may have been responsible in part for the greater effect of cilostazol than aspirin on carotid IMT. Indeed, it was recently reported that cilostazol activates AMP-activated protein kinase and inhibits cytokine-induced nuclear factor-κB activation in cultured endothelial cells and restores endothelium-dependent vasodilation in diabetic rats.27 It has also been reported recently that cilostazol inhibited oxidative stress–induced endothelial senescence and dysfunction by upregulating a longevity gene, Sirt1,28 which is thought to be linked to AMP-activated protein kinase.29,30 Cilostazol may thus influence carotid IMT by improving endothelial function because endothelial dysfunction is associated with impaired arterial vasodilator capacity, increased platelet aggregability, and intimal thickening.
Taken together, these findings suggest that cilostazol opposes the effects of various proatherogenic factors and interferes with various stages of the process of atherosclerosis. Further studies with measurements of other parameters such as endothelial function and biomarkers of antithrombotic effects will show whether these additional effects of cilostazol other than the antiplatelet effect really affect the progression of carotid IMT. In addition, the measurements of inflammatory markers such as high-sensitivity C-reactive protein may help to explain the beneficial effect of cilostazol on IMT progression.
Our study has several limitations. First, it lacked sufficient power to detect differences in cardiovascular end points, including myocardial infarction and stroke, and is therefore unable to clearly establish that treatment with cilostazol reduces these end points in patients with T2DM compared with aspirin. Larger randomized trials of longer duration focused on these most important clinical end points are thus needed to determine the practical implications of our findings.
Second, the number of individuals randomized to treatment was less than intended on the basis of the protocol because it was difficult to recruit eligible patients within the registration period. However, the study was performed because 329 subjects were considered sufficient to detect significant differences at the 5% level with >80% power.
Third, of the 329 patients initially randomized, 32 were excluded from analyses because of withdrawal from participation or for other reasons. However, the numbers of subjects excluded were balanced in the 2 treatment groups. Although discontinuation of study participation due to adverse events or for other reasons and withdrawal from the study due to inability to complete follow-up after change of hospital were slightly more frequent in the cilostazol than in the aspirin group (20% versus 12%; P>0.05), the participants who remained in the study (ie, the per-protocol set population) were similar to those in the intention-to-treat population (data not shown). In addition, an analysis of baseline characteristics of the participants who dropped out revealed no differences from those who remained in the study. These findings suggest that any bias in study findings that might have resulted from the exclusion of individuals with no postbaseline measurements was minimal.
Fourth, there may have been measurement error in IMT measurements attributed to intersonographer differences because scans were performed at 20 different institutions. However, each participant was examined by the same expert sonographer with an identical ultrasound protocol throughout all of the visits, and the readings were performed in random order by a single reader unaware of the clinical characteristics of the subjects, using automated digital edge-detection technology, which demonstrated good reproducibility for repeated measurements.
Fifth, and finally, the subjects of this study were Asian T2DM patients without the severe obesity that is often observed in non-Asian T2DM patients. It would thus be premature to generalize our findings to non-Asian populations.
Notwithstanding these limitations, our findings demonstrate that cilostazol potently inhibited an increase in carotid IMT compared with aspirin. We also found that a 100- to 200-mg dose of cilostazol was well tolerated during the 2-year study period and had a safety profile similar to that of aspirin.
In conclusion, cilostazol potently inhibited progression of carotid IMT, an established surrogate marker of cardiovascular events, in patients with T2DM suspected of having PAD compared with aspirin. A large-scale prospective trial is needed to establish the usefulness of cilostazol for primary prevention of cardiovascular events in patients with T2DM.
DAPC Study Participants
The following investigators participated in the DAPC Study (listed in alphabetical order by name of the principal investigator): in Japan, Takashi Goto, Department of Internal Medicine, Japanese Red Cross Akita Hospital (Akita); Eiichi Imano, Department of Internal Medicine, Osaka Koseinenkin Hospital (Osaka); Hideaki Jinnouchi, Department of Internal Medicine, Jinnouchi Hospital (Kumamoto); Akio Kanazawa, Department of Internal Medicine, Division of Metabolism and Endocrinology, Juntendo University School of Medicine (Tokyo); Soji Kasayama, Department of Medicine, Nissay Hospital (Osaka); Keisuke Kosugi, Department of Internal Medicine, Osaka Police Hospital (Osaka); Akina Matsuda, Department of Internal Medicine, Japanese Red Cross Akita Hospital (Akita); Munehide Matsuhisa, Department of Endocrinology and Metabolism, Osaka University Graduate School of Medicine (Osaka); Takashi Matsuoka, Division of Diabetes, Department of Internal Medicine, Kurashiki Central Hospital (Okayama); Tatsuaki Nakatou, Department of Internal Medicine, Okayama Saiseikai General Hospital (Okayama); Masahiro Ohta, Ohta Clinic (Fukushima); Michio Otsuki, Department of Molecular Medicine, Osaka University Graduate School of Medicine (Osaka); Toshio Ono, Department of Diabetes and Endocrinology, Iwaki Kyoritsu Hospital (Fukushima); Satoru Sumitani, Department of Diabetes and Endocrinology, Nissay Hospital (Osaka); Yasushi Tanaka, Endocrinology and Metabolism, St Marianna University School of Medicine Hospital (Kanagawa); Shuka Umemura, Department of Diabetes and Endocrinology, Iwaki Kyoritsu Hospital (Fukushima); Toshihito Yagi, Department of Endocrinology and Metabolism, Belland General Hospital (Osaka); in Korea, Min-Young Chung, Department of Internal Medicine, Chonnam National University College of Medicine (Gwangju); Hyun-Chul Lee, Department of Internal Medicine, Yonsei University College of Medicine (Seoul); Hye-Soon Kim, Department of Internal Medicine, Keimyung University College of Medicine (Daegu); Kun-Ho Yoon, Department of Internal Medicine, Catholic University of Korea (Seoul); in the Philippines, Marie Simonette V. Ganzon, Vascular Medicine, Heart Institute, St Luke’s Medical Center, (Manila); in China, Xiao-Hui Guo, Department of Endocrinology, Beijing University First Hospital (Beijing); Xiaowei Ma, Department of Endocrinology, Beijing University First Hospital (Beijing).
We thank Yukio Shigeta, MD, Professor Emeritus, Shiga University of Medical Sciences, Shiga (Medical Advisor); Hidetaka Hougaku, MD, Director, Health Care Center, Nara Institute of Science and Technology, Nara (Magnetic Resonance Imaging Evaluation Committee); Hiroshi Sato, MD, Osaka University Graduate School of Medicine, Osaka; Kazuo Kitagawa, MD, Osaka University Graduate School of Medicine, Osaka (Event Evaluation Committee); and the DAPC Study Participants. Independent statistical review was performed by Tsutomu Yamazaki, MD, Department of Clinical Epidemiology and Systems, Graduate School of Medicine, University of Tokyo (Tokyo), and Junji Kishimoto, MD, Division of Digital Organ, Digital Medicine Initiative, Kyusyu University (Fukuoka).
Sources of Funding
This study was financially supported by a grant for a research project on cardiovascular diseases provided by the Japan Cardiovascular Research Foundation, a nonprofit organization under the supervision of the Ministry of Health, Labor, and Welfare of Japan.
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Antiplatelet agents are widely reported to be effective in preventing the recurrence of cardiovascular events. Clinical guidelines have recommended that individuals with risk factors for coronary heart disease (eg, diabetes mellitus) take aspirin for both primary and secondary prevention. Cilostazol, a phosphodiesterase III inhibitor with antiplatelet, antithrombotic, vasodilatory, and antiproliferative effects, is currently indicated for the treatment of intermittent claudication and/or ischemic signs and symptoms associated with chronic arterial occlusion around the world and secondary prevention of cerebral infarction in Asian countries. However, there was no report comparing the efficacy and usefulness of 2 different antiplatelet drugs, aspirin and cilostazol, in the prevention of occurrence or progression of atherosclerosis in diabetic patients. This is the first study to directly compare the effect of cilostazol and aspirin on the progression of atherosclerosis in diabetic patients. In this international, prospective, randomized, open, blinded end point study involving a total of 329 Asian type 2 diabetic patients suspected of peripheral artery disease, we found that cilostazol treatment (100 to 200 mg/d) potently and safely inhibited the progression of carotid intima-media thickness, an established surrogate marker of cardiovascular events, compared with aspirin treatment (81 to 100 mg/d) during a 2-year observation period. Our findings suggest that cilostazol is a more effective antiatherosclerotic agent than aspirin in patients with type 2 diabetes mellitus. A large-scale prospective trial is needed to establish the usefulness of cilostazol for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.892414/DC1.