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. 2021 Apr 28;16(4):e0250553. doi: 10.1371/journal.pone.0250553

Ticagrelor vs Clopidogrel in addition to Aspirin in minor ischemic stroke/ transient ischemic attack—Protocol for a systematic review and network meta-analysis

Gabriele Zitikyte 1,2,‡, Danielle Carole Roy 1,‡, Shan Dhaliwal 1,#, Ronda Lun 1,3,*,#, Brian Hutton 1,2, Risa Shorr 4, Dar Dowlatshahi 1,2,3
Editor: Aristeidis H Katsanos5
PMCID: PMC8081237  PMID: 33909676

Abstract

Introduction

Patients with minor ischemic stroke or transient ischemic attack represent a high-risk population for recurrent stroke. No direct comparison exists comparing dual antiplatelet therapy regimens—namely, Ticagrelor and Aspirin versus Clopidogrel and Aspirin. This systematic review and network meta-analysis (NMA) will examine the efficacy of these two different antiplatelet regimens in preventing recurrent stroke and mortality up to 30 days.

Methods and analysis

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) will be searched with the assistance of a medical information specialist. Two independent reviewers will screen studies for inclusion; eligible studies will include randomized controlled trials that enrolled adults presenting with acute minor ischemic stroke or transient ischemic attack and compared one or more of the interventions against each other and/or a control. The primary outcomes will be recurrent ischemic stroke up to 30 days from symptom onset. Secondary outcomes will include safety outcomes (I.e. major bleeding and mortality), functional disability, and outcomes up to 90 days from symptom onset. A Bayesian approach to NMA will be implemented using the BUGSnet function in R Software. Between group comparisons for time-to-event (TTE) and dichotomous outcomes will be presented in terms of hazard ratios and odds ratios with 95% credible intervals, respectively. Secondary effect measures of treatment ranking will also be estimated.

Ethics and dissemination

No formal research ethics approval are necessary. We will disseminate our findings through scientific conference presentations, peer-reviewed publications, and social media/the press. The findings from this review will aid clinicians in decision-making on the choice of antithrombotic therapy in a high-risk stroke population and could be important in the development of future treatment trials and guidelines.

Registration ID with Open Science Framework: 10.17605/OSF.IO/XDJYZ.

Introduction

Patients with minor ischemic stroke or transient ischemic attack (TIA) represent a population at high risk for recurrent stroke [1–3]. The recurrent stroke rate in the next 3 months following an initial event has been suggested to be anywhere between 10–20% [4]. Clinical worsening with a subsequent event is common, and may result from progression of the initial infarct, or recurrent ischemic events [4]. Identifying optimal secondary prevention strategies in this high-risk population is crucial as it may reduce morbidity and mortality [5].

Recent clinical trials involving high-risk stroke subjects such as the POINT and CHANCE trials have established the superior efficacy of dual antiplatelet therapy (DAPT) with Clopidogrel and Aspirin compared to single antiplatelet therapy with Aspirin alone [6,7]. These trials have necessitated changes to multiple stroke treatment guidelines, recommending treatment with dual antiplatelet therapy for patients presenting with high-risk minor stroke/TIA [8,9]. Clopidogrel is a prodrug that is activated in two steps to irreversibly inhibit the binding of ADP to the P2Y12-receptor [10]. In the literature, significant variability in response to Clopidogrel exists, largely due to the prevalence of genetic polymorphisms (i.e.CYP2C19 loss of function alleles *2, *3, and *8) that render the metabolism of Clopidogrel ineffectively [11]. The prevalence of such genetic polymorphisms is reported to be especially high in Asian populations—up to 60% [12]. Clinically, this has been associated with an increased risk for “treatment failure” leading to recurrent ischemic events [12].

An alternative antiplatelet medication is Ticagrelor—an antiplatelet agent that does not require metabolic activation, but rather directly binds and inhibits platelet P2Y12 receptors [13,14]. A recent trial evaluated the use of Ticagrelor and Aspirin in the treatment of the same high-risk patient population [14]. It was found that the combination of Ticagrelor and Aspirin was superior to Aspirin monotherapy in reducing the risk for stroke or death—the event rate was 6.6% in the DAPT group compared to 5.5% in the Aspirin only group. However, the efficacy of DAPT with Ticagrelor and Aspirin has never been directly compared to an alternative regimen of Clopidogrel and Aspirin.

While traditional pairwise meta-analysis is of great value and familiarity, network meta-analysis (NMA) is a vital methodology that is able to cohesively analyze multiple comparators of relevance based on indirect evidence which does not exist in the primary literature. This protocol describes the methodology for a systematic review and network meta-analysis that will assess the relative effects of competing treatments for patients with acute minor ischemic stroke or TIA in terms of prevention of recurrent ischemic events, death, safety profiles (including major hemorrhage rates [15] and mortality), and the proportion of patients achieving functional independence.

Materials & methods

Study question, registration, and reporting

The review will address the following research question: What is the efficacy of ticagrelor and aspirin in preventing recurrent ischemic strokes compared to clopidogrel and aspirin?

The review protocol has been submitted to the Open Science Framework for registration (https://osf.io/xdjyz). Reporting of the completed review will be prepared in consultation of the PRISMA Extension Statement for Network Meta-Analysis. Any protocol deviations incurred will be described in the final study report.

Search strategy

The search strategy for this review will utilize the following databases: Medline (OVID interface), EMBASE (OVID interface), and Cochrane (OVID interface). The search will include articles from database inception until the February 2021. The search strategy, developed with the assistance of a health science librarian with expertise in systematic reviews, can be found in the S2 File. Additionally, we will search the abstracts database from the World Stroke Congress and International Stroke Conference in the last 20 years for potentially relevant abstracts. If such is found, we will contact the authors of the abstract to inquire about obtaining data.

Inclusion and exclusion criteria

Detailed inclusion and exclusion criteria are listed in Table 1.

Table 1. Inclusion/exclusion criteria for the planned systematic review.

Inclusion Criteria Population:

  • Adult patients only (18 years or older)

  • Presenting stroke severity of National Institute of Health Stroke Severity Scale (NIHSS) of 5 or less or a TIA ABCD2 score of 4 or higher

  • Must have started treatment within 72 hours of presenting stroke or TIA


Intervention:

  • Ticagrelor in combination with Aspirin in any dose or formulation


Comparator:

  • Clopidogrel in combination with Aspirin in any dose or formulation


Outcomes:

  • Reports recurrent ischemic event or death as an outcome with a minimum length of follow-up of at least 30 days post-stroke


Study Factors:

  • Randomized controlled trials only

  • Language: English or French
Exclusion Criteria Population:

  • Pediatric populations

  • Patients receiving thrombolysis or endovascular thrombectomy

  • Non-acute stroke (I.e. > 24 hours from symptom onset to randomization)


Intervention:

  • Use of antiplatelet agents other than Clopidogrel, Ticagrelor, or Aspirin


Comparator:

  • Use of antiplatelet agents other than Clopidogrel, Ticagrelor, or Aspirin


Outcomes:

  • Diagnosis of other subtype of stroke, including all intracerebral hemorrhage or cerebral venous sinus thrombosis


Study Factors:

  • Non-RCT study/article: cohort studies, cross-sectional studies, survey studies, reviews, etc.

  • Grey literature studies

  • Language: not in English or French

  • Overlapping trial populations will be dealt with by only including the study with the largest N
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Data management

All study records will be stored in a Sharepoint folder shared amongst the review team for simultaneous access to data and study files. This will include study protocol, documentation of screening, eligibility, search terms as well as completed data extraction forms and risk of bias assessments. Covidence Systematic Review Software (Covidence, Melbourne, VIC, Australia) will be used for screening and data extraction, as well as deletion of duplicate studies.

Selection process

Data will be collected by two independent reviewers for each phase of the review including screening, eligibility and extraction. Study selection will be done in two phases—the first will comprise of title and abstract screening only, and the second will comprise of full-text screening. If a study meets all of the inclusion criteria and none of the exclusion criteria, it will be included for extraction. At each phase, reviewers will evaluate the completeness, content and quality of the studies. If data is missing/unclear for a study, reviewers will contact the study investigators to obtain further information. The data collection will be done using a standardized electronic data collection form (S1 File) shared amongst the review team. Trial authors may be contacted if there are inadequate details allowing clear judgement of bias in a domain.

Data extraction

Data extraction will be undertaken by both content experts and methodologists. For each study/article, there will be two reviewers independently extracting the appropriate data. Any disagreements regarding the extracted data will be resolved via discussion between the reviewers, with consultation of a third party if necessary, to resolve the discrepancy. Where encountered, multiple reports for a single study will be extracted separately during the data extraction process, but will be collated and linked together for the analysis.

Data items

The data items extracted will be from the following categories:

  • Study Characteristics: Title, First author, Publication year, Journal, Country of origin, Funding

  • Study Methodology: Study Design, Study Setting, Allocation Sequence Concealment, Inclusion/Exclusion

  • Participant Characteristics: sample size, age, sex, country, % of previous stroke, follow-up period and % of TIA or minor ischemic stroke

  • Intervention/Comparator: number of participants in each group, drug, route of administration, drug dose, drug loading dose, drug maintenance dose, treatment frequency, duration

  • Outcomes: recurrent stroke (yes or no), mortality (yes or no), bleeding events (yes or no), modalities used for diagnosis, definitions
    • Ischemic stroke definition: neurologic dysfunction caused by focal cerebral infarction confirmed by neuroimaging or pathology [16]
    • Bleeding definition: bleeding events and method used to ascertain the bleeding event will be recorded for each study. If definitions vary between studies, we will assess heterogeneity across studies as needed.

  • Results: number of participants included in analysis, number of participants lost to follow-up, % of outcome(s) in intervention/comparator groups, number of adverse events, at two separate time points (30 days and 90 days), person-time at risk for each outcome

The final data extraction dataset will be reviewed by two other reviewers to ensure the data was entered correctly.

Risk of bias assessment

In this systematic review, risk of bias of individual studies will be assessed using the Cochrane Risk of Bias tool for randomized trials (RoB2) [17]. If there are any crossover or cluster designed randomized trials, we will use the respective RoB variant for these trials (RoB2 for crossover trials and RoB2 for cluster-randomized trials). To implement the risk of bias assessment, we will use the RoB2 excel tool which is to be done by two independent raters. If there is disagreement in the rating that cannot be resolved by discussion, the final decision will be made by consulting a third team member. The RoB2 assessment will consider the effect of assignment (also known as the intention to treat effect) as the effect of interest in which will target the results of the primary outcome: recurrent stroke. The main domains of the RoB2 assessment tool include: random sequence generation, effect of assignment, missing outcome data, measurement of the outcome and selective outcome reporting. These domains will be judged using “high, some concerns or low” risk of bias measures. The overall risk of bias will be determined by the measures of the domains. If all domains are judged low risk, the overall measure of bias will be low for this study. If there are some concerns in at least one domain with no high risk judged domains, the overall measure of bias will remain as “some concerns”. If a domain is judged as high risk or has many domains judged to have some concerns, this study will receive an overall score of high risk of bias. Raters will also be reviewing the studies for other possible biases such as sponsorship or publication bias. Trial authors may be contacted if there are inadequate details allowing clear judgement of bias in a domain.

Statistical analysis

Descriptive analysis

Population characteristics and methodological homogeneity for all eligible RCTs will be reviewed and summarized descriptively by the research team. If the trials are judged to be sufficiently homogenous, a pairwise meta-analysis per treatment comparison will be performed to evaluate homogeneity. We assume that patients who are included in studies that are eligible for this review are equally likely to be randomized to either of the dual anti-platelet therapies that we plan to compare.

Primary outcome

The primary outcome of interest will be recurrent ischemic stroke (Time-To-Event) up to 30 days. 30 days was chosen as the primary outcome because the majority of recurrent ischemic stroke events in this population occur within the first 21 days; data from trials investigating DAPT in this population have found that DAPT does not significantly reduce stroke risk during days 22–90 [18]. Time-To-Event (TTE) data will be presented as hazard ratios within intention-to-treat populations with 95% confidence intervals. If hazard ratios are not available for a study, they will be estimated using hazard ratio extrapolation methods presented by Guyot et al [19]. The proportion of patients with the primary outcome at 30 days will be compared between treatments using a chi-square test with logistic regression modeling to control for covariates.

Secondary outcomes

Secondary outcomes will include safety outcomes such as major bleeding, mortality (both TTE) and functional disability (dichotomous). We will additionally look at recurrent ischemic stroke events and bleeding events up to 90 days as secondary outcomes. TTE and dichotomous endpoints will be expressed as hazard ratios and odds ratios, respectively, with 95% confidence intervals.

Pairwise meta-analysis

A standard meta-analysis will be performed for each pairwise comparison of antiplatelet combinations. Hazard ratios for time-to-event outcomes and odds ratios for dichotomous outcomes, with 95% confidence intervals, will be obtained and between-study heterogeneity will be quantified using the I2 measure.

Methods for network meta-analyses

The transitivity assumption

A key underlying assumption of NMA is transitivity (otherwise referred to as homogeneity and similarity), such that competing interventions are jointly randomizable and effect modifiers do not differ between them [20,21]. In collaboration with our clinical experts, age, stroke severity, baseline mRS, and history of hypertension and diabetes have been identified as important effect modifiers that will be appraised for homogeneity by the study team. The distribution of these variables across studies will be investigated, and we will further explore whether other patient characteristics are balanced across trials. We will assess the impact of covariates through subgroup analyses and/or meta-regression adjustments, chosen in collaboration with clinical experts in the field. These may include but are not limited to: stroke severity and onset to randomization according to inclusion criteria of the initial trial, country of publication, and year of publication.

Transitivity will be attenuated by only including studies for which methodology and characteristics are as similar as possible [22]. This decision will be informed by careful consideration of study methods (eg. follow-up, etc) and patient characteristics (eg. eligibility and demographics such as stroke severity, age, baseline mRS, etc) by the research team. We will also perform pairwise meta-analyses for each direct comparison of interventions using the available studies to quantify statistical heterogeneity using the I2 measures to assess further heterogeneity between studies. If heterogeneity is judged to be excessive, findings will be presented via a narrative summary with supporting tables and figures. If homogeneity is sufficient, both fixed- and random-effects NMAs will be performed to compare interventions contained within the included studies and account for any effect modification [23].

Consistency

Consistency (also ‘Coherence’) is the statistical manifestation of transitivity and assesses whether the direct and indirect effect estimates from closed loops in the network are in agreement [20,24,25]. The relative effects on an appropriate scale must “add-up”; for example, the log-hazard ratio for the comparison of antiplatelet therapies A vs C is the sum of the log-hazard ratio for therapies A vs B and B vs C. Consistency will be evaluated by fitting an unrelated means model and comparing the model fit statistics and residuals with the consistency model.

Network meta-analysis

Network meta-analyses (NMA) allow synthesis of results from trials of interventions that form a connected network so that direct and indirect evidence can be statistically combined [21]. All analyses will be performed within Bayesian framework using BUGSnet 1.0.4, and evaluated with Markov Chain Monte Carlo simulation [23,24,26]. We will compare residual deviance with the number of unconstrained data points to assess model fit and, if quantities are approximately equal, the model fit will be deemed adequate. The selection between models will be based on deviance information criteria (DIC), with smaller values indicative of a greater fit and a difference greater than five points suggesting an important difference [27,28]. Convergence will be assessed using Gelman and Rubin criteria and by inspecting trace plots [26,28]. NMA also enables ranking of treatments according to the probability that each is the best, second best, and so on, for a given outcome. Probabilistic statistics will be calculated for each intervention and results will be plotted [29].

Ethics and dissemination

No formal research ethics approval will be necessary for this study as primary data will not be collected. The findings from this review and network meta-analysis will aid clinicians in decision-making on the choice of antithrombotic therapy in a high-risk stroke population and could be important in the development of future treatment trials and guidelines. Therefore, we will disseminate our findings through a combination of scientific conference presentations, peer-reviewed publications, and social media/the press.

Conclusions

This review is planned as there is evolving evidence suggesting variable effectiveness of antiplatelet therapies for patients with minor ischemic stroke or TIA. Traditional systematic reviews and meta-analyses exist that compare Ticagrelor or Clopidogrel against Aspirin alone; however, no network meta-analyses enabling the comparison of both indirect and direct evidence have been performed [6,7,14]. This review will be the first to compare both DAPT therapies head-to-head and provide relative effectiveness, thus facilitating evidence-based management of patients suffering from a minor ischemic stroke or TIA, and identifying key areas for future research. We will prioritize patient-important outcomes such as recurrent strokes, mortality, and bleeding events.

Supporting information

S1 Checklist

(DOCX)

Click here for additional data file. (26.1KB, docx)
S1 File

(XLSX)

Click here for additional data file. (152.2KB, xlsx)
S2 File

(DOCX)

Click here for additional data file. (13.1KB, docx)

Acknowledgments

We would like to express our sincere gratitude to our professors, Dr. Dean Fergusson, MHA, PhD, FCAHS, Full Professor, Departments of Medicine & Surgery, & School of Epidemiology and Public Health, University of Ottawa, and Dr. Matthew McInnes, MD, FRCPC, BSc, PhD, Professor, Departments of Radiology, & School of Epidemiology and Public Health, University of Ottawa, for teaching us about systematic reviews and providing guidance throughout this protocol development.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Aristeidis H Katsanos

1 Apr 2021

PONE-D-21-08104

Ticagrelor vs Clopidogrel in addition to Aspirin in minor ischemic stroke/ transient ischemic attack – protocol for a systematic review + network meta-analysis

PLOS ONE

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Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: No

Reviewer #2: No

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

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(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors present an interesting protocol aimed at comparing dual antiplatelet treatment in stroke recurrence prevention after minor stroke or TIA.

The protocol is sound, methods are well defined and eligibility criteria similar to previous reviews.

Few points to address:

- Regarding grey literature, please define the reasons underlying the exclusion of other repositories (Rxiv and similars, or search engine as GScholar).

- Regarding medications chosen, please detail the a-priori exclusion of other antithrombotics (e.g. cilostazol)

Please also consider to provide the tabular view of data extracted through accessible repositories, as well as the syntax script used for analysis to allow reproducibility of the research.

Reviewer #2: Thank you for the opportunity to review this protocol for meta-analysis and review. The study provides the planned protocol for a network meta-analysis of different DAPT regiments post-TIA, specifically Ticagrelor + Aspirin vs Clopidogrel + Aspirin. The authors provide good reasoning for the necessity of this type of analysis, and provide the required information for the study protocol.

The authors suggest going through abstracts from ISC and WSO. It would also be a good idea to go through the abstracts of the European Stroke Organisation Conferences.

While it is fully up to the authors to decide the data extraction complexity, the fact that this study does not use individual patient level data is a study design drawback that limits the conclusions of this study. As most RCT's have generous data-sharing policies, it should not be too difficult to receive these datasets given the very reasonable scientific question of this study. A comment on the limitation of not having individual patient level data should be added.

While the authors write in the “Transitivity assumption” how heterogeneity will be handled, there is no specification on what criteria for heterogeneity will be used. This section should be expanded.

THALES and POINT have differing inclusion/exclusion criteria in terms of stroke severity and TIA risk score. This will be an inherent difference between studies which will still be within the inclusion criteria of this meta-analysis. It would be of interest to perform a subgroup analysis of POINT-like patients within the THALES population, if the extracted data will allow it.

Additional between study effect modifiers that should be considered are: Onset to randomization, onset to treatment, sex.

Assessing balance of potential effect modifiers is a good start but will still be lacking because you do not have individual patient level data. You will not be able to assess if patients with multiple effect modifiers, for example hypertension + diabetes, have a synergistic effect on the outcomes. While these effects should be balanced through randomization, there is no guarantee that they are balanced between studies. A brief comment on this is needed, perhaps within the previous IPD comment.

The GRADE framework level of evidence is not included as a inclusion/exclusion criteria. Hence, the sentences describing that only RCT's of high quality will be included yet that they can also be downgraded in evidence grade are confusing. This part should be clarified or removed.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 Apr 28;16(4):e0250553. doi: 10.1371/journal.pone.0250553.r002

Author response to Decision Letter 0

8 Apr 2021

Response to Reviewers

Reviewer #1: The authors present an interesting protocol aimed at comparing dual antiplatelet treatment in stroke recurrence prevention after minor stroke or TIA.

The protocol is sound, methods are well defined and eligibility criteria similar to previous reviews.

Few points to address:

- Regarding grey literature, please define the reasons underlying the exclusion of other repositories (Rxiv and similars, or search engine as GScholar).

Thank you for your comments. While we appreciate the breadth of literature in gray literature repositories, the objective of this systematic review is to include only evidence of the highest standard, and therefore we chose to only include peer-reviewed journals and publications of the randomized controlled trial type. We recognize this is a limitation of the current study.

We are open to adding a “Limitations” paragraph to our protocol paper, but would prefer to include it in the final publication instead, since we anticipate this will ultimately be a more comprehensive reflection of the limitations of the study. However, we have drafted up a limitations paragraph (see page 4) and will leave the decision to the reviewers/ editor in terms of its inclusion in the current protocol.

- Regarding medications chosen, please detail the a-priori exclusion of other antithrombotics (e.g. cilostazol)

We chose to exclude all other antithrombotics, including anticoagulants (i.e. warfarin, direct oral anticoagulants), and all other formulations of antiplatelet medications that are not Clopidogrel, Ticagrelor, or Aspirin.

While other antiplatelet medications have been tested in the minor stroke/ TIA population (including cilostazol), the only recommended dual antiplatelet therapy in this population currently from the 2018 American Heart Association guidelines for secondary prevention after minor ischemic stroke/ TIA are for Clopidogrel and Aspirin. However, with the latest evidence from THALES (comparing Ticagrelor and aspirin), there may be emerging evidence for use of Ticagrelor – in fact, we have confirmed that the revised 2021 Canadian Stroke Best Practice recommendations (in press) will include Ticagrelor in their recommendations. We expect the American guidelines (and others) will likely change soon to account for the new emerging evidence for Ticagrelor. Therefore, we chose specifically to compare Ticagrelor and Aspirin vs Clopidogrel and Aspirin. However, we recognize there are alternative antiplatelet regimens recommended by other guidelines, and therefore we will include this as a limitation in our final manuscript.

Please also consider to provide the tabular view of data extracted through accessible repositories, as well as the syntax script used for analysis to allow reproducibility of the research.

We will make all source documents available upon request, in accordance to PLoS ONE publication policies. Thank you for your suggestion.

Reviewer #2: Thank you for the opportunity to review this protocol for meta-analysis and review. The study provides the planned protocol for a network meta-analysis of different DAPT regiments post-TIA, specifically Ticagrelor + Aspirin vs Clopidogrel + Aspirin. The authors provide good reasoning for the necessity of this type of analysis, and provide the required information for the study protocol.

The authors suggest going through abstracts from ISC and WSO. It would also be a good idea to go through the abstracts of the European Stroke Organisation Conferences.

Thank you for this great suggestion. We have added ESOC to the list of abstracts we review.

While it is fully up to the authors to decide the data extraction complexity, the fact that this study does not use individual patient level data is a study design drawback that limits the conclusions of this study. As most RCT's have generous data-sharing policies, it should not be too difficult to receive these datasets given the very reasonable scientific question of this study. A comment on the limitation of not having individual patient level data should be added.

We agree that individual patient data (IPD) meta-analyses would be ideal. However, we are concerned that the process of retrieving and collating individual patient data would significantly delay the completion of this systematic review. For example, the POINT trial has specifically stated in their study protocol (section 12): “Three years after the primary publication associated with this work is submitted, a HIPAA-compliant, de-identified version of the database will be made available publicly.” Since this trial was published in 2018 this would mean that we would have to wait until at least November 2021 to gain access to this data. Moreover, in our prior experience with IPDs, some studies will require research ethics board amendments to share their data, which can again add to completion time. As this is an emerging and important topic currently, we would prefer to perform an aggregate level meta-analysis first, and subsequently explore an IPDMA.

While the authors write in the “Transitivity assumption” how heterogeneity will be handled, there is no specification on what criteria for heterogeneity will be used. This section should be expanded.

Thank you for the suggestion. Our protocol has been updated accordingly.

See lines 235 – 240 of the revised manuscript:

“This decision will be informed by careful consideration of study methods (eg., follow-up, etc) and patient characteristics (eg., eligibility and demographics such as stroke severity, age, baseline mRS, etc) by the research team. We will also perform pairwise meta-analyses for each direct comparison of interventions using the available studies to quantify statistical heterogeneity using the I2 measures to assess further heterogeneity between studies.”

THALES and POINT have differing inclusion/exclusion criteria in terms of stroke severity and TIA risk score. This will be an inherent difference between studies which will still be within the inclusion criteria of this meta-analysis. It would be of interest to perform a subgroup analysis of POINT-like patients within the THALES population, if the extracted data will allow it.

Additional between study effect modifiers that should be considered are: Onset to randomization, onset to treatment, sex.

Unfortunately, because we are not performing an IPD-level meta-analysis, we are unable to perform specific subgroup analysis based on initial sex. However, we plan on performing subgroup analyses based on the median NIHSS/ TIA risk score and time to randomization reported on a study level. Furthermore, we will be stratifying patients by stroke severity and onset to randomization as per trial inclusion criteria, year of publication, and country of publication, and have updated our protocol to reflect these changes.

Assessing balance of potential effect modifiers is a good start but will still be lacking because you do not have individual patient level data. You will not be able to assess if patients with multiple effect modifiers, for example hypertension + diabetes, have a synergistic effect on the outcomes. While these effects should be balanced through randomization, there is no guarantee that they are balanced between studies. A brief comment on this is needed, perhaps within the previous IPD comment.

We recognize this is a limitation of our aggregate-level meta-analysis. We have expanded our limitations paragraph to account for this.

The GRADE framework level of evidence is not included as a inclusion/exclusion criteria. Hence, the sentences describing that only RCT's of high quality will be included yet that they can also be downgraded in evidence grade are confusing. This part should be clarified or removed.

This section has been removed as per the reviewer’s suggestions.

 

Limitations Paragraph – to be included at the reviewers/ editor’s discretion

There are a number of limitations that must be considered when examining this systematic review. First, by focusing on randomized trials, we may overlook potential data from non-randomized studies and gray literature. However, we believe this is also a strength of our study, as it focuses only on article types with the highest hierarchy of evidence (i.e. RCT). Second, we did not utilize individual patient data for this study which limits the number of subgroup analyses that we are able to perform. This is unfortunately a limitation that we cannot avoid in order to conduct a timely review, as some clinical trials (e.g. POINT) have not yet released their trial data at the time of developing this study protocol. Third, given that the inclusion/exclusion criteria differ slightly between studies, there may be residual clinical and statistical heterogeneity between studies, which will be assessed by performing and reporting I2 statistics in the final manuscript. Lastly, it is also possible that reporting or publication bias may be present in certain studies, which will be assessed and reported using the Risk of Bias 2 assessment tool.

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Decision Letter 1

Aristeidis H Katsanos

12 Apr 2021

Ticagrelor vs Clopidogrel in addition to Aspirin in minor ischemic stroke/ transient ischemic attack – protocol for a systematic review + network meta-analysis

PONE-D-21-08104R1

Dear Dr. Lun,

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.

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Aristeidis H. Katsanos, MD, PhD

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Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Aristeidis H Katsanos

14 Apr 2021

PONE-D-21-08104R1

Ticagrelor vs Clopidogrel in addition to Aspirin in minor ischemic stroke/ transient ischemic attack – protocol for a systematic review and network meta-analysis

Dear Dr. Lun:

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.

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