Cilostazol Stroke Prevention Study: A Placebo-Controlled Double-Blind Trial for Secondary Prevention of Cerebral Infarction Fumio Gotoh, MD, Hideo Tohgi, MD, Shunsaku Hirai, MD, Akiro Terashi, MD, Yasuo Fukuuchi, MD, Eiichi Otomo, MD, Yukito Shinohara, MD, Eiichi Itoh, MD, Tamotsu Matsuda, MD, Tohru Sawada, MD, Takenori Yamaguchi, MD, Katsuya Nishimaru, MD, and Yasuo Ohashi, PhD

Cilostazol, an antiplatelet drug that increases the cyclic adenosine monophosphate (AMP) levels in platelets via inhibition of cyclic AMP phosphodiesterase, has been used in chronic arterial occlusive disease. The purpose of the present study was to examine the effects of cilostazol on the recurrence of cerebral infarction using a multicenter, randomized, placebo-controlled, double-blind clinical trial method. Patients who suffered from cerebral infarction at 1 to 6 months before the trial were enrolled between April 1992 and March 1996. Oral administration of cilostazol (100 mg twice daily) or placebo was randomly assigned to the patients and continued until February 1997. The primary endpoint was the recurrence of cerebral infarction. In total, 1,095 patients were enrolled. An analysis based on 1,052 eligible patients (526 given cilostazol and 526 given placebo) showed that the cilostazol treatment achieved a significant relative-risk reduction (41.7%; confidence interval [CI], 9.2% to 62.5%) in the recurrence of cerebral infarction as compared with the placebo treatment (P ⫽ .0150). Intention-to-treat analysis of 1,067 patients also showed a significant relative-risk reduction (42.3%; CI, 10.3% to 62.9%, P ⫽ .0127). No clinically significant adverse drug reactions of cilostazol were encountered. Long-term administration of cilostazol was effective and safe in the secondary prevention of cerebral infarction. Key Words: Prevention of stroke—Antiplatelet—Cilostazol

Current treatments for the prevention of stroke in high-risk patients include vascular surgery, anticoagulants, and platelet antiaggregating agents.1,2 Among the various medical managements, aspirin and ticlopidine have shown well-established roles in secondary stroke prevention.3,4 The rationale for their use lies in their

ability to interfere with the formation of platelet fibrin thrombi, although the value of such therapies remains controversial due to their adverse drug reactions. For instance, ticlopidine occasionally induces neutropenia, diarrhea, and skin rash,5 while aspirin frequently causes gastrointestinal side effects.6

From the Department of Neurology, School of Medicine, Keio University, Tokyo, Japan; the Department of Neurology, Iwate Medical University School of Medicine, Iwate, Japan; the Department of Neurology, Gunma University School of Medicine, Gunma, Japan; the Second Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; the Department of Internal Medicine, Yokufukai Geriatric Hospital, Tokyo, Japan; the Department of Neurology, Tokai University School of Medicine, Kanagawa, Japan; the Department of Neurology, National Higashi-Nagoya Hospital, Aichi, Japan; the Third Department of Internal Medicine, Kanazawa University School of Medicine, Ishikawa, Japan; the Cerebrovascular Division, Depart-

ment of Medicine, National Cardiovascular Center, Osaka, Japan; the First Department of Internal Medicine, Fukuoka University School of Medicine, Fukuoka, Japan; and the Department of Biostatistics, School of Health Sciences and Nursing, University of Tokyo, Tokyo, Japan. Received October 22, 1999; accepted December 13, 1999. Supported by Otsuka Pharmaceutical Co, Ltd, Osaka, Japan. Address reprint requests to Fumio Gotoh, MD, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan. Copyright r 2000 by National Stroke Association 1052-3057/00/0904-0001$3.00/0 doi:10.1053/jscd.2000.7216

Journal of Stroke and Cerebrovascular Diseases, Vol. 9, No. 4 ( July-August), 2000: pp 147-157

147

F. GOTOH ET AL.

148

Cilostazol, 56[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]3,4-dihydro-2-(1H)-quinolinone6, is an antiplatelet drug that increases the cyclic adenosine monophosphate (AMP) levels in platelets via inhibition of cyclic AMP phosphodiesterase.7 Based on this mechanism, cilostazol inhibits primary and secondary platelet aggregation in response to adenosine diphosphate (ADP), collagen, epinephrine, and arachidonic acid.8,9 This drug is also known to induce potent enhancement of the antiplatelet effect of prostacyclin (PGI2 ),10 which is a biological inhibitor of thrombosis in vivo. Furthermore, cilostazol has been found to prevent thrombosis in a mouse model of pulmonary embolism,8 in a rabbit model of cerebral thrombosis,11 and in a feline model of thrombosis caused by occlusion of the middle cerebral artery.12 In view of these beneficial effects on the microcirculation, cilostazol has been marketed and used widely in Japan since 1988 for the treatment of ischemic symptoms of chronic arterial occlusive disease. Most of the large-scale stroke prevention studies performed so far have been undertaken in North American and Western Europe.5,6 No such trials have been conducted previously in Japan. Because cilostazol has been shown to reduce the incidence of transient ischemic attack (TIA) as effectively as aspirin in a preliminary study on patients with TIA in Japan, a randomized, placebocontrolled, double-blind clinical trial of cilostazol was performed as the CSPS (Cilostazol Stroke Prevention Study) to assess the effectiveness of this drug in prevention of the recurrence of cerebral infarction. Design and organization of the CSPS were published elsewhere.13

Materials and Methods Patient Recruitment Patients were enrolled into the trial at 183 clinical institutes in Japan between April 1992 and March 1996. The follow-up of all patients was completed by March 31, 1997. The inclusion and exclusion criteria are listed in Tables 1 and 2. In brief, patients under 80 years old, who had suffered a cerebral infarction, which was confirmed on computed tomography or magnetic resonance imaging, at 1 to 6 months before participation in the trial without serious complications, were deemed eligible. Use

Table 2. Exclusion criteria History of intracranial hemorrhage Possibility of cardiogenic cerebral embolism in the past or future All patients with any of the following complications were excluded: mitral valve stenosis, prosthetic valve, endocarditis, myocardial infarction within 6 weeks after onset, ventricular aneurysm, intraventricular or intraatrial blood clots, mitral valve prolapse (age under 45 years old, lacking other causes for cerebral embolism induction), atrial fibrillation, sick sinus syndrome, idiopathic cardiomyopathy Severe cerebral deficits rendering the patient bedridden, totally dependent, or demented Contraindications to the study drug Hemostatic disorders or systemic bleeding Pregnant or possibly pregnant women, or nursing mothers Requirement for nonstudy antiplatelet drugs, anticoagulant drugs, or fibrinolytic drugs for another disease

of anticoagulants, fibrinolytic agents, or antiplatelet drugs was discontinued before randomization. The approval of the institutional review boards at each participating institute and the informed consent of each patient were obtained. Treatment and Follow-up Eligible patients were randomly assigned by the Registration and Analysis Center, an independent organization set up at Tokyo University for the present study, to treatment with either cilostazol (100 mg twice daily) or placebo. The medications were supplied in unidentifiable tablets and containers. Randomization was performed by the dynamic balancing method using the following possibly influential factors as adjustment variables: clinical institute, diagnosis, occurrence of an apparent attack of ischemic stroke before entry, and patient’s age. All known anticoagulants, fibrinolytic agents, antiplatelet drugs, and any other trial drugs were prohibited during treatment. All of the patients were to be followed up until the conclusion of the trial, whether still taking the study drug or not. The reasons for premature termination of the treatment with the study medication were recorded.

Table 1. Inclusion criteria Age ⬍80 years old Prior cerebral infarction Onset ⱖ1 month and ⱕ6 months before randomization CT or MRI detection of responsible site Without serious complications (malignant tumor, liver cirrhosis, renal failure, or heart failure)

Study Organization Patients were evaluated at 12-week intervals after their random assignment throughout the trial. At each follow-up visit, they were questioned about any new symptoms, new medical problems, adverse events, and compliance with the treatment regimen. The patients were examined, and blood and urine samples were collected for laboratory analysis.

CILOSTAZOL SECONDARY STROKE PREVENTION STUDY

The patients, investigators, and the study’s sponsor remained blinded to assignments of the treatment throughout the study. Only the Chief Statistician had access to the randomized code. The Independent Monitoring Committee for evaluating the safety and efficacy of the drug received reports from the Chief Statistician to monitor for evidence of adverse or beneficial effects. The overall conduct of the trial was guided by the Policy Board, whose members were blinded to the patients’ assignments. The Evaluation Committee, which consisted of blinded members expert in stroke research and clinical practice, classified all endpoint events using standardized criteria, which had been drawn up before the study began, to ensure diagnostic accuracy and consistency across institutes. The Project Office was responsible for the day-to-day management of the trial and for the collection of data. At the end of the study, after completion of all adjudications, the Project Office passed the complete data file to the Registration and Analysis Center, where the data and the randomization code obtained from the Chief Statistician were combined. No further changes in the data were allowed. The analysis plan was completed and approved by the Independent Monitoring Committee before unblinding, and all analyses were performed following the plan. Outcome Events The study’s primary endpoint was the recurrence of cerebral infarction. The secondary endpoints were myocardial infarction, intracranial hemorrhage (cerebral hemorrhage and subarachnoid hemorrhage), TIA, and other thrombotic and embolic disorders (acute arterial thrombosis and embolism, angina pectoris, pulmonary embolism, and venous thrombosis), and death. The following combinations of these events were chosen as outcome variables for evaluation: (1) recurrence of cerebral infarction or myocardial infarction, (2) recurrence of cerebral infarction, intracranial hemorrhage, or TIA, (3) recurrence of cerebral infarction, intracranial hemorrhage, myocardial infarction, or vascular death, (4) all vascular events, (5) all vascular deaths (i.e., death occurring within 28 days after vascular events), and (6) death from any cause. For each event, the validity of the clinical features obtained was evaluated by the Evaluation Committee while retaining blindness. Interim Analyses Interim analyses were performed by the Registration and Analysis Center after the start of the trial to assess the safety on 4 occasions, in which 2 interim analyses were also performed to the efficacy of the treatment during the trial, following O’Brien and Fleming’s type adjustment of the significance level. The results were evaluated by the Independent Monitoring Committee. After the data for

149

individual cases had been fixed by the Evaluation Committee, the Chief Statistician made reports after keymatching. The drug names in the report were coded, although the codes could be broken by the Independent Monitoring Committee if necessary. At the second interim analysis of the efficacy, a statistically significant result (after adjustment) for the primary endpoint was obtained. However, the study was continued following a recommendation from the Independent Monitoring Committee judging that more follow-up was necessary to gather more mature safety data. Statistical Analysis The principal aim of the statistical analysis was to compare the incidence of the primary outcome event (recurrence of cerebral infarction) between the 2 treatment groups. The event-free rate was estimated by the KaplanMeier method and the comparison was made by the log-rank test. The primary analysis was performed for the evaluable patient population who were eligible and followed-up until termination of the protocol treatment without major violation. Sensitivity analyses were conducted for the intent to treat (ITT) population including part of the ineligible cases who could be judged to be evaluable for the safety of the drugs, and for data including follow-up observations made after termination of the protocol treatment. The risk reduction rate was estimated by the person-years method and normal approximation after log-transformation for calculation of the confidence intervals (CI). Cox regression was performed complementarily to check the validity of the results adjusting for possible influential prognostic factors. Subgroup analysis was also undertaken for these factors. Analyses for secondary outcome variables were conducted in the same manner. Adverse events including abnormal laboratory values were tabulated by groups for the ITT populations. The required sample size, 600 in each group, was estimated according to the Schoefeld-Richter method based on the assumption that the base-line 2-year cumulated incidence of the primary endpoint was 20% and the risk reduction due to the test drug was 30% with a 2-sided type 1 error (␣) of 0.05, type 2 error (␤) of 0.20, 3 years enrollment period, and 1 year follow-up. The sample size was reestimated because the enrollment was slower and the baseline incidence estimated blindly was lower than the expected values, respectively, and it was assumed that prolongation of the enrollment period to 4 years with a minimum sample size of 1,050 would almost assure the planned statistical power. All P values were 2-sided, and values of .05 or less for the primary endpoint were judged as statistically significant. Adjustments were not performed following a recommendation by the Independent Monitoring Committee because statistical significance had been attained at the second interim analysis of the efficacy.

F. GOTOH ET AL.

150

Results Enrollment of Patients Between April 1992 and March 1996, 1,095 patients were enrolled at 183 clinical institutes participating in the trial (544 received cilostazol, 548 received placebo, and 3 did not receive cilostazol despite its assignment; Fig 1). Patient follow-up was completed by March 1997. Determination of the analysis populations (evaluable population and ITT population) was performed by the Evaluation Committee before unblinding, and 1,067 patients were subjected to the ITT as a result of the exclusion of some patients, as follows. Nine patients in the cilostazol group and 11 patients in the placebo group were excluded due to their disqualification on the inclusion criteria. Similarly, 2 patients in the cilostazol group and 2 patients in the placebo group were excluded because there were no data after randomization. One patient in the placebo group was excluded because of double entry. In addition, 7 patients in the cilostazol group and 8 patients in the placebo group were excluded from the evaluable popula-

tion analysis because of the presence of atrial fibrillation or other severe complications such as brain tumor or hemorrhagic gastric ulcer. Thus, 1,052 patients (526 in the cilostazol group and 526 in the placebo group) were subjected to the evaluable population analysis. Clinical Profile A baseline clinical profile of the patients subjected to the ITT analysis is shown in Table 3. Demographic variables such as age and gender showed no differences between the cilostazol and placebo groups. The mean age was 65.2 (range, 36 to 80 years) in the cilostazol group, and 65.1 (range, 40 to 79 years) in the placebo group. There was no significant difference in mean time from the onset of cerebral infarction to the start of treatment: 83.0 days (range, 7 to 1,805 days) in the cilostazol group and 82.4 days (range, 8 to 1,079 days) in the placebo group (P ⫽ .7761, Wilcoxon test). The subtypes of cerebral infarction classified on the basis of the mechanisms, clinical categories, and involved sites were well matched between

Figure 1. Progress of participants through the trial.

CILOSTAZOL SECONDARY STROKE PREVENTION STUDY

Table 3. Baseline characteristics of the study patients (ITT) Variable

Cilostazol

Placebo

No. allocated 533 534 Age (yrs)* 65.2 ⫾ 8.7 65.1 ⫾ 8.8 Gender Male (%) 64.7 66.5 Mechanism of cerebral infarction (%) Cerebral thrombosis 89.5 88.6 Cerebral embolism 1.1 0.7 Undefined cerebral infarction 9.4 10.7 Time from cerebral infarction to randomization (%) ⱕ60 days 51.4 50.0 61-120 days 27.8 31.1 ⱖ121 days 20.6 18.9 Unknown 0.2 0 Clinical category of cerebral infarction (%) Lacunar 75.0 73.8 Atherothrombotic 14.1 13.1 Mixed 9.0 11.4 Others 1.1 1.5 Unknown 0.8 0.2 Involved arterial system (%) Internal carotid artery 15.4 16.1 Anterior cerebral artery 3.4 3.0 Middle cerebral artery 64.7 66.3 Posterior cerebral artery 7.7 8.2 Vertebrobasilar artery 19.5 21.3 Other 1.1 1.3 Unknown 0.4 0.2 Size of infarction (%) Small (diameter ⱕ1.5 cm) 75.2 73.6 Medium 23.1 24.3 Large (⬎1⁄2 of lobe) 1.5 1.7 Unknown 0.2 0.4 Blood pressure (mmHg)* Systolic 138.6 ⫾ 18.1 140.2 ⫾ 17.9 Diastolic 80.2 ⫾ 10.9 81.3 ⫾ 11.7 History (%) Hypertension 61.2 60.3 Ischemic heart disease 7.9 8.2 Diabetes mellitus 26.5 23.0 Hyperlipidemia 23.5 25.5 Duration of drug intake (days)* 632.2 ⫾ 467.7 695.1 ⫾ 456.3 *Values are mean ⫾ SD.

the 2 groups. The size of cerebral infarction, blood pressure, and medical histories such as hypertension and diabetes mellitus, were also comparable between both groups. In total, 491 patients in the cilostazol group and 500 patients in the placebo group completed the trial. The protocol treatment was terminated for 250 patients in the cilostazol group and 279 patients in the placebo group,

151

Table 4. Reasons for withdrawal Casual factor

Cilostazol

Placebo

Occurrence of vascular events (%) Death (%) Other adverse events (%) Occurrence of complications (%) Accident (%) Dropout (%) Hospital change (%) Withdrawal of informed consent (%) Other reasons (%) Total Administration completers (%)

9.7 1.1 13.2 4.8 1.8 8.6 4.4 1.3 9.0 54.0 46.0

13.1 0.7 6.2 2.9 1.5 6.4 5.1 2.9 10.2 49.1 50.9

respectively, due to the reasons listed in Table 4. Adherence to the study treatment was checked by the investigators by questioning each patient, and additional analysis taking such information in account was conducted (not described here), but there was no essential difference from the primary analysis. Efficacy Analysis In the evaluable population analysis, there were 121 validated vascular events, of which 117 were nonfatal, and 4 were fatal (Table 5). Among the nonfatal events, there were 48 and 69 events in the cilostazol and placebo groups, respectively. Among the fatal events, there were 0 and 4 events in the cilostazol and placebo groups, respectively. Cause of death was complication of respiratory infection in 3 patients and putaminal hemorrhage in 1 patient. No evidence was found for an increased frequency of intracranial hemorrhage in the cilostazol group as compared with the placebo group. Table 5. Validated events (per 1,052 cases) Event type Nonfatal events Cerebral infarction TIA Myocardial infarction Intracranial hemorrhage* Other vascular events Subtotal Fatal events Cerebral infarction Transient ischemic attack Myocardial infarction Intracranial hemorrhage* Other vascular events Subtotal Total

Cilostazol

Placebo

Total

30 3 3 4 8 48

54 5 3 6 1 69

84 8 6 10 9 117

0 0 0 0 0 0 48

3 0 0 1 0 4 73

3 0 0 1 0 4 121

*Intracranial hemorrhage, cerebral hemorrhage ⫹ subarachnoid hemorrhage.

F. GOTOH ET AL.

152

Recurrence of cerebral infarction was observed in 30 patients in the cilostazol group during 889.6 patient-years at risk, representing an average rate of 3.37%/year (Table 6). On the other hand, recurrence of cerebral infarction was observed in 57 patients in the placebo group during 986.0 patient-years at risk, representing an average rate of 5.78%/year. The relative-risk reduction was 41.7% (95%, CI 9.2 to 62.5) in favor of cilostazol (P ⫽ .0150, log-rank test). The proportions of patients who did not experience recurrence of cerebral infarction over a period of 1,200 days are shown in Fig 2. A beneficial effect of cilostazol was clearly apparent and continued until the end of the trial period. The results of analyses of the predefined secondary outcomes are also included in Table 6. A relative-risk reduction of 39.0% (P ⫽ .0202) was observed in the cilostazol group, when the composite outcome event involving cerebral infarction or myocardial infarction was assessed. Similarly, the incidence of cerebral infarction, intracranial hemorrhage, or TIA was reduced in the cilostazol group with a 40.9% (P ⫽ .009) relative-risk reduction. Analysis of the composite occurrence of cerebral infarction, intracranial hemorrhage, myocardial infarction, or vascular death also showed a favorable result for the cilostazol group with a relative-risk reduction of

38.8% (P ⫽ .0151). The difference was attenuated for all vascular events, with a value of 27.1% (P ⫽ .0858). ITT analysis showed similar favorable results for the prevention of recurrence of cerebral infarction (relativerisk reduction, 42.3%; P ⫽ .0127) in the cilostazol group as compared with the placebo group. Analysis using follow-up observations also yielded similar results (relativerisk reduction, 40.9%; P ⫽ .011). Mean duration of follow-up period was 651.8 and 569.7 days in the cilostazol group and placebo group, respectively. In addition, death from any cause during the trial period including the follow-up after termination of the protocol treatment was reduced (relative-risk reduction, 43.8%; P ⫽ .0415) in the cilostazol group as compared with the placebo group. Subgroups of Patients Classified by Clinical Category As shown in Table 7, the cilostazol-treated patients with lacunar infarction as a qualifying event showed a statistically significant relative-risk reduction for the recurrence of cerebral infarction as compared with the placebotreated patients (relative-risk reduction, 43.4%; P ⫽ .0373). On the other hand, the relative-risk reduction was 39.8%

Table 6. Occurrence of primary and secondary endpoints according to allocated treatment (evaluable population analysis)

Nonfatal

Fatal

Total

Event rate per year (%)

30 54

0 3

30 57

3.37 5.78

41.7 (9.2-62.5)

.0150

33 57

0 3

33 60

3.71 6.09

39.0 (6.8-60.1)

.0202

37 65

0 4

37 69

4.17 7.06

40.9 (11.9-60.4)

.0090

37 63

0 4

37 67

4.16 6.80

38.8 (8.6-59.0)

.0151

48 69

0 4

48 73

5.45 7.47

27.1 (⫺5.0-49.4)

.0858

0 4

0 4

0.41

9 10

9 10

1.01 1.01

Outcome events

Cerebral infarction (primary outcome) Cilostazol (nyr, 889.6*) Placebo (nyr, 986.0) Cerebral infarction or myocardial infarction Cilostazol (nyr, 889.6) Placebo (nyr, 986.0) Cerebral infarction, intracranial hemorrhage, or TIA Cilostazol (nyr, 887.1) Placebo (nyr, 977.4) Cerebral infarction, intracranial hemorrhage, myocardial infarction, or vascular death Cilostazol (nyr, 889.6) Placebo (nyr, 986.0) All vascular events Cilostazol (nyr, 881.4) Placebo (nyr, 977.3) Vascular death Cilostazol (nyr, 889.6) Placebo (nyr, 986.2) Death from any cause Cilostazol (nyr, 889.7) Placebo (nyr, 986.3)

Abbreviations: CI, confidence interval; nyr, number of patient-years. *Patient-years at risk for outcome.

Relative-risk reduction (%) (95% CI)

P value

.0604

0.2 (⫺145.5-59.5)

.9791

CILOSTAZOL SECONDARY STROKE PREVENTION STUDY

153

Figure 2. Kaplan-Meier plots for the primary outcome (recurrence of cerebral infarction) according to assigned treatment. The numbers of patients at risk are shown below the figure.

these symptoms were generally mild or moderate and often self-limited, they did persist in some patients, resulting in discontinuation of the treatment. Arterial blood pressure was measured regularly at each patient visit, but no significant treatment-related alterations were noted. On the other hand, an increase in pulse rate was observed more frequently in the cilostazol group as compared with the placebo group. Liver function was monitored routinely, but no treatment-related effects were found. Similarly, no statistically significant treatmentrelated changes were evident in the laboratory data for the blood and urine including the hematological data, except that there was a decrease in serum triglycerides and an increase in serum high-density lipoprotein (HDL) cholesterol. The serum total cholesterol level was not significantly altered by the cilostazol treatment.

in the cilostazol-treated patients with atherothrombotic type infarction as a qualifying event, and this value did not reach statistical significance. Safety Analysis Table 8 lists the proportions of patients ever reporting any adverse events including abnormal laboratory values. There was no evidence of an increase in any bleeding abnormality, allergic reactions, or gastrointestinal disorders in the cilostazol group. On the other hand, 12.8% of the patients in the cilostazol group did experience headache, most of which was thought to be related to the intake of cilostazol. Similarly, 5.3% of the cilostazoltreated patients complained of palpitations, most of which was considered to be related to the drug intake. Although

Table 7. Primary endpoint (recurrence of cerebral infarction) in subgroups of cerebral infarction (evaluable population analysis)

Lacunar infarction Cilostazol (nyr, 673.8*) Placebo (nyr, 743.4) Atherothrombotic infarction Cilostazol (nyr, 109.8) Placebo (nyr, 104.0) Mixed type infarction Cilostazol (nyr, 90.7) Placebo (nyr, 117.5)

Outcome events

Event rate per year (%)

20 39

2.97 5.25

7 11 3 7

Relative-risk reduction (%) (95% CI)

P value

43.4 (3.0-67.0)

.0373

6.37 10.58

39.8 (⫺55.4-76.7)

.2620

3.31 5.96

44.5 (⫺114.6-85.7)

.4361

Abbreviations: CI, confidence interval; nyr, number of patient-years. *Patient-years at risk for outcome.

F. GOTOH ET AL.

154

Table 8. Adverse symptoms and abnormal values, whether thought to be drug-related or not (ITT)

Experience

Cilostazol (%)

Placebo (%)

No. of patients exposed to study medication 531‡ 533‡ Symptoms Any bleeding disorder* 15 (2.8) 11 (2.1) Subcutaneous bleeding 2 (0.4) 3 (0.6) Gastrointestinal bleeding 1 (0.2) 0 (0) Headache 68 (12.8) 17 (3.2) Dizziness 19 (3.6) 18 (3.4) Palpitations 28 (5.3) 2 (0.4) Nausea 14 (2.6) 7 (1.3) Gastrointestinal pain 12 (2.3) 12 (2.3) Skin rash 6 (1.1) 7 (1.3) Laboratory data Increase in pulse rate 77 (19.0) 34 (7.9) Increase in blood pressure 155 (32.2) 167 (33.1) Abnormality in EKG 55 (21.7) 52 (18.7) Decrease in serum triglycerides 28 (6.6) 13 (2.9) Increase in serum HDL cholesterol 54 (14.3) 21 (5.2) Decrease in serum total cholesterol 22 (4.9) 23 (4.9)

P value†

.4214 .6570 .3162 .0000 .8580 .0000 .1208 .9926 .7854 .0000 .7601 .3840 .0097 .0000 .9546

*Excluding cerebral hemorrhage and subarachnoid hemorrhage. †Chi square test. ‡Two patients in the cilostazol group and 1 in the placebo group have been excluded from this table because they did not revisit their clinical institutes after the start of the trial.

Discussion The results of the present trial clearly showed that long-term administration of cilostazol significantly prevented the recurrence of cerebral infarction with a relativerisk reduction of 41.7% (95% CI, 9.2 to 62.5) and numbers needed to treat (NNT) of 41.5 (95% CI, 23.3 to 188.7) as compared with placebo. Cilostazol was also found to be effective in reducing the composite outcome event involving cerebral infarction or myocardial infarction, as well as the combined event involving cerebral infarction, intracranial hemorrhage, or TIA. Likewise, the incidence of cerebral infarction, intracranial hemorrhage, myocardial infarction, or vascular death was effectively reduced by cilostazol. Subgroup analysis showed that the cilostazoltreated patients with lacunar infarction as a qualifying event displayed a statistically significant decrease in recurrence of cerebral infarction as compared with the placebo-treated patients, whereas the decrease in those with atherothrombotic infarction or mixed type infarction did not reach statistical significance. Cilostazol is a specific inhibitor of type III phosphodiesterase,14,15 which is known as cAMP-phosphodiesterase, and is strongly expressed in platelets and vascular smooth

muscle cells. This enzyme constitutes one of the major rate-limiting steps in the cascade of the cAMP pathway. Calcium ion (Ca2⫹ ) plays an important role in platelet activation, such as in shape changes, aggregation, and the secretion response. Several studies have shown that cAMP inhibits elevation of the intracellular Ca2⫹,16 and such an action appears to be manifested primarily through inhibition of Ca2⫹ mobilization and/or through an enhanced sequestration of Ca2⫹.17 Indeed, cilostazol has been shown to lower the intraplatelet Ca2⫹ concentration in association with higher cAMP and exerts an antiaggregation effect on platelets and a vasodilator effect on blood vessels. For example, cilostazol has been reported to prevent human platelet aggregation in vitro7,8 and to relax vascular strips prepared from the rabbit aorta.14 It has been found to increase peripheral blood flow in patients with arteriosclerosis obliterans18 and to inhibit proliferation of rat aorta smooth muscle cells in culture.19 Recently, shear stress-induced platelet aggregation has been observed to be significantly inhibited by cilostazol.20 Based on these pharmacological properties, cilostazol has been used clinically for the treatment of chronic arterial occlusive disease in Japan. With regard to cerebral circulation, cilostazol has been reported to dilate the pial arteries and to inhibit the formation of platelet thrombi during focal ischemia in the cat brain.12 A similar antithrombus effect of cilostazol has been described in a rabbit stroke model, where arachidonic acid was injected into the carotid artery to induce cerebral infarction.11 Both aspirin and ticlopidine have been found to be of benefit for the secondary prevention of ischemic stroke in placebo-controlled clinical trials.5,6 The relative risk reductions for the composite outcome of stroke, myocardial infarction, or vascular death were 25% with aspirin6 and 30.2% with ticlopidine.5 In the present study, treatment with cilostazol showed a 38.8% relative-risk reduction for this composite outcome (Table 6), which is higher than the values obtained in previous studies with aspirin or ticlopidine as described above.5,6 Recently, a randomized, blinded trial of clopidogrel, a new thienopyridine derivative similar to ticlopidine, yielded an 8.7% relative-risk reduction in the composite outcome for ischemic stroke, myocardial infarction, or vascular death as compared with aspirin.21 The event rate per year for this composite outcome was 5.32% in the clopidogrel group, which is slightly higher than that in the cilostazol group of the present study (4.16%). The apparently greater efficacy of cilostazol compared with aspirin, ticlopidine, or clopidogrel may be attributed not only to inhibition of platelet activation, but also to the vasodilatatory effect of clostazol. A recent European stroke prevention study has shown that combination treatment with aspirin (50 mg/ day) and dipyridamole (400 mg/day) brought about a 37% relative-risk reduction for secondary stroke after TIA or ischemic stroke as compared with placebo treatment.22

CILOSTAZOL SECONDARY STROKE PREVENTION STUDY

This degree of risk reduction appears to be comparable to the present results, although aspirin alone in this European study yielded only a 21% relative-risk reduction as compared with placebo. Kaplan-Meier plots showed that the efficacy of cilostazol was consistent during the trial term. The beneficial effects of cilostazol were similar for both men and women. Subanalysis based on the clinical categories of a qualifying event (viz., lacunar, atherothrombotic, and mixed type infarction) showed that cilostazol was effective for the prevention of secondary cerebral infarction in patients with lacunar infarction. In patients with atherothrombotic infarction, relative-risk reduction was 39.8%, which is comparative to 43.4% of lacunar infarction. However, it did not reach statistical significance, probably due to the small number under enrollment as compared with that of the patients with lacunar infarction. Although lacunar infarction is defined as a small deep infarction,23 the pathological mechanisms of lacunar infarction are less homogeneous than previously thought. They may involve not necessarily arteriolosclerosis of deep, small penetrating arteries, but also atherosclerosis of major arteries, especially at the orifice of the penetrating arteries. In fact, the patients with lacunar infarction showed atherothrombotic outcome in 6 of 39 events. Overall, it is inferred that cilostazol can be effective in preventing the recurrence of cerebral infarction in patients with atherothrombotic infarction, as well as those with lacunar infarction. The most commonly observed symptomatic adverse event was headache, which occurred in 68 cilostazoltreated patients (12.8%), although its severity was mostly mild or moderate. Such headache may have been attributed to cerebral vasodilatation induced by the relaxing effect of cilostazol on the vascular smooth muscle, especially of the external carotid artery.24 The next common complaint was palpitations, which occurred in 28 patients of the cilostazol group (5.3%), although this symptom was typically mild or moderate. Long-term intake of cilostazol in the present study was accompanied by some cause of bleeding in 2.8% of the patients, whereas 6% to 9% of patients treated with aspirin, ticlopidine, or clopidogrel have been found to show such complications.5,6,21 Cilostazol did not induce neutropenia, which has occasionally been observed in patients treated with ticlopidine.5 In general, cilostazol was well tolerated, and most of the encountered adverse drug reactions were managed symptomatically. The present trial showed that cilostazol decreased the level of serum triglycerides and increased the HDL cholesterol, as reported previously.25-27 The precise mechanisms underlying such effects remain unknown. The lipid-altering effects of cilostazol appeared to be independent of changes in physical activity or glucose tolerance. There are several mechanisms whereby an increased

155

cyclic AMP could result in lowered serum triglycerides. One possibility is considered to involve a reduction of hepatic triglyceride (i.e., very low-density lipoprotein [VLDL]) secretion, either directly or indirectly by potentiating the effect of glucagon to inhibit VLDL secretion.28 On the other hand, increased cyclic AMP levels have been shown to promote the release of lipoprotein lipase from rat adipocytes, which could reduce the serum triglycerides.29 At present, different mechanisms are thought to be responsible for the effects of cilostazol on triglycerides and HDL cholesterol, as the changes in the former were not correlated with those in the latter during cilostazol treatment.26 Although the magnitude of these lipidaltering effects was small to moderate, they may add to the potential clinical use of this drug. In summary, the present clinical study showed that the new antiplatelet drug, cilostazol (100 mg twice daily), is safe and effective in preventing the recurrence of cerebral infarction. This drug may represent a new therapeutic option for the secondary prevention of ischemic stroke in patients with cerebral infarction, especially lacunar infarction, at the chronic stage.

Appendix This trial was performed with the cooperation of the doctors and staff of the following clinical institutes, which entered patients, in Japan: Abashiri Neurosurgical Hospital, Aichi Saiseikai Hospital, Akune Municipal Hospital, Asahikawa Kohsei Hospital, Asahikawa Medical College, Asahikawa Rehabilitation Hospital, Ashikaga Red Cross Hospital, Bibai Rosai Hospital, Central Hospital of Yamaguchi, Chikuho Rosai Hospital, Chubu National Hospital, Chubu Rosai Hospital, Chugoku Rosai Hospital, Chukyo Hospital, Daigo Hospital, Dohoku National Hospital, Dokkyo University School of Medicine, Endowed Foundation Reimeikyo Rehabilitation Hospital, Engaru Kohsei Hospital, Fujita Public Hospital, Fukuiken Saiseikai Hospital, Fukushima Medical College, Gifu Prefectural Tajimi Hospital, Health Insurance Naruto Hospital, Hiroshima General Hospital, Hiroshima Municipal Hospital, Hiroshima Prefectural Hospital, Hiroshima University School of Medicine, Hokkaido Neurosurgical Memorial Hospital, Hyogo College of Medicine, Imakiire General Hospital, Inami General Hospital, Isehara Kyodo Hospital, Iwamisawa Rosai Hospital, Iwate Medical University School of Medicine, Iwate Prefectural Central Hospital, Izumi Municipal Hospital, Jichi Medical School, Jichi Medical School Omiya Medical Center, Jikeikai Hospital, Kagawa Medical School, Kagoshima Prefectural Hokusatsu Hospital, Kagoshima Prefectural Oshima Hospital, Kahan Hospital, Kajikawa Hospital, Kanazawa Medical University, Kanazawa University School of Medicine, Kansai Medical University, Kasugai Municipal Hospital, Kasukabe Municipal Hospital, Kawasaki Ida Municipal Hospital, Kawasaki Municipal Hospital, Keio

F. GOTOH ET AL.

156

University School of Medicine, Kinki University School of Medicine, Kitakyushu City Yahata Hospital, Kitami Red Cross Hospital, Kitano Hospital, Kitasato Institute Medical Center Hospital, Kitasato University East Hospital, Kitasato University School of Medicine, Kobe Central Municipal Hospital, Kohnan Hospital, Kumamoto City Hospital, Kumamoto University Medical School, Kure Kyousai Hospital, Kure National Hospital, Kurume University School of Medicine, Kushiro Rosai Hospital, Kyoto University Faculty of Medicine, Kyushu Rosai Hospital, Kyushu University Faculty of Medicine, Matsudo Municipal Hospital, Matsumoto Clinic, Meitetsu Hospital, Mie University Faculty of Medicine, Mihara Memorial Hospital, Institute of Brain and Blood Vessels, Mitsui Omuta Hospital, Miyagi National Hospital, Miyaishi Clinic, Miyazaki Medical College, Miyazaki Prefectural Hospital, Morioka Tsunagi Onsen Hospital, Myojo National Hospital, Nagaoka Chuo General Hospital, Nagoya City Higashi General Hospital, Nagoya City Rehabilitation and Sports Center, Nagoya Daini Red Cross Hospital, Nagoya Ekisaikai Hospital, Nagoya National Hospital, Nagoya University School of Medicine, Nara Medical University, National Cardiovascular Center, National FukuokaHigashi Hospital, National Higashi-Nagoya Hospital, National Saigata Hospital, Nippon Medical School Daiichi Hospital, Nishisendai Hospital, Nishi-Tottori National Hospital, Nojima Hospital, Oe Kyodo Hospital, Ogaki Municipal Hospital, Ohmi-hachiman City Hospital, Ohta Atami Hospital, Oita Prefectural Hospital, Oji General Hospital, Okatsu Hospital, Okayama Saiseikai General Hospital, Onishi Hospital, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka Medical College, Osaka National Hospital, Osaka Neurosurgical Institute, Osaka Prefectural General Hospital, Osaka University Medical School, Otake National Hospital, Oume Municipal General Hospital, Oyama Municipal Hospital, Research Institute for Brain and Blood Vessels-Akita, Saiseikai Utsunomiya Hospital, Saitama Medical School, Saitama National Hospital, Saito Hospital, San-in Rosai Hospital, Sapporo Medical College, School of Medicine, Fukuoka University, Seirei Hamamatsu General Hospital, Sendai National Hospital, Shiga University of Medical Science, Shimane Medical University, Shimizu Municipal Hospital, Shiroishi Kyouritsu Hospital, Shizuoka National Hospital, Showa University School of Medicine, Showa University School of Medicine Fujigaoka Hospital, Social Insurance Saitama Central Hospital, St. Marianna University Toyoko Hospital, Suita City Hospital, Tachikawa Kyosai Hospital, Tajirigaoka Hospital, Tamatsukuri Koseinenkin Hospital, Taoka Hospital, Teikyo University School of Medicine, Tenri Hospital, Teraoka Memorial Hospital, Tochigi Prefectural Ken-nan General Hospital, Tohoku Kosei-Nenkin Hospital, Tohoku University School of Medicine, Tokai University School of Medicine, Tokai University School of Medicine, Ohiso Hospital, Toko

General Hospital, Tokyo Medical and Dental University School of Medicine, Tokyo Medical College, Tokyo Metropolitan Komagome Hospital, Tokyo Metropolitan Tama Geriatric Hospital, Tokyo Saiseikai Central Hospital, Tokyo Teishin Hospital, Tokyo Women’s Medical College, Toneyama National Hospital, Tottori University Faculty of Medicine, Tousei General Hospital, Tsurumaki Onsen Hospital, Ube Industries Central Hospital, University of Chiba School of Medicine, University of Tokushima School of Medicine, University of Tsukuba School of Medicine, Urawa Municipal Hospital, Wakayama Rosai Hospital, Yamaguchi University School of Medicine, Yamanashi Medical College, Yao Municipal Hospital, Yodogawa Christian Hospital, Yofuen Clinic, Yokohama City University School of Medicine, Yokohama General Hospital, Yokohama Minami Kyosai Hospital, Yokohama Municipal Citizen’s Hospital, Yokohama Red Cross Hospital, Yokufukai Geriatric Hospital.

References 1. Grotta JC. Current medical and surgical therapy for cerebrovascular disease. N Engl J Med 1987;317:15051516. 2. Norrving B. Medical therapy to prevent ischemic stroke. In: Fisher M (ed). Stroke therapy. Boston: ButterworthHeinemann, 1995:207-218. 3. Helgason CM. Mechanisms of antiplatelet agents and the prevention of stroke. In: Welch KMA, Caplan LR, Reis DJ, et al, eds. Primer on cerebrovascular diseases. San Diego: Academic, 1997:712-716. 4. Organizing Committees. Asia Pacific consensus forum on stroke management. Stroke 1998;29:1730-1736. 5. Gent M, Blakely JA, Easton JD, et al. The Canadian American ticlopidine study (CATS) in thromboembolic stroke. Lancet 1989;1:1215-1220. 6. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106. 7. Umekawa H, Tanaka T, Kimura Y, et al. Purification of cyclic adenosine monophosphate phosphodiesterase from human platelets using new-inhibitor sepharose chromatography. Biochem Pharmacol 1984;33:3339-3344. 8. Kimura Y, Tani T, Kanbe T, et al. Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittelforschung 1985;35:1144-1149. 9. Ikeda Y, Kikuchi M, Murakami H, et al. Comparison of the inhibitory effects of cilostazol, acetylsalicylic acid and ticlopidine on platelet functions ex vivo: Randomized, double-blind cross-over study. Arzneimittelforschung 1987;37:563-566. 10. Igawa T, Tani T, Chijiwa T, et al. Potentiation of antiplatelet aggregating activity of cilostazol with vascular endothelial cells. Thromb Res 1990;57:617-623. 11. Watanabe K, Nakase H, Kimura Y. Effect of cilostazol on experimental cerebral infarction in rabbits. Arzneimittelforschung 1986;36:1022-1024.

CILOSTAZOL SECONDARY STROKE PREVENTION STUDY 12. Tanaka K, Gotoh F, Fukuuchi Y, et al. Effects of a selective inhibitor of cyclic AMP phosphodiesterase on the pial microcirculation in feline cerebral ischemia. Stroke 1989; 20:668-673. 13. Gotoh F, Ohashi Y, CSPS Group. Design and organization of the Cilostazol Stroke Prevention Study. J Stroke Cerebrovasc Dis 2000;9:36-44. 14. Tanaka T, Ishikawa T, Hagiwara M, et al. Effects of cilostazol, a selective cAMP phosphodiesterase inhibitor on the contraction of vascular smooth muscle. Pharmacology 1988;36:313-320. 15. Kimura Y. Selective type III phosphodiesterase inhibitor as an antithrombotic agent. Nippon Yakurigaku Zasshi 1995;106:205-216. 16. Yamanishi J, Kawahara Y, Fukuzaki H. Effect of cyclic AMP on cytoplasmic free calcium in human platelets stimulated by thrombin: Direct measurement with quin2. Thromb Res 1983;32:183-188. 17. Feinstein MB, Zavoico GB, Halenda SP. Calcium and cyclic AMP: Antagonistic modulators of platelet function. In: Longenecker GL, ed. The platelets: Physiology and pharmacology. Orlando: Academic, 1985:237-269. 18. Yasuda K, Sakuma M, Tanabe T. Hemodynamic effect of cilostazol on increasing peripheral blood flow in arteriosclerosis obliterans. Arzneimittelforschung 1985;35:11981200. 19. Takahashi S, Oida K, Fujiwara R, et al. Effect of cilostazol, a cyclic AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in culture. J Cardiovasc Pharmacol 1992;20:900-906. 20. Minami N, Suzuki Y, Yamamoto M, et al. Inhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo. Life Sci 1997;61:383-389.

157 21. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339. 22. Diener HC, Cunha L, Forbes C, et al. European stroke prevention study 2. Dipyridamole and acetylsalicyclic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1-13. 23. The National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 1990;21:637-676. 24. Yamashita K, Kobayashi S, Okada K, et al. Increased external carotid artery blood flow in headache patients induced by cilostazol. Arzneimittelforschung 1990;40:587588. 25. Sekiguchi M, Morikawa A, Nakajima K, et al. Clinical usefulness of cilostazol (Pletaal) on diabetic neuropathy and serum lipid levels. Jpn Pharmacol Ther 1991;19:32733277. 26. Elam MB, Heckman J, Crouse JR, et al. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arterioscler Thromb Vasc Biol 1998;18:1942-1947. 27. Dawson DL, Cutler BS, Meissner MH, et al. Cilostazol has beneficial effects in treatment of intermittent claudication. Circulation 1998;98:678-686. 28. Bjornsson OG, Sparks JD, Sparks CE, et al. Regulation of VLDL secretion in primary culture of rat hepatocytes: Involvement of cAMP and cAMP-dependent protein kinases. Eur J Clin Invest 1994;24:137-148. 29. Motoyashiki T, Morita T, Ueki H. Involvement of the rapid increase in cAMP content in the vanadatestimulated release of lipoprotein lipase activity from rat fat pads. Biol Pharm Bull 1996;19:1412-1416.