2023 Volume 30 Issue 6 Pages 675-683
Aim: Although some sex differences in stroke have been reported, differences in the effects of antiplatelet therapy for secondary stroke prevention have not been clarified.
Methods: In the Cilostazol Stroke Prevention Study combination trial, patients with high-risk, non-cardioembolic ischemic stroke between 8 and 180 days after onset treated with aspirin or clopidogrel alone were recruited and randomly assigned to receive either monotherapy or dual antiplatelet therapy (DAPT) using cilostazol and followed up for 0.5–3.5 years. The primary efficacy outcome was recurrence of ischemic stroke. The safety outcome was severe or life-threatening hemorrhage. Outcomes were analyzed by sex.
Results: A total of 1,320 male patients and 558 female patients were included. The male patients had more risk factors than the female patients. In male patients, the primary endpoint occurred at a rate of 2.0 per 100 patient-years in the DAPT group and 5.1 per 100 patient-years in the monotherapy group (hazard ratio (HR), 0.40; 95% confidence interval (CI), 0.23–0.68). In male patients, DAPT prolonged the time to recurrent stroke by 4.02-fold (95% CI, 1.63–9.96) compared with monotherapy. In female patients, the average annual event rates were 2.7 per 100 patient-years in the DAPT group and 3.3 per 100 patient-years in the monotherapy group (HR, 0.82; 95% CI, 0.37–1.84). Safety outcomes did not differ significantly in both male and female patients.
Conclusions: Long-term DAPT using cilostazol reduced the recurrence of ischemic stroke and prolonged the recurrence-free time in male patients, but not in female patients.
Some sex differences in stroke have been described1). Epidemiologically, the mean age is 4.5 years older in female patients, and stroke is more common in male patients, but female patients are more severely ill2). The International STRoke oUtComes sTudy (INSTRUCT) demonstrated that severity and mortality were greater in female patients. Severity was attenuated after adjustment for confounding factors, including age, prestroke functional limitations, stroke severity, and history of atrial fibrillation, but remained statistically significant3). For treatment in ischemic stroke, with regard to carotid endarterectomy (CEA), lack of benefit has been reported in women4), and the guideline recommended that CEA should be done based on patient-specific factors, including sex in patients with moderate extracranial carotid stenosis5). For antiplatelet therapy, aspirin was found to be effective in preventing myocardial infarction, but not cerebral infarction in men for primary prevention, whereas it was not effective in preventing myocardial infarction, but it was for cerebral infarction in women6-8). Since many clinical trials for secondary prevention recruit more male patients, and there are no reports of clinical trials that mainly examined sex differences in antiplatelet therapy for the secondary prevention of non-cardioembolic stroke, sex differences in the effects of antiplatelet therapy for secondary stroke prevention are not clear9).
Cilostazol is another category of antiplatelet with low hemorrhagic events10, 11). The Cilostazol Stroke Prevention Study combination (CSPS.com) showed that dual antiplatelet therapy (DAPT) using cilostazol was significantly more effective than monotherapy in preventing recurrent stroke and did not increase hemorrhagic complications in chronic high-risk non-cardioembolic stroke12). In the present study, the results of CSPC.com were analyzed with a focus on sex differences.
The de-identified individual participant data and the study protocol of the CSPS.com may be available upon request to the Japan Cardiovascular Research Foundation.
Design and PatientsDetails regarding the CSPS.com trial rationale, design, and methods have been described elsewhere13). The protocol for the CSPS.com trial was approved by the ethics committee at each participating site, and all patients provided written, informed consent before randomization. In that multicenter, randomized, open-label, parallel-group trial, patients at 292 sites in Japan underwent assignment following randomization from December 2013 through March 2018. Any event related to the primary and secondary outcomes was reviewed by the event review committee, which was blinded to the patients’ antiplatelet medications.
The trial’s eligible patients were subjects between 20 and 85 years old who had experienced a non-cardioembolic ischemic stroke, as identified on magnetic resonance imaging (MRI), between 8 and 180 days before the start of protocol treatment. These patients were administered either aspirin or clopidogrel alone as antiplatelet therapy after providing informed consent. The patients were also required to meet one or more of the following three criteria indicating a high risk of stroke recurrence: (1) ≥ 50% stenosis of a major intracranial artery (to the level of A2, M2, or P2); (2) ≥ 50% stenosis of an extracranial artery (common carotid artery, internal carotid artery, vertebral artery, brachiocephalic artery, or subclavian artery); and (3) two or more of the following risk factors: age ≥ 65 years, diabetes mellitus, hypertension, peripheral arterial disease, chronic kidney disease (CKD), history of ischemic stroke other than the qualifying stroke for the trial, history of ischemic heart disease, and current smoking13).
In the CSPS.com trial, the patients were randomly assigned, in a 1:1 ratio using a block-randomization scheme, to receive either monotherapy with aspirin (81 or 100 mg) or clopidogrel (50 or 75 mg), administered once daily, or dual therapy using cilostazol (100 mg, twice daily; the recommended dose for stroke prevention in Japan) in combination with either aspirin (81 or 100 mg) or clopidogrel (50 or 75 mg), administered once daily. In Japan, clopidogrel at 50 mg is approved for older (e.g., ≥ 75 years old) and low-weight patients (weight ≤ 50 kg). For the prevention of adverse drug reactions such as headache and tachycardia, treating physicians were provided the option of initiating cilostazol treatment at 100 mg/day and increasing to 200 mg/day within 15 days. Changes in the choice of these three antiplatelet medications were not permitted after informed consent was obtained13). The data of the CSPS.com trial were analyzed by sex.
OutcomesThe primary efficacy outcome was the first recurrence of ischemic stroke. The secondary efficacy outcomes were: (1) any stroke (ischemic or hemorrhagic); (2) hemorrhagic stroke (intracerebral or subarachnoid hemorrhage); (3) ischemic stroke or transient ischemic attack (TIA); (4) death from any cause; (5) a composite of stroke, myocardial infarction, and vascular death; and (6) all vascular events, including stroke, myocardial infarction, and other vascular events13).
The safety outcomes were severe or life-threatening bleeding as defined in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) classification, which includes intracranial hemorrhage and bleeding resulting in substantial hemodynamic compromise requiring treatment13).
Statistical AnalysisEfficacy analyses were conducted in the intention-to-treat population, focused only on the time to first event. Safety analyses were conducted with patients who had received at least one dose of a trial regimen. The treatment groups were compared using the log-rank test. Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the comparison of the DAPT group with the monotherapy group. Annual recurrence rates were estimated using the person-year method. To evaluate the treatment effect of DAPT compared with monotherapy on multivariate analysis, a Cox proportional hazards model with a forward–backward stepwise selection algorithm based on Akaike’s Information Criterion (AIC) was applied to calculate adjusted HRs and 95% CIs. Multivariate analysis was not performed when the number of events was small and the parameters of the regression model diverged during the estimation procedure. A p value of ＜0.05 based on a two-sided test was considered as statistically significant. In addition to comparing HRs using the Cox regression model, a semiparametric acceleration model with recurrence-free interval as the outcome was applied to evaluate how much DAPT prolongs the recurrence-free interval on average, to examine the sex difference in the benefit of DAPT in more detail. Statistical analysis was performed using R (version 4.0.2; Microsoft Co., Redmond, WA, USA) and SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).
Of a total of 1,879 randomized patients, including 932 patients assigned to the DAPT and 947 assigned to the monotherapy arms, there were 1,320 male and 559 female patients. Some of the background clinical features differed by sex (Table 1). The male patients were younger than the female patients; had a higher body mass index (BMI); had a higher prevalence of diabetes mellitus, peripheral artery disease, history of ischemic stroke, history of ischemic heart disease, and extracranial artery stenosis; and had a lower prevalence of dyslipidemia. Antiplatelet use at randomization, stroke subtype, infarct location, and median time to randomization after index events were not different between male and female patients.
| Male (n=1320) | Female (n=559) | p value | Male | Female | |||
|---|---|---|---|---|---|---|---|
| Monotherapy (n=683) | Dual therapy (n=637) | Monotherapy (n=264) | Dual therapy (n=295) | ||||
| Age, years | 68.6 (64-75) | 71.9 (67-79) | ＜0.01 | 69 (64-76) | 69 (64-75) | 73 (67-79) | 73 (67-78) |
| Asian ethnicity | 1320 (100%) | 559 (100%) | 683 (100%) | 637 (100%) | 264 (100%) | 295 (100%) | |
| Body-mass index | 23.6 (21.8-25.8) | 22.8 (21.1-25.8) | ＜0.01 | 23.6 (21.8-25.7) | 23.6 (21.8-25.8) | 22.5 (20.8-25.4)＊ | 23.2 (21.3-26.2)＊ |
| Median blood pressure, mm Hg | |||||||
| Systolic | 137 (126-150) | 138 (126-151) | 0.55 | 138 (126-151) | 136 (127-148) | 138 (127-152) | 136 (126-150) |
| Diastolic | 79 (70-88) | 78 (70-86) | 0.05 | 79 (70-88) | 78 (70-87) | 78 (70-86) | 78 (69-86) |
| Medical history | |||||||
| Hypertension | 1105 (84%) | 465 (83%) | 0.72 | 566 (83%) | 539 (85%) | 223 (84%) | 242 (82%) |
| Dyslipidaemia | 677 (51%) | 343 (61%) | ＜0.01 | 370 (54%)＊ | 307 (48%)＊ | 158 (60%) | 185 (63%) |
| Diabetes mellitus | 523 (40%) | 178 (32%) | ＜0.01 | 281 (41%) | 242 (38%) | 74 (28%) | 104 (35%) |
| Chronic kidney disease | 89 (7%) | 30 (5%) | 0.35 | 41 (6%) | 48 (8%) | 8 (3%)＊ | 22 (7%)＊ |
| Peripheral arterial disease | 42 (3%) | 7 (1%) | ＜0.05 | 19 (3%) | 23 (4%) | 3 (1%) | 4 (1%) |
| History of ischemic stroke† | 204 (15%) | 68 (12%) | 0.08 | 113 (17%) | 91 (14%) | 34 (13%) | 34 (12%) |
| History of ischemic heart disease | 78 (6%) | 18 (3%) | ＜0.05 | 39 (6%) | 39 (6%) | 9 (3%) | 9 (3%) |
| Current smoking | 484 (37%) | 50 (9%) | ＜0.01 | 251 (37%) | 233 (37%) | 24 (9%) | 26 (9%) |
| Two or more risk factors | 1206 (91%) | 491 (88%) | ＜0.05 | 587 (86%) | 619 (97%) | 256 (97%) | 235 (80%) |
| Intracranial artery stenosis | 367 (28%) | 180 (32%) | ＜0.05 | 193 (28%) | 174 (27%) | 79 (30%) | 101 (34%) |
| Extracranial artery stenosis | 215 (16%) | 38 (7%) | ＜0.01 | 121 (18%) | 94 (15%) | 16 (6%) | 22 (7%) |
| Modified Rankin Scale‡ score at randomisation | |||||||
| 0-1 | 736 (56%) | 287 (51%) | 0.19 | 381 (56%) | 355 (56%) | 126 (48%) | 161 (55%) |
| 0-2 | 1118 (85%) | 442 (79%) | ＜0.05 | 571 (84%) | 547 (86%) | 206 (78%) | 236 (80%) |
| Antiplatelet use at randomisation | |||||||
| Aspirin | 523 (40%) | 240 (43%) | 0.18 | 265 (39%) | 258 (41%) | 115 (44%) | 125 (42%) |
| Clopidogrel§ | 797 (60%) | 319 (57%) | 418 (61%) | 379 (59%) | 149 (56%) | 170 (58%) | |
| Stroke subtype | |||||||
| Lacunar | 642 (49%) | 283 (51%) | 0.26 | 327 (48%) | 315 (49%) | 134 (51%) | 149 (51%) |
| Atherothrombotic | 573 (43%) | 215 (38%) | 303 (44%) | 270 (42%) | 96 (36%) | 119 (40%) | |
| Other or undetermined | 83 (6%) | 43 (8%) | 42 (6%) | 41 (6%) | 24 (9%) | 19 (6%) | |
| Infarct location | |||||||
| Supratentorial | 963 (73%) | 423 (76%) | 0.18 | 504 (74%) | 459 (72%) | 194 (73%) | 229 (78%) |
| Infratentorial | 317 (24%) | 113 (20%) | 157 (23%) | 160 (25%) | 57 (22%) | 56 (19%) | |
| Both | 18 (1%) | 5 (1%) | 11 (2%) | 7 (1%) | 3 (1%) | 2 (1%) | |
| Unreported | 22 (2%) | 18 (3%) | 11 (2%) | 11 (2%) | 10 (4%) | 8 (3%) | |
| Median time to randomisation after index events, days | 26 (13-66) | 28 (14-58.5) | 0.77 | 25 (12-67.5) | 26 (13-63) | 27 (14-56) | 28 (14-63) |
| Median duration of observational period, days | 519 (281-811) | 497 (289-807) | 0.95 | 511 (325-811) | 522 (212-811) | 537 (354-811) | 486 (175-804) |
Data are n (%) of overall patients. ＊p＜0.05 for comparison of monotherapy and DAPT groups. †Except the qualifying stroke for this trial. ‡The modified Rankin Scale measures the degree of disability in the daily activities of patients, ranging from 0 to 6, with higher scores indicating worse functional deficits than lower scores. §39 male patients and 20 female patients were taking clopidogrel 50 mg once per day; the other patients were taking clopidogrel 75 mg once per day.
The primary endpoint of ischemic stroke occurred in 69 (3.6 per 100 patient-years) out of the 1,320 male patients during follow-up and in 24 (3.0 per 100 patient-years) out of the 559 female patients (HR, 0.83; 95% CI, 0.52–1.33). The subgroup analysis showed no apparent interaction between sex and DAPT therapy (p=0.1331)12). None of the secondary efficacy outcomes was significantly different. The rate of the safety outcome of severe or life-threatening hemorrhage did not differ significantly between male and female patients (0.6 per 100 patient-years vs. 1.3 per 100 patient-years, respectively; HR, 2.42; 95% CI, 0.85–6.83) (Table 2).
| Male | Female | HR (95% CI) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| No. of patients | Annual event rate | No. of patients | Annual event rate | |||||||
| Primary efficacy outcomes | n=1320 | n=559 | ||||||||
| Ischemic stroke | 69 | 3.6 | 24 | 3.0 | 0.83 (0.52-1.33) | |||||
| Secondary efficacy outcomes | ||||||||||
| Any stroke | 76 | 4.0 | 29 | 3.6 | 0.92 (0.60-1.40) | |||||
| Hemorrhagic stroke | 7 | 0.4 | 5 | 0.6 | 1.71 (0.54-5.40) | |||||
| Ischemic stroke or TIA | 75 | 3.9 | 26 | 3.2 | 0.83 (0.53-1.30) | |||||
| Death from any cause | 10 | 0.5 | 3 | 0.4 | 0.72 (0.20-2.63) | |||||
| Composite stroke + MI + vascular death | 85 | 4.4 | 31 | 3.9 | 0.88 (0.58-1.32) | |||||
| All vascular events | 101 | 5.3 | 36 | 4.5 | 0.86 (0.59-1.25) | |||||
| Safety outcomes | n=1291 | n=540 | ||||||||
| Severe or life-threatening bleeding | 11 | 0.6 | 10 | 1.3 | 2.42 (0.85-6.83) | |||||
| Hemorrhagic adverse event | 45 | 2.3 | 28 | 3.2 | 0.95 (0.59-1.53) | |||||
| Male | Female | |||||||||
| Monotherapy | DAPT | HR (95% CI) | Monotherapy | DAPT | HR (95% CI) | |||||
| No. of patients | Annual event rate | No. of patients | Annual event rate | No. of patients | Annual event rate | No. of patients | Annual event rate | |||
| Primary efficacy outcomes | n=683 | n=637 | n=264 | n=295 | ||||||
| Ischemic stroke | 51 | 5.1 | 18 | 2.0 | 0.40 (0.23-0.68) | 13 | 3.3 | 11 | 2.7 | 0.82 (0.37-1.84) |
| Secondary efficacy outcomes | ||||||||||
| Any stroke | 55 | 5.5 | 21 | 2.3 | 0.43 (0.26-0.71) | 16 | 4.0 | 13 | 3.2 | 0.79 (0.38-1.65) |
| Hemorrhagic stroke | 4 | 0.4 | 3 | 0.3 | 0.82 (0.18-3.69) | 3 | 0.8 | 2 | 0.5 | 0.66 (0.11-3.94) |
| Ischemic stroke or TIA | 55 | 5.5 | 20 | 2.2 | 0.41 (0.24-0.68) | 14 | 3.5 | 12 | 3.0 | 0.84 (0.39-1.81) |
| Death from any cause | 6 | 0.6 | 4 | 0.4 | 0.73 (0.21-2.60) | 1 | 0.3 | 2 | 0.5 | 2.01 (0.18-22.13) |
| Composite stroke + MI + vascular death | 62 | 6.2 | 23 | 2.5 | 0.41 (0.25-0.66) | 16 | 4.0 | 15 | 3.7 | 0.92 (0.45-1.85) |
| All vascular events | 72 | 7.1 | 29 | 3.2 | 0.45 (0.29-0.69) | 18 | 4.5 | 18 | 4.5 | 0.98 (0.51-1.88) |
| Safety outcomes | n=667 | n=624 | n=254 | n=286 | ||||||
| Severe or life-threatening bleeding | 6 | 0.6 | 5 | 0.6 | 0.91 (0.26-3.02) | 7 | 1.8 | 3 | 0.8 | 0.42 (0.09-1.52) |
| Hemorrhagic adverse event | 21 | 2.1 | 23 | 2.5 | 1.18 (0.65-2.16) | 11 | 2.8 | 15 | 3.7 | 1.33 (0.62-2.98) |
Annual event rate indicates the number of events per 100 person-years. HR = hazard ratio. CI=confidence interval. TIA = transient ischemic attack, MI = myocardial infarction.
Regarding the patients’ clinical background characteristics, the prevalence of dyslipidemia was lower in the DAPT group than in the monotherapy group (48% vs. 54%, respectively; p＜0.05) (Table 1). The primary endpoint of ischemic stroke occurred in 18 (2.0 per 100 patient-years) out of the 637 patients during follow-up in the DAPT group and in 51 (5.1 per 100 patient-years) out of the 683 patients in the monotherapy group (HR, 0.40; 95% CI, 0.23–0.68) (Table 2, Fig.1A). The risks of any stroke, ischemic stroke or TIA, composite vascular events, and all vascular events were also significantly lower in the DAPT group (Table 2). The rate of the safety outcome of severe or life-threatening hemorrhage did not differ significantly between the two groups (0.6 per 100 patient-years vs. 0.6 per 100 patient-years, respectively; HR, 0.91; 95% CI, 0.26–3.02) (Table 2, Fig.1B). The rate of discontinuation for reasons other than the development of a major event was significantly higher in the DAPT patients than in the monotherapy patients (199 patients [31.2%] vs. 144 patients [21.1%], respectively; p＜0.01). Palpitations or tachycardia and headache were common reasons for discontinuation in the DAPT group (Table 3).
The Kaplan–Meier curves for time to the first event of the primary efficacy outcome, defined as ischemic stroke in male patients (A), to the safety outcome of severe or life-threatening bleeding in male patients (B), to the ischemic stroke in female patients (C), and to the safety outcome of severe or life-threatening bleeding in female patients (D), are shown. HR, hazard ratio; CI, confidence interval.
| Male | Female | |||
|---|---|---|---|---|
| Monotherapy (n=683) | Dual therapy (n=637) | Monotherapy (n=264) | Dual therapy (n=295) | |
| Total | 144 (21.1) | 199 (31.2) | 43 (16.3) | 89 (30.2) |
| Adverse event | ||||
| Palpitation or tachycardia | 0 (0.0) | 23 (11.5) | 0 (0.0) | 18 (20.5) |
| Headache | 0 (0.0) | 17 (8.5) | 0 (0.0) | 4 (4.5) |
| Minor bleeding | 0 (0.0) | 4 (2.0) | 0 (0.0) | 3 (3.4) |
| Cancer | 4 (1.8) | 10 (5.0) | 1 (1.4) | 2 (2.3) |
| Skin adverse event | 6 (2.7) | 12 (6.0) | 1 (1.4) | 3 (3.4) |
| Gastrointestinal adverse event | 3 (1.3) | 8 (4.0) | 2 (2.7) | 5 (5.7) |
| Renal disease | 0 (0.0) | 3 (1.5) | 0 (0.0) | 1 (1.1) |
| Other adverse event | 15 (6.7) | 17 (8.5) | 3 (4.1) | 8 (9.1) |
| Medical judgment to stop, add, or change antithrombotics | ||||
| Atrial fibrillation | 5 (2.2) | 5 (2.5) | 0 (0.0) | 2 (2.3) |
| Deep venous thrombosis | 2 (0.9) | 0 (0.0) | 1 (1.4) | 0 (0.0) |
| Interruption of medication before or after surgical procedure | 3 (1.3) | 1 (0.5) | 1 (1.4) | 2 (2.3) |
| Change to generic products | 2 (0.9) | 12 (6.0) | 0 (0.0) | 3 (3.4) |
| Other physician-determined reason | 15 (6.7) | 9 (4.5) | 2 (2.7) | 5 (5.7) |
| Discontinuation by patient’s decision | 79 (35.1) | 69 (34.5) | 31 (42.5) | 30 (34.1) |
| Median duration of observational period, days | 239 (97-426) | 98 (27-363) | 126.5 (49.75-367) | 90 (21-323) |
Data are n (%) of overall patients.
Regarding the patients’ clinical background characteristics, the prevalence of CKD was higher in the DAPT group than in the monotherapy group (7% vs. 3%, respectively; p＜0.05), and they had a higher BMI (23.2 vs. 22.5 kg/m2, respectively; p＜0.05) (Table 1). The primary endpoint of ischemic stroke occurred in 11 (2.7 per 100 patient-years) out of the 295 patients during follow-up in the DAPT group and in 13 (3.3 per 100 patient-years) out of the 264 patients in the monotherapy group (HR, 0.82; 95% CI, 0.37–1.84) (Table 2, Fig.1C). Stepwise selection using AIC did not select CKD or BMI, as well as assigned treatment. None of the secondary efficacy outcomes was significantly different (Table 2). The rate of the safety outcome of severe or life-threatening hemorrhage did not differ significantly between these two groups (0.8 per 100 patient-years in the DAPT group vs. 1.8 per 100 patient-years in the monotherapy group; HR, 0.42; 95% CI, 0.09–1.52) (Table 2, Fig.1D). The rate of discontinuation for reasons other than the development of a major event was significantly higher in the DAPT patients than in the monotherapy patients (30.2% vs. 16.3%, respectively; p=0.001). Palpitations or tachycardia and headache were common reasons for discontinuation in the DAPT group (Table 3).
Efficacy with respect to recurrence-free time extensionIn male patients, the semiparametric acceleration model with covariates as treatment, sex, and treatment–sex interaction revealed that DAPT prolonged the time to recurrent stroke by 4.02-fold (95% CI, 1.63–9.96) versus monotherapy. In contrast, DAPT reduced the time to recurrent stroke by 0.57-fold (95% CI, 0.12–2.67) in female patients compared to monotherapy (Fig.2).
Semiparametric acceleration model with covariates as treatment, sex, and treatment–sex interaction
Though stroke recurrence was not different between male and female patients, the efficacy of DAPT using cilostazol was better than that of monotherapy in male patients, but not in female patients. The reasons for the difference in DAPT by sex are a higher recurrence rate and a larger number of cases in male patients. The higher incidence of recurrent ischemic stroke in the monotherapy group of male patients might be due to the higher risk factors and the difficulty in achieving the preventive effect of monotherapy. The addition of cilostazol to this high recurrence rate group significantly reduced the recurrence rate, indicating that this DAPT using cilostazol may be useful in this high-risk population. In contrast, in female patients, the low recurrence rate during monotherapy and smaller number of cases might make it difficult for DAPT to show excess effects. Although the difference in risk may be based on differences in clinical background between the two groups, it is possible that the add-on effect of cilostazol may be greater in male than in female patients. In addition, the semiparametric acceleration model analysis showed that DAPT significantly prolonged the duration of recurrence in male patients. The strong effect of a significant increase in the duration of recurrence prevention means that it is considered to be helpful in selecting treatment.
It is unclear whether there is a sex difference in the efficacy of antiplatelet agents for preventing recurrent stroke. The Canadian Cooperative Study Group reported that aspirin significantly reduced stroke incidence and death in threatened stroke only in male patients, not in female patients14). In contrast, the notion that the female patients might not benefit from aspirin therapy was contradicted by a large meta-analysis15). Thus, whether the difference in the aspirin effects between male and female patients is due to the small number of cases enrolled, differences in their clinical backgrounds, or whether sex itself causes the difference in the effects of aspirin is a major issue.
In addition to aspirin, clopidogrel was used as a monotherapy antiplatelet agent in the CSPS.com, but the sex difference in clopidogrel was unclear. The effectiveness of clopidogrel compared to aspirin was reported in the clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE) trial. However, female patients accounted for only 28% of patients included in the CAPRIE trial, and no sub-analysis of sex-related effects was performed16). Genetic polymorphisms related to clopidogrel metabolism are thought to be more related to antiplatelet effects, but since genetic polymorphisms are thought to be equally distributed in men and women, it is unlikely that this has an influence.
In a study of combination antiplatelet therapy, the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, which compared aspirin and clopidogrel with aspirin alone, showed no clear difference between male and female patients17). Similarly, the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial showed no difference between male and female patients, but the combination therapy was slightly better in male patients18). The Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) study, which compared an aspirin and clopidogrel combination with clopidogrel alone, demonstrated a better treatment effect in male patients than in female patients19). The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, which compared clopidogrel with a fixed-dose combination of aspirin and dipyridamole, also showed no clear sex difference. In this trial, the percentage of female patients in each treatment arm was only 36%20). None of these trials have used sex difference as a primary consideration, and none have specifically addressed efficacy in female patients9).
Cilostazol is another category of antiplatelet with pleiotropic effects. For clinical efficacy in the integrated analysis of the Cilostazol Stroke Prevention Study 2 (CSPS2) and the Cilostazol versus Aspirin for Secondary Ischaemic Stroke Prevention (CASISP) study for cilostazol compared with aspirin, the significant factors for recurrent stroke were sex and age. When these significant factors were analyzed, the incidences of stroke, ischemic stroke, and intracranial hemorrhage were all significantly higher in male patients. Subgroup analysis by treatment group showed that the annual incidences of stroke (cilostazol 2.89%, aspirin 4.50%; p=0.0032) and intracranial hemorrhage (0.25% vs. 1.22%; p＜0.001) were significantly lower in male patients in the cilostazol group, but there was no significant difference between the two treatment groups in female patients (stroke 2.40% vs. 2.66%; p=0.7498) (intracranial hemorrhage 0.53% vs. 0.48%; p=0.8813)21). Although it was an animal study, the expression of phosphodiesterase 3 in endothelial cells was reported to be different by sex22). Combining this result with the results of the present study, some sex differences in cilostazol efficacy were suggested, and further research is needed.
Some limitations of the present analysis need to be acknowledged. First, this result came from a sub-analysis of a randomized trial that did not use the biased coin randomized procedure for sex. Thus, the number of female patients was relatively small. Second, the number of interrupted cases is relatively high. Discontinuation occurred in the dual therapy group more frequently than that in the monotherapy group. The observational period was also shorter in the dual therapy group. The reasons for discontinuation appeared to be not only drug-related side effects but also social factors such as drug costs and the switch to generics. Third, the patients in the present analyses were all of Japanese heritage. Most of the large clinical trials of cilostazol have been conducted with East Asian patients. It is not yet clear whether the results of these trials (including the CSPS.com trial) can be generalized to other populations.
In a sub-analysis of the CSPS.com data, the present study demonstrated that the combination using cilostazol reduced the recurrence of ischemic stroke and prolonged the recurrence-free time in male patients in the chronic stage without increasing the bleeding risk. However, significant efficacy was not observed in female patients. Although the fact that the male patients were at higher risk than the female patients based on clinical background may have clearly demonstrated the efficacy of DAPT. It is possible that sex differences exist as a property of cilostazol, and further studies are needed to address this issue.
All of the following conflicts are outside the submitted work. Dr. Hoshino reports personal fees from Daiichi-Sankyo, Bristol-Myers Squibb, Bayer, Otsuka Pharmaceutical and Pfizer. Dr. Toyoda reports personal fees from Otsuka Pharmaceutical, Daiichi-Sankyo, Bayer, Bristol-Myers-Squibb, Novartis, and Abbott Medical. Dr. Uchiyama reports lecture fees from Bayer and Boehringer Ingelheim. Dr. Keiji Yamaguchi reports honoraria from Daiichi Sankyo. Dr. Minematsu reports receiving honoraria from Bayer, Bristol-Myers Squibb, and Pfizer. The other authors report no conflicts.
The CSPS.com (PI: Yamaguchi T) was conducted under a trial contract between the consignee, Japan Cardiovascular Research Foundation, and the consignor, Otsuka Pharmaceutical Co., Ltd. The Japan Cardiovascular Research Foundation received funding for trial implementation and management from Otsuka Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. did not directly contribute to trial design, data management, or statistical analysis and did not contribute to any issues in this subanalysis study. Statistical analysis of this article was performed at the Department of Data Science, National Cerebral and Cardiovascular Center (Omae, Takahashi). This study was funded mainly by the Japan Agency for Medical Research and Development to Toyoda K (AMED, JP22lk0201094 and JP220201109).
