Skip to main content
NCBI home page
PLOS One logoLink to PLOS One
. 2020 Dec 28;15(12):e0242466. doi: 10.1371/journal.pone.0242466

Efficacy of aspirin, clopidogrel, and ticlopidine in stroke prevention: A population-based case-cohort study in Taiwan

Yi-Sin Wong 1, Ching-Fang Tsai 2, Yueh-Han Hsu 2, Cheung-Ter Ong 3,*
Editor: Hugo ten Cate4
PMCID: PMC7769270  PMID: 33370282

Abstract

Background

In real-world practice settings, there is insufficient evidence on the efficacy of antiplatelet drugs, including clopidogrel, aspirin, and ticlopidine, in stroke prevention.

Purpose

To compare the efficacies between aspirin and clopidogrel and aspirin and ticlopidine in stroke prevention.

Methods

This population-based case-cohort study utilized the data obtained from a randomized sample of one million subjects in the Taiwan National Health Insurance Research Database. Patients who were hospitalized owing to the primary diagnosis of ischemic stroke from January 1, 2000 to December 31, 2010 and treated with aspirin, ticlopidine, or clopidogrel were included in the study. Propensity score matching with a 1:4 ratio was performed to compare aspirin with ticlopidine and clopidogrel. The criteria for inclusion were the use of one of the three antiplatelet drugs for more than 14 days within the first month after the stroke and then continued use of the antiplatelet drugs until the study endpoint of recurrent stroke.

Results

During the 3-year follow-up period, the recurrent stroke rates were 1.62% (42/2585), 1.48% (3/203), and 2.55% (8/314) in the aspirin, ticlopidine, and clopidogrel groups, respectively. Compared with the patients treated with aspirin, those treated with clopidogrel and ticlopidine showed competing risk-adjusted hazard ratios of recurrent stroke of 2.27 (1.02–5.07) and 0.62 (0.08–4.86), respectively.

Conclusion

Compared with the patients treated with aspirin, those treated with clopidogrel were at a higher risk of recurrent stroke. For stroke prevention, aspirin was superior to clopidogrel whereas ticlopidine was not inferior to aspirin.

Introduction

In Taiwan, approximately 150,000 individuals experience first ever ischemic strokes every year [1]. Stroke is a major cause of mortality and morbidity and constitutes a high risk of recurrent stroke. The annual recurrent ischemic stroke rate in Taiwan is approximately 10%, which is higher than that reported in the United States [2]. Over the past four decades, stroke incidence has decreased significantly in high-income countries; however, a similar trend has not been observed in low-income countries. This observed reduction in stroke incidence in specific countries is most likely related to implementing preventive therapies and effective control of stroke risk factors [3]. Besides controlling blood pressure and sugar, and the treatment of hyperlipidemia, antiplatelet agents for non-cardioembolic stroke are the most important factors for preventing recurrent stroke in patients with stroke or transient ischemic attack. At present, the US Food and Drug Administration has approved four antiplatelet treatments to prevent ischemic stroke: aspirin, aspirin in combination with dipyridamole, clopidogrel, and ticlopidine [4].

Aspirin’s antithrombotic effect is due to the irreversible acetylation of platelet cyclooxygenase-1 and inhibition of thromboxane A2 synthesis [5]. Adenosine diphosphate (ADP) is a platelet activator that is released from red blood cells. It activates platelets to induce platelet adhesion and aggregation. Clopidogrel and ticlopidine inhibit platelet aggregation by inhibiting adenosine diphosphate [6]. Further, like aspirin, both ticlopidine and clopidogrel prevent thrombosis and related cardiovascular and cerebrovascular events [6–10]. Aspirin is the most commonly prescribed antiplatelet drug for stroke prevention and can significantly decrease the recurrent stroke rate. However, the annual recurrent ischemic stroke rate remains above 3.58% [11, 12]. A study comparing the efficacy of ticlopidine with aspirin for the prevention of recurrent stroke in non-white patients found that ticlopidine was superior to aspirin [12]. In contrast, Gorelick et al. investigated the efficacy of aspirin and ticlopidine for recurrent stroke prevention in African American patients showed no significant difference in the recurrent stroke rate between the aspirin and ticlopidine groups [8]. Conversely, the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial demonstrated that clopidogrel was more effective in preventing ischemic stroke, myocardial infarction, and death related to vascular disease than aspirin [13].

Given the relatively high incidence of recurrent stroke, several studies investigated potential preventive treatment approaches in patients who failed stroke prevention by aspirin. They did this by testing combination treatments, including aspirin plus clopidogrel and clopidogrel plus ticlopidine [8, 14, 15]. These studies revealed that all three antiplatelet drugs reduced the risk of recurrent stroke. Recurrent stroke in patients on antiplatelet drugs for stroke prevention is a common concern. Studies previously showed that switching from aspirin to another antiplatelet drug or combining aspirin with another antiplatelet agent was associated with improved prevention of recurrent stroke compared with the maintained use of aspirin alone [1, 11].

Recent trials evaluated the benefits of dual antiplatelet therapy and the associated bleeding risk in stroke prevention. The Management of Atherothrombosis With Clopidogrel in High-Risk Patients trial reported that aspirin plus clopidogrel did not reduce the risk of major events but increased major bleeding risk compared with clopidogrel alone [16]. In addition, the Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence (FASTER) trial found that aspirin plus clopidogrel did not significantly decrease stroke risk at 90 days and did not increase the hemorrhagic rate compared with aspirin alone [17]. However, several other studies reported that clopidogrel plus aspirin reduced the risk of recurrent stroke compared with aspirin alone [18, 19].

Previous studies found that Asian patients were at a higher risk for cerebrovascular disease. The carrier rate of the CYP2C19 loss-of-function variant was higher in Asian populations, which might affect the efficacy of clopidogrel [20, 21]. Aspirin’s failure in preventing recurrent stroke is not uncommon, and clopidogrel may not be the most suitable antiplatelet drug for the Chinese population. Given that specific antiplatelet treatments that might be more efficient in preventing recurrent stroke in Asian patients have not been investigated to date, we conducted a population-based case-cohort study to compare the efficacy of aspirin, clopidogrel, and ticlopidine in preventing recurrent ischemic stroke in Taiwanese patients.

Methods

Data source and ethics approval

This population-based case-cohort study used data from the Taiwan National Health Insurance Research Database (NHIRD) that comprises data obtained from millions of people. The National Health Insurance (NHI) program in Taiwan has operated since 1995. The NHIRD is a research database developed by the NHI Research Institute and contains patient healthcare data from hospitals, outpatient clinics, and community pharmacies. It encompasses more than 99% of 23 million individuals and 95% of the hospitals in Taiwan. The NHI Research Institute provides the database to researchers after anonymizing all personal information. The current study includes data retrieved from the “Longitudinal Health Insurance Database” (LHID 2005) from a random sample of one million individuals within the NHIRD, with linked longitudinal data available from 2000 to 2010. The LHID 2005 contains complete medical claims and registration for a random sample of one million individuals within the NHIRD. The randomized data (LHID 2005) are represent all beneficiaries as there are no significant differences in sex, age, and premium rate between individuals in the LHID 2005 and the original NHIRD data sets. The codes of the Internal Classification of Disease, Nine Revision (ICD-9) were used to define diseases. This study was approved by the Institutional Review Board of the Ditmanson Medical Foundation Chiayi Christian Hospital, Taiwan (CYCH-IRB: 2018013).

Study subjects and definitions

Ischemic stroke was defined as an episode of the neurological deficit by cerebral infarction confirmed by imaging (computed tomography or magnetic resonance imaging) [22]. All patients hospitalized with a primary diagnosis of ischemic stroke (ICD-9 codes, 433, 434, and 436) from January 1, 2000, to December 31, 2010, were included in the study. The exclusion criteria were the following: age younger than 18 years; a history of stroke before January 1, 2000; a history of myocardial infarction, atrial fibrillation, or infective endocarditis; use of antiplatelet drugs for more than one month before the first stroke; recurrent stroke within one month after the first stroke; use of more than one antiplatelet drug. We believe that the patients who did not regularly use antiplatelet drugs potentially had poor medical compliance. To avoid bias, we excluded patients who did not use antiplatelet drugs for more than 14 days within the first month after the stroke and patients who had not used antiplatelet drugs for more than 90 consecutive days.

A total of 19,543 patients were hospitalized with the discharge diagnosis of ischemic stroke. Among these, 8806 patients, who used antiplatelet drugs for more than 14 days during the first month after stroke onset, were included in the study (Fig 1). The patients were categorized into three groups: aspirin (aspirin, 100 mg/day), ticlopidine (ticlopidine, 250 mg/day), and clopidogrel (clopidogrel, 75 mg/day). Age, sex, and clinical comorbidity index (CCI) were used as propensity score matching parameters. All patients who used ticlopidine or clopidogrel for stroke prevention were included in the study. Two separate propensity score matches were performed using a ratio of 1:4 to compare the aspirin group with the ticlopidine and the clopidogrel groups.

Fig 1. Flow chart of patient enrollment.

Fig 1

Open in a new tab

CCI: clinical comorbidity index, Licodin: ticlopidine, Plavix: clopidogrel.

Outcome measures

The primary endpoint of the study was the development of a new ischemic or hemorrhagic stroke. Patients who did not use antiplatelet drugs for more than 90 days were defined as those not on antiplatelet drugs and were not included in the analyses. The patients who changed antiplatelet drugs or died due to causes not related to stroke were not included in the study. The endpoint was the clinical condition of patients on regular antiplatelet treatment who did not experience a stroke for a minimum of three years.

Statistical analysis

In the current study, we used propensity score matching with a ratio of 1:4 to match the study patients based on age, sex, and CCI. The baseline characteristics of the patients in categorical and continuous variables were compared using the chi-square test. Because the prescription of antiplatelet agents for stroke prevention changed over time, a time-dependent Cox proportional hazards model was used to compare the risk of recurrent stroke between the propensity score-matched groups. Hazard ratios were used to measure the related risk of recurrent stroke. Because of the high mortality rate in stroke patients, we performed competing-risk regression by the Fine and Gray model. We also used stratified analysis to determine the risk of recurrent stroke among patients according to diabetes mellitus and peptic ulcer status. The Kaplan-Meier method was used to analyze the proportion of patients with recurrent stroke during the follow-up period. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc, Cary, NC). Two-sided P-values of < .05 were considered statistically significant.

Results

From 2000 to 2010, a total of 5117 patients fulfilled the inclusion criteria for the current study. After the 1:4 propensity score matching for age, sex, and CCI, a total of 2585 patients who were included in the analysis, including 2068, 203, and 314 patients in the aspirin, ticlopidine, and clopidogrel groups, respectively. The patients’ baseline characteristics, including sex, age, hypertension status, stroke severity, and hemorrhagic stroke history, were not significantly different among the three groups. The length of hospital stay was longer in the clopidogrel group; the rates of diabetes mellitus and hyperlipidemia were lower in the ticlopidine group. The rate of peptic ulcers was higher in the clopidogrel group. The rate of thrombocytopenia as an adverse effect was not significantly different among the three groups (Table 1).

Table 1. The characteristics of the stroke patients at baseline.

Variables Aspirin Ticlopidine Clopidogrel P value
Number 2068 203 314
Age, years
    20–44 63 (3.05%) 4 (1.97%) 14 (4.46%) 0.481
    45–59 485 (23.45%) 53 (26.11%) 76 (24.2%)
    ≥60 1520 (73.5%) 146 (71.92%) 224 (71.34%)
    Mean ± SD 67.66 ± 11.59 68.28 ± 11.64 67.22 ± 12.05 0.602
Sex
    Female 799 (38.64%) 87 (42.86%) 114 (36.31%) 0.326
    Male 1269 (61.36%) 116 (57.14%) 200 (63.69%)
Length of stay, days
    <9 1684 (81.43%) 170 (83.74%) 230 (73.25%) 0.002
    ≥9 384 (18.57%) 33 (16.26%) 84 (26.75%)
CCI, mean ± SD 4.46 ± 2.58 4.25 ± 2.43 4.65 ± 2.71 0.218
Diabetes mellitus 1046 (50.58%) 84 (41.38%) 153 (48.73%) 0.041
Hypertension 1819 (87.96%) 176 (86.70%) 275 (87.58%) 0.864
Hyperlipidemia 1166 (56.38%) 96 (47.29%) 183 (58.28%) 0.030
CKD 155 (7.50%) 13 (6.40%) 37 (11.78%) 0.023
Peptic ulcer disease 865 (41.83%) 91 (44.83%) 212 (67.52%) <0.001
Thrombocytopenia 16 (0.77%) 3 (1.48%) 6 (1.91%) 0.084
Hemorrhagic stroke 53 (2.56%) 7 (3.45%) 11 (3.5%) 0.52
Open in a new tab

CCI, clinical comorbidity index; CKD, chronic kidney disease; SD, standard deviation

During the 3-year follow-up period, the recurrent ischemic stroke rates were 2.03% (42/2068), 1.48% (3/203), and 2.55% (8/314) in the aspirin, ticlopidine, and clopidogrel groups, respectively. The time-dependent Cox proportional hazards model analysis determined that age, CCI, clopidogrel use, diabetes mellitus, peptic ulcers, thrombocytopenia, and hemorrhagic stroke history were associated with an increased risk of recurrent stroke. After adjusting for the risk factors that affect recurrent stroke, age, CCI, clopidogrel use, and history of hemorrhage were associated with an increased risk of recurrent stroke (Table 2). The competing risk-adjusted hazard ratio (HR) of recurrent stroke was higher in patients with a hemorrhagic stroke history and those on clopidogrel treatment for stroke prevention (2.79 [1.02–7.61] and 2.27 [1.02–5.07], respectively). Compared with aspirin, ticlopidine did not increase the risk of recurrent stroke (competing risk-adjusted HR, 0.62 [0.08–4.80]) (Table 2). The Kaplan-Meier curves indicated that the time to recurrent stroke (Fig 2) was significantly different among the three groups (P < .0001, log-rank test).

Table 2. The relationship of antiplatelet drug use with 3-year recurrent stroke among patients with first-time ischemic stroke using the time-dependent Cox proportional hazards model.

Variables Crude HR (95%CI) Adjusted HR (95%CI) Competing risk-adjusted HR (95%CI)
Age, year 1.05 (1.02–1.08) 1.05 (1.02–1.09) 1.03 (0.99–1.06)
Sex
    Female Ref. Ref. Ref.
    Male 1.25 (0.72–2.18) 1.58 (0.86–2.91) 1.64 (0.91–2.94)
Length of stay, days
    <9 Ref. Ref. Ref.
    ≥9 1.03 (0.54–1.98) 1.01 (0.52–1.99) 0.96 (0.50–1.82)
CCI 1.23 (1.12–1.35) 1.18 (1.03–1.35) 1.11 (0.99–1.23)
Antiplatelet agents
    Aspirin Ref. Ref. Ref.
    Ticlopidine 0.69 (0.10–5.07) 0.71 (0.10–5.29) 0.62 (0.08–4.86)
    Clopidogrel 2.64 (1.34–5.22) 2.16 (1.01–4.65) 2.27 (1.02–5.07)
Diabetes mellitus
    No Ref. Ref. Ref.
    Yes 1.89 (1.08–3.30) 1.21 (0.65–2.28) 1.28 (0.67–2.46)
Hypertension
    No Ref. Ref. Ref.
    Yes 3.58 (0.49–25.91) 2.45 (0.33–18.11) 2.75 (0.37–20.6)
Hyperlipidemia
    No Ref. Ref. Ref.
    Yes 0.84 (0.49–1.46) 0.83 (0.47–1.46) 0.84 (0.49–1.46)
CKD
    No Ref. Ref. Ref.
    Yes 1.83 (0.65–5.10) 0.92 (0.30–2.87) 0.93 (0.30–2.91)
Peptic ulcer disease
    No Ref. Ref. Ref.
    Yes 2.08 (1.20–3.58) 1.23 (0.66–2.32) 1.36 (0.70–2.65)
Thrombocytopenia
    No Ref. Ref. Ref.
    Yes 6.88 (2.13–22.23) 3.16 (0.85–11.76) 3.31 (0.69–15.94)
Hemorrhagic stroke
    No Ref. Ref. Ref.
    Yes 4.38 (1.57–12.2) 3.10 (1.05–9.18) 2.79 (1.02–7.61)
Open in a new tab

*Time-dependent Cox proportional hazards model, **ICU was not adjusted in time-dependent Cox proportional hazard model; CCI, clinical comorbidity index; CI, confidence interval

CKD, chronic kidney disease; HR, hazard ratio

Fig 2. Kalpan–Meier curve for recurrent stroke.

Fig 2

Open in a new tab

Licodin: ticlopidine, Plavix: clopidogrel.

The hemorrhagic stroke rates were not significantly different among the three groups (p = .85), 1.40% (29/2068), 1.48% (3/203), and 0.95% (3/314) in the aspirin, ticlopidine, and clopidogrel groups, respectively. Neutropenia was found in 0.29% (6/2068) of patients receiving aspirin, whereas no neutropenia was found in patients receiving ticlopidine and clopidogrel.

In patients with diabetes mellitus, age was associated with an increased risk of recurrent stroke, whereas the risk of recurrent stroke was not significantly different among those treated with aspirin, clopidogrel, and ticlopidine (Table 3). Among patients with peptic ulcers, age and hemorrhagic stroke history were associated with an increased risk of recurrent stroke (HR, 8.18 [2.11–31.61]). In contrast, recurrent stroke risk was not significantly different among the aspirin, clopidogrel, and ticlopidine groups (Table 4).

Table 3. The relationship of antiplatelet drug use and 3-year recurrent stroke among patients with first-time ischemic stroke using the time-dependent Cox proportional hazards model stratified by diabetes mellitus.

Diabetes mellitus
No Yes
Variables Adjusted HR (95%CI) Adjusted HR (95%CI)
Age, year 1.04 (0.99–1.09) 1.07 (1.02–1.12)
Sex
    Female Ref. Ref.
    Male 1.29 (0.44–3.80) 1.73 (0.77–3.86)
Length of stay, days
    <9 Ref. Ref.
    ≥9 0.23 (0.04–1.20) 1.64 (0.71–3.77)
CCI 1.21 (0.98–1.49) 1.19 (0.97–1.46)
Antiplatelet agents
    Aspirin Ref. Ref.
    Ticlopidine <0.01 (<0.01–NA) 1.66 (0.21–13.28)
    Clopidogrel 1.12 (0.27–4.62) 2.62 (0.99–6.95)
Hypertension
    No Ref. Ref.
    Yes 1.01 (0.13–8.06) >999.99 (<0.01–NA)
Hyperlipidemia
    No Ref. Ref.
    Yes 1.32 (0.47–3.74) 0.76 (0.36–1.61)
CKD
    No Ref. Ref.
    Yes 11.47 (2.68–49.2) 0.21 (0.03–1.69)
Peptic ulcer disease
    No Ref. Ref.
    Yes 2.77 (0.92–8.37) 1.14 (0.50–2.63)
Thrombocytopenia
    No Ref. Ref.
    Yes 28.88 (3.17–263.24) 1.72 (0.19–15.20)
Hemorrhagic stroke
    No Ref. Ref.
    Yes 2.51 (0.29–22.07) 3.18 (0.86–11.82)
Open in a new tab

*Time-dependent Cox proportional hazard model

CCI, clinical comorbidity index; CI, confidence interval; CKD, chronic kidney disease

HR, hazard ratio

Table 4. The relationship of antiplatelet drug use and 3-year recurrent stroke among patients with first-time ischemic stroke using the time-dependent Cox proportional hazards model stratified by peptic ulcer disease.

Peptic ulcer disease
No Yes
Adjusted HR (95%CI) Adjusted HR (95%CI)
Age, year 1.05 (1.00–1.11) 1.04 (1.00–1.09)
Sex
    Female Ref. Ref.
    Male 1.48 (0.56–3.91) 1.78 (0.77–4.15)
Length of stay, days
    <9 Ref. Ref.
    ≥9 0.91 (0.28–2.93) 1.29 (0.54–3.09)
CCI 1.40 (1.11–1.77) 1.10 (0.92–1.31)
Antiplatelet agents
    Aspirin Ref. Ref.
    Ticlopidine <0.01 (<0.01–NA) 1.33 (0.17–10.49)
    Clopidogrel 3.70 (0.81–16.99) 1.65 (0.66–4.16)
Diabetes mellitus
    No Ref. Ref.
    Yes 1.12 (0.42–2.97) 1.10 (0.45–2.73)
Hypertension
    No Ref. Ref.
    Yes >999.99 (<0.01–NA) 1.25 (0.16–9.69)
Hyperlipidemia
    No Ref. Ref.
    Yes 0.77 (0.30–1.96) 0.84 (0.38–1.86)
CKD
    No Ref. Ref.
    Yes 1.51 (0.28–8.15) 0.80 (0.16–3.91)
Thrombocytopenia
    No Ref. Ref.
    Yes 5.46 (0.38–78.26) 3.36 (0.65–17.38)
Hemorrhagic stroke
    No Ref. Ref.
    Yes 0.71 (0.08–6.68) 8.18 (2.11–31.62)
Open in a new tab

*Time-dependent Cox proportional hazards model

**ICU was not adjusted in time-dependent Cox proportional hazard model

CCI, clinical comorbidity index; CI, confidence interval; CKD, chronic kidney disease

HR, hazard ratio

Discussion

The present population-based case-cohort study included the data of 1,000,000 randomly selected individuals in Taiwan and revealed three major findings. First, clopidogrel was associated with a higher recurrent stroke rate than aspirin among patients on antiplatelet treatment for secondary stroke prevention. Second, the risk of recurrent stroke was higher in patients with ischemic stroke and hemorrhagic stroke history. Third, among patients with diabetes mellitus and gastric ulcers, the recurrent stroke risk with aspirin treatment was not significantly different from that with clopidogrel or ticlopidine treatment.

Our finding that the recurrent stroke rate was not significantly different between the ticlopidine and aspirin groups agrees with the results reported by Gorelick et al., who showed that the two-year recurrent stroke rates with ticlopidine and aspirin were 11.9% and 9.5%, respectively (P = 0.1) [8]. The current study’s recurrent stroke rate is lower than those reported in previous studies [8, 23], which might be partly because of the exclusion of patients who died due to causes other than stroke and those who experienced recurrent stroke within one month after the first stroke. The lower competing risk-adjusted HR of recurrent stroke in the ticlopidine group (0.62 [0.08–4.86]) compared with the aspirin group in the current study is comparable to that reported by Hass et al., who showed that ticlopidine was slightly more effective than aspirin in preventing stroke [23].

In the CAPRIE trial, a randomized, blinded study evaluating the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily), clopidogrel was more effective than aspirin in the prevention of stroke, myocardial infarction, and death related to vascular disease [13]. However, another study reported no significant difference in the efficacy of aspirin and clopidogrel for the prevention of recurrent stroke or functional outcomes [24]. The present study results revealed that the recurrent stroke risk was higher in the clopidogrel group than in the aspirin group. This finding agrees with the studies by Liu et al. and Wang et al., who showed that the carrier rate of the cytochrome P450 2C19 loss-of-function variant was higher in Asian populations, which may affect clopidogrel’s efficacy [20, 21]. However, we did not find a significant difference in the recurrent stroke risk between the aspirin and clopidogrel groups among patients with diabetes mellitus or those with gastric ulcers. This difference between the current study and previous reports might be related to the NHI guidelines. Specifically, clopidogrel can only be used in patients with gastric ulcers and those with a contraindication for aspirin. Patients without gastric ulcers who are prescribed clopidogrel might harbor other risk factors that may affect the risk of recurrent stroke. However, whether gastric or upper gastrointestinal bleeding might affect the risk of recurrent stroke remains unclear.

Compared with the current study, aspirin and ticlopidine doses were significantly higher in the previous studies investigating secondary stroke prevention [8, 13, 23, 25]. At present, the commonly used daily doses of aspirin, ticlopidine, and clopidogrel for stroke prevention in Taiwan are 100, 250, and 75 mg, respectively. Clopidogrel and ticlopidine have similar structures, and both are metabolized by the hepatic cytochrome P450 1A enzyme to acquire activity. Since the active metabolite is the same for both compounds, in theory, the dose for stroke prevention should be the same for both compounds. However, in previous studies, the doses of ticlopidine and clopidogrel were 500 and 75 mg/day, respectively, with ticlopidine being more than six times that of clopidogrel. Since 75 mg/day clopidogrel was confirmed to be as effective as aspirin, 75 mg/day ticlopidine may provide the effect achieved by 100 mg/day aspirin or 75 mg clopidogrel. In the current study, 250 mg/day ticlopidine was not inferior to 100 mg/day aspirin in preventing recurrent stroke, and 75 mg/day clopidogrel was associated with a higher risk of recurrent stroke. These results are comparable to those reported by Uchiyama et al., who found that the effect of 200 mg/day ticlopidine was comparable to 75 mg/day clopidogrel for the secondary prevention of vascular events in patients with ischemic stroke [26].

Hematologic abnormalities, including neutropenia and thrombocytopenia, due to ticlopidine, were reported. In studies in which patients received ticlopidine 500 mg/day, the incidence of neutropenia was between 0.6% and 3.4% [8, 23, 27, 28]. The incidence of neutropenia in patients who used ticlopidine 250 mg/day was between 0.29% and 0.37% [29, 30]. The incidence of neutropenia seems related to the dose of this antiplatelet.

The incidence of neutropenia in patients who used aspirin 650 mg/day is 2.2% [8]. A lower ticlopidine dose can reduce the risk of neutropenia. In the study, neutropenia was not found in patients receiving ticlopidine and clopidogrel. The result is uncertain about our patients receiving a low dose of ticlopidine (250 mg/day). Our study found that the risk of intracranial hemorrhage is not significantly different among patients receiving aspirin, ticlopidine, and clopidogrel. These results are similar to those reported by previous studies that the hemorrhagic stroke rate was not significantly different between aspirin and clopidogrel [1, 13] and between aspirin and ticlopidine [23].

Overall, these results suggest that a ticlopidine dose of 500 mg/day may not be necessary for the secondary prevention of recurrent stroke. The adverse event of severe neutropenia might be related to the high ticlopidine dose. Our study showed that 250 mg/day ticlopidine was superior to 75 mg/day clopidogrel for recurrent stroke prevention. The antithrombotic effect of clopidogrel is influenced by the patient’s CYP2C19 genotype. Because of CYP2C19 genetic polymorphism, the response of clopidogrel differs widely among patients. Previous studies showed that adjusting thienopyridine treatment in patients after primary percutaneous coronary intervention for ST-Elevation Myocardial Infarction, according to the CYP2C19 genotype, can improve a patient’s outcome [31, 32]. Whether adjusting the clopidogrel dose after CYP2C19 genotyping in stroke patients can reduce recurrent stroke risk needs further investigation.

Limitations

The current study has several limitations. First, data on complete blood and platelet counts were not available in the NHIRD, which did not permit the analyses of thrombocytopenia and neutropenia. Second, the information on certain potential confounding factors, such as smoking, alcohol use, body mass index, and low-density lipoprotein cholesterol, were not available in the NHIRD. This inaccessibility may have confounded the association between antiplatelet drugs and recurrent stroke risk. Third, the recurrent stroke definition in the current study was based on the diagnosis of ischemic stroke among hospitalized patients, which might have underestimated the recurrent stroke rate. Fourth, the data were over 10 years old; the actual values of these findings for current stroke treatment remain uncertain. Fifth, we excluded patients who did not regularly use antiplatelet drugs, which may exclude patients who discontinued antiplatelet medications due to an adverse effect. These exclusions may underestimate the risk of adverse effects of antiplatelet medications. However, in Taiwan, when adverse effects occur, most patients will come to the hospital for help, and physicians will change the drug but will not discontinue medications.

Conclusion

Compared with patients using aspirin, those using clopidogrel were at a higher risk of recurrent stroke. For secondary stroke prevention, aspirin was superior to clopidogrel, whereas ticlopidine was not inferior to aspirin.

Supporting information

S1 Table. Condition of antiplatelet use.

(DOCX)

Click here for additional data file. (13.7KB, docx)

Acknowledgments

We thank Chih-Cheng Hsu from the National Health Research Institute Taiwan, for providing valuable comments on data collection and statistical analysis.

Data Availability

This retrospective study used data from the Taiwan National Health Insurance Research Database (NHIRD). The NHI Research Institute provides the database to researchers after anonymizing all personal information. Researchers may only share the data resulting from their analysis; in the study, all of this data is within the manuscript and the Supporting Information. Researchers who would like to access the full data underlying this study can apply to the Data Science Centre of the Ministry of Health and Welfare (MOHW) of Taiwan (https://dep.mohw.gov.tw/dos/np-2497-113.html). To apply, the researcher must design a research plan and gain IRB approval, after which point the research plan can be submitted to the MOHW for approval. The data in the manuscript were retrieved from LHID 2005. The IRB number of the study is CYCH-IRB 2018013. The search code were ICD-9 code (433, 434 and 436) for ischemic stroke. Medication search code were aspirin, clopidogrel and ticlopidine. The search for risk factor of stroke and complication or adverse effect also use ICD-9 code.

Funding Statement

The author(s) received no specific funding for this work.

References

  • 1.Lee M, Wu Y-L, Ovbiagele B. Trends in incident and recurrent rates of first-ever ischemic stroke in Taiwan between 2000 and 2011. J stroke 2016; 18 (1): 60–65. 10.5853/jos.2015.01326 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke; 2014; 45: 00–00. 10.1161/STR.0000000000000024 [DOI] [PubMed] [Google Scholar]
  • 3.Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 2009; 8 (4): 355–369. 10.1016/S1474-4422(09)70025-0 [DOI] [PubMed] [Google Scholar]
  • 4.Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42: 00–00 10.1161/STR.0b013e3181f7d043 [DOI] [PubMed] [Google Scholar]
  • 5.Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105 (14): 1650–1655. 10.1161/01.cir.0000013777.21160.07 [DOI] [PubMed] [Google Scholar]
  • 6.Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100 (15): 1667–1672. 10.1161/01.cir.100.15.1667 [DOI] [PubMed] [Google Scholar]
  • 7.Couch JR. Antiplatelet therapy in the treatment of cerebrovascular disease. Clin cardiol 1993; 16 (10): 703–710. 10.1002/clc.4960161004 [DOI] [PubMed] [Google Scholar]
  • 8.Gorelick PB, Richardson D, Kelly M, Ruland S, Hung E, Harris Y, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 2003; 289 (22): 2947–2957. 10.1001/jama.289.22.2947 [DOI] [PubMed] [Google Scholar]
  • 9.Wang X, Zhao X, Johnston SC, Xian Y, Hu B, Wang C, et al. Effect of clopidogrel with aspirin on functional outcome in TIA or minor stroke: CHANCE substudy. Neurology 2015; 85 (7):573–579. 10.1212/WNL.0000000000001844 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Bertrand ME, Rupprecht H-J, Urban P, Gershlick AH, Classics Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102 (6): 624–629. 10.1161/01.cir.102.6.624 [DOI] [PubMed] [Google Scholar]
  • 11.Berkowitz AL, Westover MB, Bianchi MT, Chou SHY. Aspirin for secondary prevention after stroke of unknown etiology in resource-limited settings. Neurology 2014; 83(11): 1004–1011. 10.1212/WNL.0000000000000779 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Weisberg LAMD, Ticlopidine Aspirin Stroke Study G. The efficacy and safety of ticlopidine and aspirin in non-whites: Analysis of a patient subgroup from the Ticlopidine Aspirin Stroke Study. Neurology 1993; 43 (1, Part 1): 27–31. 10.1212/wnl.43.1_part_1.27 [DOI] [PubMed] [Google Scholar]
  • 13.CAPRIE steering committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348 (9038): 1329–1339. [DOI] [PubMed] [Google Scholar]
  • 14.Hankey GJ, Eikelboom JW. Adding aspirin to clopidogrel after TIA and ischemic stroke: Benefits do not match risks. Neurology 2005; 64 (7):1117–1121. 10.1212/01.WNL.0000156357.50448.8A [DOI] [PubMed] [Google Scholar]
  • 15.Patrono C. Aspirin resistance: definition, mechanisms and clinical read‐outs. J Thrombo Haemost 2003; 1 (8): 1710–1713. 10.1046/j.1538-7836.2003.00284.x [DOI] [PubMed] [Google Scholar]
  • 16.Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspitin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364 (9431): 331–337. 10.1016/S0140-6736(04)16721-4 [DOI] [PubMed] [Google Scholar]
  • 17.Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol 2007; 6 (11): 961–969. 10.1016/S1474-4422(07)70250-8 [DOI] [PubMed] [Google Scholar]
  • 18.Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369 (1): 11–9. 10.1056/NEJMoa1215340 [DOI] [PubMed] [Google Scholar]
  • 19.Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med 2018; 379 (3): 215–225. 10.1056/NEJMoa1800410 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Liu L, Dowlatshahi D. Dual Antiplatelet Therapy for Minor Stroke and High-Risk Transient Ischemic Attack: What Have We Learned?. Stroke 2018; 49 (9): 2278–2279. 10.1161/STROKEAHA.118.022696 [DOI] [PubMed] [Google Scholar]
  • 21.Wang Y, Zhao X, Lin J, Li H, Johnston SC, Lin Y, et al. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA 2016; 316 (1): 70–78. 10.1001/jama.2016.8662 [DOI] [PubMed] [Google Scholar]
  • 22.Sacco RL, Kasner SE, Broderick JP, Caplan LR, Culebras A, Elkind MSV, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44 (7): 2064–2089. 10.1161/STR.0b013e318296aeca [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Hass WK, Easton JD, Adams HP Jr, Pryse-phillps W, Molony BA, Anderson S, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989; 321 (8): 501–507. 10.1056/NEJM198908243210804 [DOI] [PubMed] [Google Scholar]
  • 24.Bath PM, Cotton DMS, Martin RH, Palesch Y, Yusuf SMB, Sacco R, et al. Effect of Combined Aspirin and Extended-Release Dipyridamole Versus Clopidogrel on Functional Outcome and Recurrence in Acute, Mild Ischemic Stroke: PRoFESS Subgroup Analysis. Stroke 2010; 41 (4): 732–738. 10.1161/STROKEAHA.109.564906 [DOI] [PubMed] [Google Scholar]
  • 25.Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1 (8649): 1215–1220. 10.1016/s0140-6736(89)92327-1 [DOI] [PubMed] [Google Scholar]
  • 26.Uchiyama S, Fukuuchi Y, Yamaguchi T. The safety and efficacy of clopidogrel versus ticlopidine in Japanese stroke patients: combined results of two Phase III, multicenter, randomized clinical trials. J neurol 2009; 256 (6): 888–897. 10.1007/s00415-009-5035-4 [DOI] [PubMed] [Google Scholar]
  • 27.Lablanche JM, McFadden EP, Bonnet JL, Grollier G, Danchin N, Bedossa M, et al. Combined antiplatelet therapy with ticlopidine and aspirin. A simplified approach to intracoronary stent management. Eur Heart J 1996; 17: 1373–1380. 10.1093/oxfordjournals.eurheartj.a015072 [DOI] [PubMed] [Google Scholar]
  • 28.Hall P, Nakamura S, Maiello L, Itoh A, Blengino S, Martini C, et al. A Randomized Comparison of Combined Ticlopidine and Aspirin Therapy versus Aspirin Therapy Alone After Successful Intravascular Ultrasound–Guided Stent Implantation. Circulation. 1996; 93 (2): 215–222 10.1161/01.cir.93.2.215 [DOI] [PubMed] [Google Scholar]
  • 29.Jeong HG, Yoon JS, Lee J, Bae HJ. Incidence of neutropenia in patients with ticlopidine/Ginkgo biloba extract combination drug for vascular events: A post-marketing cohort study. PLoS ONE 2019; 14(6): e0217723 10.1371/journal.pone.0217723 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Ito E, Takahashi A, Yamamoto H, Kuzuhara S, Uchiyama S, Nakajima M. Ticlopidine alone versus ticlopidine plus aspirin for preventing recurrent stroke. Internal medicine 2003; 42(9): 793–799 10.2169/internalmedicine.42.793 [DOI] [PubMed] [Google Scholar]
  • 31.Hulot JS, Chevalier B, Belle L, Cayla G, Khalife K, Funck F, et al. Routine CYP2C19 Genotyping to Adjust Thienopyridine Treatment After Primary PCI for STEMI Results of the GIANT Study. J Am Coll Cardiol Intv 2020; 13: 621–630. 10.1016/j.jcin.2020.01.219 [DOI] [PubMed] [Google Scholar]
  • 32.Ten Berg JM, Janssen PWA. Personalized P2Y12 Inhibitor Treatment: Are We Ready to Go? J Am Coll Cardiol Intv 2020; 13: 631–633. 10.1016/j.jcin.2020.01.221 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Hugo ten Cate

4 Aug 2020

PONE-D-20-18884

The efficacy of aspirin, clopidogrel, and ticlopidine in stroke prevention: a population-based case-cohort study in Taiwan

PLOS ONE

Dear Dr. Ong,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please see my comments below. 

Please submit your revised manuscript by Sep 18 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Hugo ten Cate, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments:

Two issues may be added to the discussion section. One is a limitation, indicating that the data were over 10 years old, hence the actual value of these findings for current stroke treatment remain uncertain. A second issue that could be added is that instead of considering higher doses of clopidogrel genotyping of patients for the relevant polymorphisms may be a more appealing approach to verify metabolism of clopidogrel. This approach may be quite helpful, asa discussed in the recent commentary by ten Berg et al, JACC Cardiovascular Intervention 2020, at least for the coronary population. Evidence for stroke patient still needs to be established.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. In addition, please include the dates upon which this data was accessed.

3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Methods state "The primary endpoint of the study was the development of a new ischemic or

hemorrhagic stroke." It would be helpful for the authors to break down this outcome by ischemic v hemorrhagic, as in some studies of antiplatelet medications alone and in combination, the benefit for ischemic stroke prevention is outweighed by increased risk of hemorrhage. Therefore the authors should report the effect of these 3 antiplatelet agents on both recurrent ischemic stroke and new hemorrhagic stroke.

Reviewer #2: Summary of the research

The present manuscript by Wong et al reports the results of a case-cohort study comparing recurrent stroke rates among Taiwanese patients discharged with ischemic stroke and treated with either aspirin, ticlopidine or clopidogrel monotherapy. A random sample of 1-million patients was extracted from a National Health Insurance Research database. Patients (n=19543) hospitalized between January 2000 and December 2010 with a primary diagnosis of ischemic stroke were identified and after propensity score matching 3102 patients were left to be included in this analysis. The authors found that for recurrent stroke prevention, aspirin was superior to clopidogrel and ticlopidine non-inferior to aspirin.

Overall impression

The manuscript gives a clear introduction addressing the key problems and knowledge gaps in stroke prevention among the Asian population and the importance of this topic. However, there are issues that need to be addressed.

• The methods of data collection should be more detailed. How was the 1-million sample ‘randomly’ collected? Why chosen for 1-million sample instead of directly identifying patients from the NHIRD based on discharge diagnosis in a certain time span?

• Of the patients identified with primary diagnosis ischemic stroke (n=19543) >50% were excluded. As this is a large number excluded from the population of interest (in a cohort study), I would like to gain more insight in the exclusion criteria.

• To be able to interpret the role of different antithrombotic agents, not only thrombotic risks should be reported, but also bleeding risks. Is there any information available on bleeding complications among patients on aspirin vs ticlopidine vs clopidogrel therapy?

• Ticlopidine was found to be non-inferior to aspirin. However, ticlopidine use is world-wide mainly limited due to its serious side effect such as neutropenia and TTP. Although data on neutropenia and thrombocytopenia were not available in the NHIRD, I believe the prevalence of these ticlopidine side effects among Asian population should be highlighted more in the discussion to put results in better perspective.

Specific comments:

• The manuscript reports that, based on the time-dependent Cox proportional hazards model analysis, length of stay was associated with increased risk of recurrent stroke. However, the crude HR for length of stay >9d was 1.03 (0.54-1.98).

• The manuscript reports that after adjusting for risk factors, length of stay and thrombocytopenia were associated with increased risk of recurrent stroke. However, the adjusted HR for length of stay >9d was 1.01 (0.52-1.99) and for thrombocytopenia was 3.16 (0.85-11.76).

• Add reference in the last paragraph of the Discussion stating: “…Altogether, these results suggest that a ticlopidine dose of 500mg/day may not be necessary for the prevention of recurrent stroke and that the adverse event of severe neutropenia might be related to the high ticlopidine dose.”

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Dec 28;15(12):e0242466. doi: 10.1371/journal.pone.0242466.r002

Author response to Decision Letter 0

1 Sep 2020

Response to editor

Thank editor important comments. Base on editor comments we have made necessary revision. In the comments, two issue was pointed out. Now we present our revision.

1. One is a limitation, indicating that the data were over 10 years old, hence the actual value of these findings for current stroke treatment remain uncertain.

Revision: In the last sentence of limitation section, we add the sentence “Fourth, the data were over 10 years old, the actual value of these finding for current stroke treatment remain uncertain.”

2. A second issue that could be added is that instead of considering higher doses of clopidogrel genotyping of patients for the relevant polymorphisms may be a more appealing approach to verify metabolism of clopidogrel.

Revision: In discussion section last sentence, we add the revision. “The antithrombotic effect of clopidogrel is influenced by the patient’s CYP2C19 genotype. Because of CYP2C19 genetic polymorphism, the response of clopidogrel differ widely among patients. Previous studies showed according CYP2C19 genotype adjust thienopyridine treatment in patients after primary PCI for STEMI can improve patient’s outcome. Whether adjust clopidogrel dose after CYP2C19 genotyping in stroke patients can reduce risk of recurrent stroke need further investigation.”

Response to reviewer 1

We thank reviewer valuable comments. Base on reviewer’s comments, we have made necessary revision.

Comments: The primary endpoint of the study was the development of a new ischemic or hemorrhagic stroke." It would be helpful for the authors to break down this outcome by ischemic v hemorrhagic, as in some studies of antiplatelet medications alone and in combination, the benefit for ischemic stroke prevention is outweighed by increased risk of hemorrhage. Therefore the authors should report the effect of these 3 antiplatelet agents on both recurrent ischemic stroke and new hemorrhagic stroke.

Revision:

1. In the result section, we add the information of neutropenia and hemorrhagic stroke. “The hemorrhagic stroke rates were no significant difference among 3 groups (p=0.85), 1.40% (29/2068), 1.48% (3/203), and 0.95% (3/314) in the aspirin, ticlopidine, and clopidogrel groups, respectively. Neutropenia was found in 0.29% (6/2068) of patients receiving aspirin, no neutropenia was found in patients receiving ticlopidine and clopidogrel.”

2. In discussion section, we add the discussion about neutropenia and hemorrhage stroke.

“Hematologic abnormalities including neutropenia and thrombocytopenia attribute to ticlopidine had been reported. In the studies which patient receiving ticlopidine 500mg/day, the incidence of neutropenia was between 0.6% and 3.4%. The incidence of neutropenia in patients receiving ticlopidine 250mg/day was between 0.29% and 0.37%. The incidence of neutropenia seems related to the dose of antiplatelet.

The incidence of neutropenia in the patients use aspirin 650 mg/day is 2.2%. Lower ticlopidine dose can reduce the risk of neutropenia. In the study, neutropenia was not found in patients receiving ticlopidine and clopidogrel. The result suspect related to our patients receiving low dose of ticlopidine (250mg/day). Our study found the risk of intracranial hemorrhage is no significant difference among the patients receiving aspirin, ticlopidine and clopidogrel. The result is the same as previous studies that the hemorrhage stroke rate was no significant difference between aspirin and clopidogrel and between aspirin and ticlopidine.

Response to reviewer 2

We thank reviewer's valuable comments. Base on reviewer’s comments, we have made necessary revision.

1. The methods of data collection should be more detailed. How was the 1-million sample ‘randomly’ collected? Why chosen for 1-million sample instead of directly identifying patients from the NHIRD based on discharge diagnosis in a certain time span?

Revision: In the methods section, we have add the information about the methods of data collection. “The current study included the data were retrieved from the “Longitudinal Health Insurance Database (LHID 2005) from a random sample of 1 million individuals within the NHIRD, with linked longitudinal data available from 2000 to 2010. The LHID 2005 contains complete medical claims and registration for a random sample of one million individuals within the NHIRD. The randomized data (LHID 2005) are overall representative of all beneficiaries as no significant difference in the sex, age and premium rate between individuals in the LHID 2005 and in the original NHIRD data sets.”

2. Of the patients identified with primary diagnosis ischemic stroke (n=19543) >50% were excluded. As this is a large number excluded from the population of interest (in a cohort study), I would like to gain more insight in the exclusion criteria.

Revision: In the methods section, we add the exclusion criteria. “We excluded the patients who did not use of one of the three antiplatelet drugs for more than 14 days within the first month after the stroke and the patients not continued use of the antiplatelet drugs were not included in the study.”

3. To be able to interpret the role of different antithrombotic agents, not only thrombotic risks should be reported, but also bleeding risks. Is there any information available on bleeding complications among patients on aspirin vs ticlopidine vs clopidogrel therapy?

Revision: In the results and discussion section, we add the information about hemorrhage stroke and neutropenia.

In results section: “The hemorrhagic stroke rates were no significant difference among 3 groups (p=0.85), 1.40% (29/2068), 1.48% (3/203), and 0.95% (3/314) in the aspirin, ticlopidine, and clopidogrel groups, respectively. Neutropenia was found in 0.29% (6/2068) of patients receiving aspirin, no neutropenia was found in patients receiving ticlopidine and clopidogrel.”

In discussion section: “Hematologic abnormalities including neutropenia and thrombocytopenia attribute to ticlopidine had been reported. In the studies which patient use ticlopidine 500mg/day, the incidence of neutropenia was between 0.6% and 3.4%. The incidence of neutropenia in patients use ticlopidine 250mg/day was between 0.29% and 0.37%.31, 32 The incidence of neutropenia seems related to the dose of antiplatelet.

The incidence of neutropenia in the patients use aspirin 650 mg/day is 2.2%. Lower ticlopidine dose can reduce the risk of neutropenia. In the study, neutropenia was not found in patients receiving ticlopidine and clopidogrel. The result suspect related to our patients receiving low dose of ticlopidine (250mg/day). Our study found the risk of intracranial hemorrhage is no significant difference among the patients receiving aspirin, ticlopidine and clopidogrel. The result is the same as previous studies that the hemorrhage stroke rate was no significant difference between aspirin and clopidogrel and between aspirin and ticlopidine.

4. Ticlopidine was found to be non-inferior to aspirin. However, ticlopidine use is world-wide mainly limited due to its serious side effect such as neutropenia and TTP. Although data on neutropenia and thrombocytopenia were not available in the NHIRD, I believe the prevalence of these ticlopidine side effects among Asian population should be highlighted more in the discussion to put results in better perspective.

Revision: Neutropenia and hemorrhage adverse effect was reported and discussion as issue 3.

5. • The manuscript reports that, based on the time-dependent Cox proportional hazards model analysis, length of stay was associated with increased risk of recurrent stroke. However, the crude HR for length of stay >9d was 1.03 (0.54-1.98).

Revision: We have deleted length of stay.

6. The manuscript reports that after adjusting for risk factors, length of stay and thrombocytopenia were associated with increased risk of recurrent stroke. However, the adjusted HR for length of stay >9d was 1.01 (0.52-1.99) and for thrombocytopenia was 3.16 (0.85-11.76).

Revision: We have deleted length of stay and thrombocytopenia.

7. Add reference in the last paragraph of the Discussion stating: “…Altogether, these results suggest that a ticlopidine dose of 500mg/day may not be necessary for the prevention of recurrent stroke and that the adverse event of severe neutropenia might be related to the high ticlopidine dose.”

Revision: In discussion section, we have add the reference about the relationship between ticlopidine dose and neutropenia or thrombocytopenia. “Hematologic abnormalities including neutropenia and thrombocytopenia attribute to ticlopidine had been reported. In the studies which patient receiving ticlopidine 500mg/day, the incidence of neutropenia was between 0.6% and 3.4%.27-30. The incidence of neutropenia in patients use ticlopidine 250mg/day was between 0.29% and 0.37%.31, 32 The incidence of neutropenia seems related to the dose of antiplatelet.

The incidence of neutropenia in the patients use aspirin 650 mg/day is 2.2%.30 Lower ticlopidine dose can reduce the risk of neutropenia. In the study, neutropenia was not found in patients receiving ticlopidine and clopidogrel. The result suspect related to our patients receiving low dose of ticlopidine (250mg/day). Our study found the risk of intracranial hemorrhage is no significant difference among the patients receiving aspirin, ticlopidine and clopidogrel. The result is the same as previous studies that the hemorrhage stroke rate was no significant difference between aspirin and clopidogrel and between aspirin and ticlopidine.

Attachment

Submitted filename: Response to reviewer 2.docx

Click here for additional data file. (16.2KB, docx)

Decision Letter 1

Hugo ten Cate

25 Sep 2020

PONE-D-20-18884R1

The efficacy of aspirin, clopidogrel, and ticlopidine in stroke prevention: a population-based case-cohort study in Taiwan

PLOS ONE

Dear Dr. Ong,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Nov 09 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Hugo ten Cate, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

One reviewer has some additional remarks that merit your attention.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: To the authors,

Thank you for your responses and hard work. I would like to address two more issues:

1. Of patients identified with primary diagnosis ischemic stroke (n=19543) >50% were excluded. The authors report in the revised version exclusion of the patients who did not use one of the three antiplatelet drugs for more than 14 days within the first month after the stroke and the patients not continued use of the antiplatelet drugs. I recommend the authors to explain this latter exclusion criteria, be more specific: discontinuation after what period of treatment. Discontinuation of antiplatelet drugs during treatment can also be due to bleeding or ischemic complications. In that case exclusion of these patients resulted in selection bias with possible influence of study results.

2. Figure 1 reports 8,806 patients screened for inclusion. Based on the exclusion criteria, 8806-2085=6721 patients should be included for propensity score matching (2085 = sum of criteria 1-6 in figure). Author report 5117, thus 6721 – 5117 = 1604 patients were excluded currently for unknown reason. Please correct the numbers or report the reason of exclusion of these 1604 patients.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: Review.docx

Click here for additional data file. (149KB, docx)
PLoS One. 2020 Dec 28;15(12):e0242466. doi: 10.1371/journal.pone.0242466.r004

Author response to Decision Letter 1

29 Sep 2020

Response to reviewer 2

Thanks reviewer’s comments, based on reviewer’s comments we have made necessary change.

1. Of patients identified with primary diagnosis ischemic stroke (n=19543) >50% were excluded. The authors report in the revised version exclusion of the patients who did not use one of the three antiplatelet drugs for more than 14 days within the first month after the stroke and the patients not continued use of the antiplatelet drugs. I recommend the authors to explain this latter exclusion criteria, be more specific: discontinuation after what period of treatment. Discontinuation of antiplatelet drugs during treatment can also be due to bleeding or ischemic complications. In that case exclusion of these patients resulted in selection bias with possible influence of study results.

Response: In methods “Study subjects and definitions” section, Page 8 to page 9, we add a sentence “We believe the patients who did not regularly use antiplatelet drugs potentially poor medical compliance. To reduce bias, we excluded the patients who did not use antiplatelet drugs for more than 14 days within the first month after the stroke and the patients who had not use antiplatelet drugs for more than 90 consecutive days .”

In figure 1, we add an exclusion criteria, “(7). Patients who have not use antiplatelet drugs for more than 90 consecutive days (n=1604).”

2. Figure 1 reports 8,806 patients screened for inclusion. Based on the exclusion criteria, 8806-2085=6721 patients should be included for propensity score matching (2085 = sum of criteria 1-6 in figure). Author report 5117, thus 6721 – 5117 = 1604 patients were excluded currently for unknown reason. Please correct the numbers or report the reason of exclusion of these 1604 patients.

Response: In figure 1. We add an exclusion criteria. “(7). Patients who had not use antiplatelet drugs for more than 90 consecutive days (n=1604).”

Response to editor

We thank reviewer valuable comments. Base on reviewer’s comments, we have made necessary change.

1. In the patient exclusion criteria, we have add a sentence “We believe the patients who did not regularly use antiplatelet drugs potentially poor medical compliance. To reduce bias, we excluded the patients who did not use antiplatelet drugs for more than 14 days within the first month after the stroke and the patients who had not use antiplatelet drugs for more than 90 consecutive days .

2. In figure 1, we add an exclusion criteria. “Patients who had not use antiplatelet drugs for more than 90 consecutive days (n=1604).

Attachment

Submitted filename: Response to reviewer 3.docx

Click here for additional data file. (15.8KB, docx)

Decision Letter 2

Hugo ten Cate

22 Oct 2020

PONE-D-20-18884R2

The efficacy of aspirin, clopidogrel, and ticlopidine in stroke prevention: a population-based case-cohort study in Taiwan

PLOS ONE

Dear Dr. Ong,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Dec 06 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Hugo ten Cate, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

One reviewer still wants you to address the possibility of selection bias and I think the question is reasonable. Could you take one moor look?

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: To the authors,

Thank you for considering my comments. However, I still have concern regarding possible selection bias in this study.

You describe that patients did not use APT for more than >90 consecutive days due to poor medical compliance and therefore you excluded these patients form this study to reduce bias. However, it is not known whether this hypothesis is correct. It is likely that patients did not use APT for >90 days due to bleeding complications. And if poor medical compliance played a role, it could also be the result of nuisance bleeding. I would have suggested to include also patients not that did not use APT for more than >90 consecutive days in the primary analysis and afterwards, exclude this group in a sensitivity analysis.

However, as the study is now, I believe that there is a possible relevant selection bias which at least should be mentioned as a limitation in the discussion.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Dec 28;15(12):e0242466. doi: 10.1371/journal.pone.0242466.r006

Author response to Decision Letter 2

30 Oct 2020

We thanks reviewer’s valuable comments. We very concern selection bias, because it may influence the result, so we excluded the patients who potential poor medical compliance. However, it may also excluded the patients who discontinue antiplatelet due to major adverse effect of antiplatelet. It is the limitation of the retrospective study from the data base. We add a paragraph in limitation section. Two issue was point out by reviewer, we have made necessary revision.

1. Is the manuscript presented in an intelligible fashion and written in standard English?

Response: The English have been proofreading and editing by Enago-Taiwan

(enago.tw).

2. Thank you for considering my comments. However, I still have concern regarding possible selection bias in this study.

You describe that patients did not use APT for more than >90 consecutive days due to poor medical compliance and therefore you excluded these patients form this study to reduce bias. However, it is not known whether this hypothesis is correct. It is likely that patients did not use APT for >90 days due to bleeding complications. And if poor medical compliance played a role, it could also be the result of nuisance bleeding. I would have suggested to include also patients not that did not use APT for more than >90 consecutive days in the primary analysis and afterwards, exclude this group in a sensitivity analysis.

However, as the study is now, I believe that there is a possible relevant selection bias which at least should be mentioned as a limitation in the discussion.

Response:

In the limitation section, we add a limitation “Fifth, we excluded patients who did not regularly use antiplatelet drugs, which may also exclude patients who discontinued antiplatelet medications due to an adverse effect. These exclusions may underestimate the risk of adverse effects of antiplatelet medications. However, in Taiwan, when adverse effects occur, most patients will come to the hospital for help, and physicians will change the drug but will not discontinue medications.”

Attachment

Submitted filename: Response to reviewer 2.PONE4.docx

Click here for additional data file. (12.4KB, docx)

Decision Letter 3

Hugo ten Cate

3 Nov 2020

Efficacy of Aspirin, Clopidogrel, and Ticlopidine in Stroke Prevention: A Population-Based Case-Cohort Study in Taiwan

PONE-D-20-18884R3

Dear Dr. Ong,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Hugo ten Cate, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Hugo ten Cate

8 Dec 2020

PONE-D-20-18884R3

Efficacy of Aspirin, Clopidogrel, and Ticlopidine in Stroke Prevention: A Population-Based Case-Cohort Study in Taiwan

Dear Dr. Ong:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Prof. Hugo ten Cate

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Condition of antiplatelet use.

    (DOCX)

    Click here for additional data file. (13.7KB, docx)
    Attachment

    Submitted filename: Response to reviewer 2.docx

    Click here for additional data file. (16.2KB, docx)
    Attachment

    Submitted filename: Review.docx

    Click here for additional data file. (149KB, docx)
    Attachment

    Submitted filename: Response to reviewer 3.docx

    Click here for additional data file. (15.8KB, docx)
    Attachment

    Submitted filename: Response to reviewer 2.PONE4.docx

    Click here for additional data file. (12.4KB, docx)

    Data Availability Statement

    This retrospective study used data from the Taiwan National Health Insurance Research Database (NHIRD). The NHI Research Institute provides the database to researchers after anonymizing all personal information. Researchers may only share the data resulting from their analysis; in the study, all of this data is within the manuscript and the Supporting Information. Researchers who would like to access the full data underlying this study can apply to the Data Science Centre of the Ministry of Health and Welfare (MOHW) of Taiwan (https://dep.mohw.gov.tw/dos/np-2497-113.html). To apply, the researcher must design a research plan and gain IRB approval, after which point the research plan can be submitted to the MOHW for approval. The data in the manuscript were retrieved from LHID 2005. The IRB number of the study is CYCH-IRB 2018013. The search code were ICD-9 code (433, 434 and 436) for ischemic stroke. Medication search code were aspirin, clopidogrel and ticlopidine. The search for risk factor of stroke and complication or adverse effect also use ICD-9 code.

    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES