Article Figures & Data
- Figure 1
Forest plot depicting risk of ischaemic stroke recurrence. ASA, aspirin; CIL, cilostazol; CLO, clopidogrel; No CIL, placebo or best medical therapy.
- Figure 2
Forest plot depicting risk of any stroke recurrence. ASA, aspirin; CIL, cilostazol; CLO, clopidogrel; No CIL, placebo or best medical therapy.
- Figure 3
Forest plot depicting risk of intracranial haemorrhage. ASA, aspirin; CIL, cilostazol; CLO, clopidogrel; No CIL, placebo or best medical therapy.
- Figure 4
Forest plot depicting risk of major haemorrhagic events. ASA, aspirin; CIL, cilostazol; CLO, clopidogrel; No CIL, placebo or best medical therapy.
- Figure 5
Forest plot depicting risk of mortality. ASA, aspirin; CIL, cilostazol; CLO, clopidogrel; No CIL, placebo or best medical therapy.
- Table 1
Characteristics of included studies
Study ID Country Sample size, ITT (% male) Age (intervention) Age (control) Intervention Control Aoki 2019 (ADS)*22 Japan 1201 (66%) 69 (IQR 60–77) 69 (IQR 61–78) Cilostazol 200 mg + aspirin 81–200 mg Aspirin 81–200 mg Blair 2019 (LACI-1)23 UK 57 (68%) Mean of all participants: 66.1 (11.1) Cilostazol 100 mg BD + aspirin/clopidogrel Aspirin/clopidogrel Gotoh 2000 (CSPS)24 Japan 1067 (66%) 65.2 (8.7) 65.1 (8.8) Cilostazol 100 mg BD Placebo Guo 200925 China 68 (35%) 59.44 (10.63) 62.02 (11.12) Cilostazol 100 mg BD Aspirin 100 mg Han 2013 (ECLIPse)26 Korea 182 (25%) 64.63 (9.07) 65.48 (9.92) Cilostazol 100 mg BD + aspirin 100 mg Aspirin 100 mg Huang 2008 (CASISP)27 China 719 (69%) 60.14 (10.05) 60.31 (9.71) Cilostazol Aspirin Johkura 201228 Japan 106 (43%) 76.7 (9.8) 73.7 (9.4) Cilostazol 200 mg Aspirin 100 mg Kim 2018 (PICASSO)29 South Korea, Hong Kong, Philippines 1534 (62%) 65.5 (10.9) 65.8 (10.7) Cilostazol 100 mg BD Aspirin 100 mg Kwon 2005 (TOSS)30 South Korea 135 (61%) 62.28 (10.42) 62.54 (8.97) Cilostazol 100 mg BD + aspirin 100 mg Aspirin 100 mg Kwon 2011 (TOSS-2)31 4 East Asian countries 457 (51%) 66.42 (11.33) 64.58 (11.11) Cilostazol 100 mg BD + aspirin 75–150 mg Clopidogrel 75 mg + aspirin 75–150 mg Lee 2011 (CAIST)32 Korea 458 (61%) 63 (12) 63 (12) Cilostazol 200 mg Aspirin 300 mg Lee 201733 Korea 80 (65%) 57.4 (12.7) 59.5 (11.7) Cilostazol 100 mg BD Aspirin 100 mg Nakamura 201234 Japan 76 (74%) 66 (12) 67 (10) Cilostazol 100 mg BD + aspirin 300 mg Aspirin 300 mg Ohnuki 201735 Japan 24 (71%) 60.5 (10) 63.6 (9.1) Cilostazol 200 mg + aspirin 100 mg Aspirin 100 mg Shimizu 201336 Japan 507 (67%) 66.2 (9.4) 66.6 (8.9) Cilostazol 200 mg + optimal medical treatment Optimal medical treatment Shinohara 2010 (CSPS 2)37 Japan 2716 (72%) 63.5 (9.2) 63.4 (9.0) Cilostazol 100 mg BD Aspirin 81 mg Toyoda 2019 (CSPS.com)38 Japan 1879 (70%) 69.6 (9.2) 69.7 (9.2) Cilostazol 100 mg BD + aspirin 81–100 mg/ clopidogrel 50–75 mg Aspirin 81–100 mg/ clopidogrel 50–75 mg Uchiyama 2015 (CATHARSIS)39 Japan 163 (66%) 68.3 (range 45–84) 68.3 (range 50–82) Cilostazol 200 mg + aspirin 100 mg Aspirin 100 mg All data are in mean (SD) or median (IQR/range).
*After 14 days, both arms were swapped to cilostazol 200 mg until 3 months. Where possible, we analysed data at 14 days instead of 3 months.
ITT, intention to treat.
- Table 2
Details of included studies
Study ID Time to randomisation/treatment Duration of treatment/ follow-up Type of stroke Cilostazol Control Aoki 2019 (ADS)22 Within 48 hours
Cilostazol: 10.1 hours (IQR 4.6–20.0)
Control: 11.5 hours (IQR 4.8–20.9)14 days, 3 months Symptomatic ICAS (23%)
Large-artery atherosclerosis (13%),
LACI (46%), branch atheromatous disease (13%)Symptomatic ICAS (22%)
Large-artery atherosclerosis (15%),
LACI (43%), branch atheromatous disease (16%)Blair 2019 (LACI-1)23 Within 4 years
Median: 203 days (range 6–920)Treatment: 6–9 weeks
Follow-up: 11 weeksLACI LACI Gotoh 2000 (CSPS)24 1–6 months
Cilostazol: 83.0 days (range 7–1805)
Control: 82.4 days (range 8–1079)Mean follow-up duration:
Cilostazol: 651.8 days
Control: 569.7 days
Treatment duration:
Cilostazol: 632.2 (467.7) days Control: 695.1 (456.3) daysAtherothrombotic (14.1%), LACI (75.0%), mixed (9.0%) Atherothrombotic (13.1%), LACI (73.8%), mixed (11.4%) Guo 200925 1–6 months 12 months Han 2013 (ECLIPse)26 Within 7 days
Median: 5 days (78.3% of patients were randomised within 7 days)90 days LACI LACI Huang 2008 (CASISP)27 1–6 months
Cilostazol: 77.26 (50.05) days
Control: 79.72 (51.96) days12–18 months (average: 740 person-years) Johkura 201228 1–6 months 6 months Kim 2018 (PICASSO)*29 Within 180 days
Cilostazol: 18 days (IQR 8–40)
Control: 17 days (IQR 7–35)1.9 years (IQR 1.0–3.0) Ischaemic stroke (95%), TIA (5%) Ischaemic stroke (94%), TIA (6%) Kwon 2005 (TOSS)30 Within 2 weeks 6 months ICAS ICAS Kwon 2011 (TOSS-2)31 Within 2 weeks
Cilostazol: 8.03 (3.34) days
Control: 7.82 (3.15) days7 months ICAS ICAS Lee 2011 (CAIST)32 Within 48 hours
Cilostazol: 33 (12) hours
Control: 35 (11) hours90 days Large-artery disease (32%), small-vessel disease (55%), cardioembolism (1%), other determined aetiology (<1%), undetermined (12%) Large-artery disease (25%), small-vessel disease (62%), cardioembolism (1%), other determined aetiology (<1%), undetermined (12%) Lee 201733 Within 7 days 3 months Atherosclerosis (9.4%), small-artery disease (87.5%), TIA (3.1%) Atherosclerosis (2.9%), small-artery disease (87.5%), TIA (5.9%), unknown (8.8%) Nakamura 201234 Within 48 hours
Cilostazol: 25 (12) hours
Control: 23 (14) hours6 months Large-artery atherosclerosis (21%), small-vessel occlusion (47%), other determined or undetermined aetiology (32%) Large-artery atherosclerosis (18%), small-vessel occlusion (47%), other determined or undetermined aetiology (34%) Ohnuki 201735 Within 7 days 4 weeks Atherothrombosis (15%), LACI (62%), TIA (8%), unknown (15%) Atherothrombosis (45%), LACI (45%), TIA (9%) Shimizu 201336 Within 24 hours 3 months Atherothrombotic (30.7%), LACI (64.1%), others (5.2%) Atherothrombotic (25.0%), LACI (70.7%), others (4.3%) Shinohara 2010 (CSPS 2)37 Within 26 weeks (6 months) 1–5 years
Mean: 29 (16) monthsAtherothrombotic (33%), LACI (65%), others (3%) Atherothrombotic (31%), LACI (65%), others (3%) Toyoda 2019 (CSPS.com)†38 8–180 days
Cilostazol: 27 days (IQR 13–63)
Control: 25 days (IQR 13–64)0.5–3.5 years
Median: 1.4 (IQR 0.8–2.2)ICAS (30%), ECAS (12%)
Atherothrombotic (42%), LACI (50%), others/unknown (8%)ICAS (29%), ECAS (14%)
Atherothrombotic (42%), LACI (49%), others/unknown (9%)Uchiyama 2015 (CATHARSIS)39 2 weeks to 6 months 2 years
Mean: 762 daysICAS ICAS Data are in median (IQR), mean (range) or mean (SD) unless otherwise stated.
*Only patients with asymptomatic or previous intracerebral haemorrhage were included.
†Only patients with high-risk ischaemic stroke were included.
ICAS, intracranial arterial stenosis; LACI, lacunar infarction; TIA, transient ischaemic attack.
- Table 3
Summary of outcomes
Subgroup N Cilostazol Control RR (95% CI) P value I2 (%) Test for subgroup differences Ischaemic stroke recurrence A Overall 18 217/5724 317/5705 0.69 (0.58–0.81) <0.0001 0 NA B CIL SAPT vs SAPT 7 131/2844 168/2837 0.78 (0.62–0.97) 0.03 0 χ3 2=7.50, p=0.06, I2=60.0% CIL DAPT vs SAPT 8 43/1864 82/1853 0.52 (0.36–0.75) 0.0005 0 CIL DAPT vs DAPT 1 10/232 6/225 1.62 (0.60–4.37) 0.34 NA CIL vs No CIL 2 33/784 61/790 0.54 (0.36–0.82) 0.003 0 C Stroke onset <3 days 4 16/1120 24/1122 0.67 (0.36–1.25) 0.20 0 χ1 2=0.01, p=0.93, I2=0% Stroke onset >3 days 14 201/4604 293/4583 0.69 (0.56–0.84) 0.0002 8 D Short term (<3 months) 3 7/655 8/627 0.78 (0.29–2.12) 0.63 0 χ1 2=0.07, p=0.80, I2=0% Long term (≥3 months) 15 210/5069 309/5078 0.68 (0.58–0.81) <0.0001 0 E Symptomatic ICAS 3 14/382 12/373 1.10 (0.45–2.68) 0.84 24 χ2 2=1.33, p=0.52, I2=0% LACI 2 2/131 1/108 1.08 (0.14–8.56) 0.95 0 Others/mixed/unknown 13 201/5211 304/5224 0.67 (0.56–0.79) <0.00001 0 Any stroke recurrence A Overall 18 250/5724 394/5705 0.64 (0.54–0.74) <0.00001 0 NA B Stroke onset <3 days 4 20/1120 29/1122 0.70 (0.39–1.23) 0.21 0 χ1 2=0.11, p=0.75, I2=0% Stroke onset >3 days 14 230/4604 365/4583 0.63 (0.54–0.74) <0.00001 0 C Short term (<3 months) 3 9/655 9/627 0.91 (0.37–2.24) 0.83 0 χ1 2=0.61, p=0.43, I2=0% Long term (≥3 months) 15 241/5069 385/5078 0.63 (0.54–0.74) <0.00001 0 D Symptomatic ICAS 3 15/382 14/373 0.96 (0.27–3.45) 0.95 65 χ2 2=0.71, p=0.70, I2=0% LACI 2 2/131 1/108 1.08 (0.14–8.56) 0.95 0 Others/mixed/unknown 13 233/5211 379/5224 0.62 (0.53–0.73) <0.00001 0 Intracranial haemorrhage A Overall 18 37/5724 86/5705 0.46 (0.31–0.68) <0.0001 0 NA B Stroke onset <3 days 4 4/1120 5/1122 0.91 (0.24–3.53) 0.89 0 χ1 2=1.05, p=0.31, I2=4.8% Stroke onset >3 days 14 33/4604 81/4583 0.43 (0.29–0.65) <0.0001 0 C Short term (<3 months) 3 2/655 1/627 2.00 (0.18–22.03) 0.57 NA χ1 2=1.48, p=0.22, I2=32.3% Long term (≥3 months) 15 35/5069 85/5078 0.44 (0.30–0.66) <0.0001 0 D Symptomatic ICAS 3 1/382 3/373 0.46 (0.06–3.57) 0.46 0 χ1 2=0.00, p=1.00, I2=0% LACI 2 0/131 0/108 NA NA NA Others/mixed/unknown 13 36/5211 83/5224 0.46 (0.31–0.68) 0.0001 0 Major haemorrhagic events A Overall 14 44/4031 93/4010 0.49 (0.34–0.70) <0.0001 0 NA B Stroke onset <3 days 4 7/1120 13/1122 0.60 (0.24–1.52) 0.28 0 χ1 2=0.23, p=0.63, I2=0% Stroke onset >3 days 10 37/2911 80/2888 0.47 (0.32–0.69) 0.0001 0 C Short term (<3 months) 3 4/655 5/627 0.80 (0.22–2.97) 0.74 NA χ1 2=0.59, p=0.44, I2=0% Long term (≥3 months) 11 40/3376 88/3383 0.47 (0.32–0.68) <0.0001 0 D Symptomatic ICAS 3 6/382 9/373 0.67 (0.17–2.59) 0.56 37 χ1 2=0.24, p=0.62, I2=0% LACI 2 0/131 0/108 NA NA NA Others/mixed/unknown 9 38/3518 84/3529 0.47 (0.32–0.68) <0.0001 0 Mortality A Overall 15 64/5029 72/5017 0.90 (0.64–1.25) 0.53 0 NA B Stroke onset <3 days 2 3/482 1/483 2.33 (0.34–15.82) 0.39 0 χ1 2=0.98, p=0.32, I2=0% Stroke onset >3 days 13 61/4547 71/4534 0.87 (0.62–1.22) 0.43 0 C Short term (<3 months) 2 0/55 0/26 NA NA NA NA Long term (≥3 months) 13 64/4974 72/4991 0.90 (0.64–1.25) 0.53 0 D Symptomatic ICAS 3 2/382 3/373 0.67 (0.11–4.06) 0.66 0 χ1 2=0.11, p=0.74, I2=0% LACI 2 0/131 0/108 NA NA NA Others/mixed/unknown 10 62/4516 69/4536 0.91 (0.65–1.27) 0.58 0 MACE A Overall 13 184/3826 276/3842 0.67 (0.56–0.81) <0.0001 0 NA B Stroke onset <3 days 4 25/1120 33/1122 0.76 (0.45–1.27) 0.30 0 χ1 2=0.18, p=0.67, I2=0% Stroke onset >3 days 9 159/2706 243/2720 0.67 (0.52–0.86) 0.002 20 C Short term (<3 months) 2 12/613 12/612 1.00 (0.45–2.21) 1.00 NA χ1 2=1.03, p=0.31, I2=3.0% Long term (≥3 months) 11 172/3213 264/3230 0.66 (0.55–0.79) <0.0001 0 D Symptomatic ICAS 2 17/299 12/293 1.38 (0.67–2.85) 0.38 0 χ2 2=4.22, p=0.12, I2=52.6% LACI 1 1/89 1/93 1.04 (0.07–16.45) 0.98 NA Others/mixed/unknown 10 166/3438 263/3456 0.64 (0.53–0.77) <0.00001 0 CIL, cilostazol; DAPT, dual antiplatelet therapy; ICAS, intracranial arterial stenosis; LACI, lacunar infarction; No CIL, placebo or best medical therapy; RR, risk ratio; SAPT, single antiplatelet therapy.
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