Utility of the DAPT score to guide antiplatelet therapy: a systematic review and meta-analysis

Abstract

Background:

The DAPT score, one of the first prediction tools to attempt to uncouple bleeding and ischemic risk following percutaneous coronary intervention, can help guide antiplatelet duration after coronary intervention. Evaluating the generalizability of the score is important to understand its utility in clinical practice.

Methods:

We conducted a systematic review and meta-analysis of studies that validated the DAPT score. Patients with high DAPT scores (≥2) are predicted to have high ischemic risks and low bleeding risks, whereas those with low DAPT scores (<2) are predicted to have high bleeding risks and low ischemic risks. A random effect meta-analysis was performed of ischemic and bleeding risk based on DAPT score. A secondary analysis assessed the risk of longer versus shorter P2Y₁₂ inhibitor duration on ischemic and bleeding risk in randomized controlled trials of DAPT duration.

Results:

We identified 10 patient cohorts involving 88,563 patients. Compared with a low DAPT score, a high DAPT score was associated with increased ischemic risk (RR: 1.62, 95% CI: 1.41–1.87) and reduced bleeding risk (RR: 0.80, 95% CI: 0.70–0.92). In 3 randomized trials of DAPT duration that contained information on the DAPT score, the relative risk of net adverse clinical events (combined ischemic and bleeding events) with longer duration of DAPT was 1.56 (95% CI: 0.77–3.19) for low DAPT score patients, and 0.86 (95% CI: 0.61–1.21) for high DAPT score patients (P_interaction=0.14).

Conclusions:

In this large meta-analysis, the DAPT score consistently stratified bleeding and ischemic risk in opposing directions across several different study populations. More evaluation is needed to understand if the effect of longer DAPT duration on NACE is modified by the DAPT score in current practice.

Introduction

Dual antiplatelet therapy (DAPT), a combination of aspirin and a P2Y₁₂ inhibitor, remains the cornerstone therapy for the prevention of ischemic complications following stent implantation. While contemporary guidelines recommend a minimum of 6–12 months of DAPT, the extension of DAPT therapy beyond 12-months in select patients has demonstrated a reduction in cardiovascular events at the cost of increased bleeding (1–4). In parallel, randomized controlled trials (RCT) have sought to assess even shorter DAPT duration in ACS and SIHD, with mixed evidence of non-inferiority to the current standard (5–7). Balancing these competing ischemic and bleeding risks has led to much debate around the optimal duration of DAPT.

Initial clinical prediction tools, developed in an effort to quantify bleeding and ischemic risk, effectively but independently predicted the risk of either ischemic or bleeding events (8–15). Due to the high correlation between bleeding and ischemic risk, patients selected for shorter duration of DAPT on the basis of high bleeding risk might also be the same ones exposed to greater ischemic complications due to concomitant high ischemic risk. This conundrum has historically limited the utility of many risk models to predict either ischemic or bleeding risk alone for informing clinical decision making (16).

The DAPT score was among the first clinical risk scores to successfully uncouple the correlated risks of bleeding and ischemic events among PCI patients (17, 18). Utilizing nine clinical variables, the DAPT score was able to identify patients with high ischemic but low bleeding risk (DAPT score≥2) who derived ischemic benefit from extending DAPT duration to 30 months, as well as those with high bleeding but low ischemic risk (DAPT score<2) who were harmed by prolonging DAPT duration.

Although the DAPT score can help determine optimal antiplatelet duration among PCI patients, questions about its generalizability and external validity have remained (19). A number of studies have attempted to externally validate the DAPT score in different patient populations (19–24). We therefore sought to perform a systematic review and meta-analysis of these validation studies to assess the DAPT score’s ability to stratify bleeding and ischemic risk, as well as net adverse clinical events of longer DAPT durations, among a heterogeneous group of patients undergoing percutaneous coronary intervention (PCI).

Methods

Search Strategy

We conducted a systematic review and meta-analysis to examine the ability of the DAPT score to discern bleeding and ischemic risk among patients following PCI in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analyses of healthcare interventions (Appendix Table 1) (25). Medline (with the Pubmed interface), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for relevant studies published after the online publication of the original DAPT score on March 29, 2016. The following search terms were used in each database: “DAPT”, “Dual antiplatelet therapy”, “score”, “prediction”, and “validation”. References of identified studies were manually searched. Searches were restricted to trials of human participants with full text published in English. In addition to these studies, the DAPT study derivation cohort and the PROTECT validation cohort were included.

The systematic search and critical review were performed to ensure that each study satisfied the following inclusion criteria: 1) Study assessed the DAPT score in a prespecified patient population, 2) Subjects within the study were stratified based on high (≥2) or low (<2) DAPT scores, 3) Bleeding and ischemic rates were reported based on DAPT score stratification. Studies were excluded if they did not stratify event rates by high/low DAPT score or if the study focused only on a subgroup analysis of a large trial.

Meta-analysis of Ischemic & Bleeding Events

The following variables were abstracted from each study: population characteristics, trial design, number of patients in each DAPT strata, follow-up duration, and cumulative ischemic and bleeding event rates. Ischemic events were defined as myocardial infarction and/or definite/probable stent thrombosis according to the Academic Research Consortium definition (26). Bleeding endpoints were primarily assessed using the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria for moderate to severe bleeding (27). When GUSTO adjudicated bleeding was not reported, the closest equivalent bleeding classification was used. For studies that assessed the DAPT score in randomized control studies of DAPT duration, cumulative bleeding and ischemic event rates stratified by DAPT score within each treatment arm were also collected.

Risk ratios with 95% confidence intervals (CI) were defined as the ratio of the high DAPT score event rate over the low DAPT score event rate (irrespective of treatment arm for randomized trials). Risk ratios were determined for ischemic and bleeding events for each study. When absolute events were not reported, event rates and population size were used to calculate absolute event numbers. A meta-analysis was then performed of ischemic and bleeding risk for high versus low DAPT score patients, with a summary risk ratio and 95% CI for each of the endpoints calculated from the individual study risk ratios using Mantel-Haenszel methods. Heterogeneity was quantified through the I-squared statistic with values of 25%, 50%, and 75% corresponding to low, moderate, and high heterogeneity, respectively (28). In light of the heterogeneity across trials, random effect models were utilized to synthesize the results.

Secondary Analysis of RCTs assessing P2Y₁₂ Inhibitor Duration

To investigate the DAPT score’s ability to stratify the effect of duration of P2Y₁₂ inhibitor therapy on ischemic and bleeding events, we performed a pre-specified secondary analysis examining the risk of ischemic and bleeding events between long and short P2Y₁₂ inhibitor duration by intention-to-treat, stratified by the DAPT score. The search strategy only included studies that reported bleeding and ischemic events by DAPT score. This analysis was deemed exploratory because few randomized trials of DAPT duration have evaluated the DAPT score, and those that have included very different DAPT regimens. Summary risk ratios with 95% CI were calculated to estimate the overall treatment effect of longer versus shorter P2Y₁₂ inhibitor duration for high DAPT score patients and separately, low DAPT score patients. Additionally, the composite of bleeding and ischemic events, defined as net adverse clinical events (NACE), was assessed as an outcome.

The interaction between DAPT score (high versus low) and the treatment arm (longer P2Y₁₂ inhibitor arm versus shorter P2Y₁₂ inhibitor arm) for each outcome was tested using a two sample Z-test. We obtained the point estimate and standard error of the treatment effect estimate separately for each of the two sub-populations of interest. Since the point estimate is approximately normally distributed, the comparison of the treatment effect between the two sub-populations can be performed using a Z-test, where the numerator and denominator of the Z statistic are the difference in point estimates between the two subpopulations and the square root of the sum of the square of the standard errors, respectively. The Z statistic was then translated to a p-value.

Data extraction and assessment of study bias was performed utilizing The Newcastle-Ottawa Scale (NOS) and Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for evaluating the quality of non-randomized studies in meta-analysis quality assessment (29, 36). Publication bias was assessed visually by asymmetry in funnel plots, interpretation of which occurred in the context of the limited number of studies in this analysis (Appendix Figure 2). Discrepancies in study selection were resolved by consensus.

All analyses were performed using package “meta” in the R computing environment. Institutional review board review was not sought due to the nature of this study. There was no funding source for this study. All authors had full access to all the data used in the study, and R.W.Y. had final responsibility for the decision to submit for publication.

Results

Our systematic literature search identified 59 articles, of which 7 met the inclusion criteria for this analysis (Figure 1). The data from one study were made available by the study authors (30). The PROTECT validation cohort was then added to these studies, leading to a total of 8 studies and 10 distinct patient cohorts with 88,563 patients (17, 19–24, 30). The subject populations enrolled in the validation cohorts were as follows: three RCTs of DAPT strategies or durations (n=17,235) (17, 21, 22, 30), one RCT of stent type (n=8,136) (17), three registry studies (n=50,969) (20, 23), and one combined analysis of two registries and one RCT of stent type (n=12,223) (24). Duration of follow-up after PCI ranged from 6 to 36 months and the utilization of 2^nd generation or newer drug-eluting stents ranged from 38% to 100% of the included patients (Table 1). All studies included patients who received stents for either acute coronary syndrome or stable ischemic heart disease. The NOS quality assessment rated all studies as good and the ROBINS-I suggests an overall low risk of bias (Appendix Table 2, Appendix Figure 1).

Figure 1:

Flow diagram of literature search and study selection.

Table 1:

Characteristics of studies included in meta-analysis.

First Author (Year)	Study Cohort	Study Type	Total # of Patients in DAPT Analysis	ACS as PCI Indication n (%)	2nd Generation or newer DES (%)	Interval Follow-up from Index PCI	Ischemic End Point	Bleeding End Point
Yeh, RW (2016) (17)	DAPT	RCT: DAPT Strategy	11648	5397 (46%)	51%	12–30m	MI or definite/probable ST	GUSTO moderate/severe
	PROTECT	RCT: Stent type	8136	N/A	50%	12–30m	MI or definite/probable ST	GUSTO moderate/severe
Piccolo, R (2017) (22)	PRODIGY	RCT: DAPT Strategy	1970	1465 (74%)	50%	6–24m	MI or definite/probable ST	GUSTO moderate/severe
Harada, Y (2017) (21)	ISAR-SAFE	RCT: DAPT Strategy	3976	1593 (40%)	72%	6–15m	MI or definite/probable ST	TIMI major or minor
Ueda, P (2018) (19)	SWEDEHEART	Registry	41101	31771 (77%)	59%	12–30m	MI or definite/probable ST	GUSTO moderate/severe equivalent
Brener, SJ (2018) (20)	ADAPT-DES	Registry	5397	1593 (30%)	Not reported	12–24m	MI or definite/probable ST	BARC 2, 3 or 5 equivalent
Yoshikawa, Y (2018) (24)	CREDO-Kyoto	Registry	12223	2698 (22%)	38%	13–36m	MI or definite/probable ST	GUSTO moderate/severe
	RESET	RCT: Stent type
	NEXT	RCT: Stent type
Witberg, G (2019) (23)	N/A	Registry	4471	2596 (58%)	45%	12–36m	MI	BARC 2, 3 or 5 equivalent
Chichareon, P (2020) (30)	GLOBAL LEADERS	RCT: DAPT Strategy	11289	5226 (46%)	100%	12–24m	MI or definite/probable ST	BARC type 3 or 5

RCT: Randomized control trial; DAPT: Dual antiplatelet therapy; DES: Drug eluting stent; m: months; PCI: percutaneous coronary intervention; MI: myocardial infarction; ST: stent thrombosis; GUSTO: Global Utilization of Streptokinase & Tissue Plasminogen Activator for Occluded Coronary Arteries; BARC: Bleeding Academic Research Consortium; TIMI: Thrombolysis in myocardial infarction

All but one trial reported a combined ischemic end point of myocardial infarction (MI) and/or definite/probable stent thrombosis (ST), as defined by the Academic Research Consortium (17, 19–22, 24, 26, 30). One trial reported MI rates only (23). With RCT treatment groups consolidated, ischemic event rates ranged from 0.5–3.0% among the low DAPT score patients and 0.9–4.5% among the high DAPT score patients (Figure 2A). All but one trial (22) identified a higher ischemic event rate with high DAPT score patients.

Figure 2:

Cumulative incidence rates of myocardial infarction and/or definitive/probable stent thrombosis (Panel A) or bleeding events (Panel B) by low (blue) and high (red) DAPT score across DAPT score validation studies.

Five trials utilized GUSTO moderate/severe bleeding or equivalent criteria for event rates (17, 19, 22, 24), two trials utilized Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding or equivalent criteria (20, 23, 31), one trial reported BARC type 3 or 5 (30, 31), and one trial reported thrombolysis in myocardial infarction (TIMI) major or minor bleeding (21). Bleeding event rates ranged from 0.5–2.7% among low DAPT score patients and 0.3–2.2% among high DAPT score patients (Figure 2B). All identified trials demonstrated a higher bleeding event rate with low DAPT score patients compared to high DAPT score patients.

Meta-Analysis of DAPT Score Discerning Ischemic & Bleeding Risk

Compared with a low DAPT score, a high DAPT score was associated with an increased risk of ischemic events (RR: 1.62; 95% CI: 1.41–1.87 Figure 3A). There was evidence of moderate heterogeneity in the risk ratio between high and low DAPT scores for the ischemic endpoint (I² = 31%).

Figure 3:

Forest plot of relative risk of ischemic events (Panel A) or bleeding events (Panel B) by DAPT score.

With regards to bleeding events, a high DAPT score relative to a low DAPT score was associated with a lower risk of bleeding events (RR: 0.80, 95% CI: 0.70–0.92, Figure 3B). There was no heterogeneity among the included studies (I² = 0%).

Meta-analysis of DAPT Duration Treatment Effect on DAPT Score Stratification

Four studies assessed the DAPT score in RCTs of DAPT duration, totaling 17,235 patients (Table 2) (21, 22, 30). The PRODIGY trial compared 6-months of DAPT to 24-months of DAPT with event adjudication for the DAPT score validation occurring between 6 and 24-months following PCI (22, 32). The ISAR-SAFE study compared 6-months of DAPT followed by 6-months of aspirin monotherapy to 12-months of DAPT with DAPT score event adjudication occurring from 6-months to 15-months (21, 33). Lastly, GLOBAL LEADERS compared 12-months of DAPT followed by 12-months of aspirin monotherapy (reference strategy) to 1-month of DAPT followed by 23-months of ticagrelor monotherapy (experimental strategy) (34). The DAPT score analysis in GLOBAL LEADERS assessed events from 12 to 24-months and the experimental strategy was considered the longer P2Y₁₂ inhibitor group for this analysis (30). While the reference strategy utilized DAPT with aspirin and clopidogrel or ticagrelor from 0–12 months, only those patients that were free of ischemic or bleeding events at 12 months were included in the GLOBAL LEADERS DAPT score validation study. To assess the treatment effect of increased P2Y₁₂ inhibitor duration on the DAPT score’s ability to predict ischemic and bleeding events, we performed a separate meta-analysis of short versus long P2Y₁₂ inhibitor duration for bleeding and ischemic risk within the high and low DAPT score groups.

Table 2:

Characteristics of randomized control trials of dual antiplatelet therapy (DAPT) intensity against which the DAPT score was validated.

First Author (Year)	Study Cohort	Study Arm	Study Arm Design	Low DAPT Score (n)	High DAPT Score (n)
Harada, Y (2017) (21)	ISAR-SAFE	Short P2Y12	6-months A/C followed by 6-months A	1211	774
		Long P2Y12	12-months A/C	1196	795
Piccolo, R (2017) (22)	PRODIGY	Short P2Y12	6-months A/C followed by indefinite A	549	434
		Long P2Y12	24-months aspirin/clopidogrel	537	450
Chichareon, P (2020) (30)	GLOBAL LEADERS	Less Intense P2Y12	12-months A/(C or T) followed by 12-months A	3635	2288
		More Intense P2Y12	1-month A/T followed by 23-months T	3247	2119

A: Aspirin; C: Clopidogrel; T: Ticagrelor; P: Prasugrel

Among low DAPT score patients, there was no difference in ischemic events between longer P2Y₁₂ inhibitor duration when compared to shorter P2Y₁₂ inhibitor duration (RR: 1.10, 95% CI: 0.40–3.00, Figure 4A). There was significant heterogeneity among the included studies (I² =78%). Similarly, there was no difference in ischemic events among high DAPT score patients with longer duration P2Y₁₂ inhibitor therapy compared to shorter duration P2Y₁₂ inhibitor therapy (RR: 0.80, 95% CI: 0.54–1.17, Figure 4B). There was no heterogeneity (I²=0%). There was no significant interaction between DAPT score and P2Y₁₂ inhibitor duration for ischemic events (P_interaction=0.56)

Figure 4:

Forest plot of relative risk of ischemic events between longer duration of P2Y₁₂ inhibitor therapy and shorter duration of P2Y₁₂ inhibitor therapy in low DAPT score (Panel A) versus high DAPT score (Panel B).

With regards to bleeding risk, a low DAPT score was associated with a greater bleeding risk with longer P2Y₁₂ inhibitor therapy when compared to shorter P2Y₁₂ inhibitor therapy (RR: 2.28, 95% CI: 1.39–3.76, Figure 5A). However, among high DAPT score patients, there was no difference in bleeding events between long and short P2Y₁₂ inhibitor therapy (RR: 1.19, 95% CI: 0.54–2.59, Figure 5B). There was no heterogeneity across the trials (I² =0%). The interaction between DAPT score and P2Y₁₂ inhibitor duration for bleeding events was 0.17.

Figure 5:

Forest plot of relative risk of bleeding events between longer duration of P2Y₁₂ inhibitor therapy and shorter duration of P2Y₁₂ inhibitor therapy in low DAPT score (Panel A) versus high DAPT score (Panel B).

In an analysis of NACE, defined as a composite of ischemic and bleeding events, the risk ratio for longer versus shorter P2Y₁₂ inhibitor therapy for low DAPT score patients was 1.56 (95% CI: 0.77–3.19) (Figure 6A). There was significant heterogeneity (I²=77%). For high DAPT score patients, there was a 0.86 relative risk of NACE with longer P2Y₁₂ inhibitor therapy when compared to shorter P2Y₁₂ inhibitor therapy (95% CI: 0.61–1.21, Figure 6B). There was no heterogeneity (I² =0%). The interaction P value between DAPT score and P2Y₁₂ inhibitor duration on NACE was not significant (p=0.14).

Figure 6:

Forest plot of relative risk of net adverse clinical events (NACE) between longer duration of P2Y₁₂ inhibitor therapy and shorter duration of P2Y₁₂ inhibitor therapy in low DAPT score (Panel A) versus high DAPT score (Panel B).

Discussion:

In a meta-analysis of 88,563 patients from 10 heterogeneous patient populations, the DAPT score reliably stratified bleeding and ischemic risk in opposing directions. Patients with a high DAPT score (DAPT score≥2) were at higher risk of ischemic events when compared with patients with a low DAPT score (DAPT score<2). Conversely, patients with a low DAPT score had a greater risk of bleeding when compared with patients with a high DAPT score. Thus, although the generalizability and external validity of the DAPT risk score has been questioned, appropriate application of this risk tool suggests that bleeding and ischemic risk can be uncoupled, consistent with the findings of all other trials (Figure 3).

Only three randomized trials have evaluated the DAPT score’s ability to identify which patients would derive the greatest benefit versus harm from longer DAPT duration. In this analysis, the DAPT score did not significantly discern ischemic and bleeding risk based on P2Y₁₂ inhibitor duration, with an interaction p value of 0.14. Nonetheless, among high DAPT score patients, longer P2Y₁₂ inhibitor duration demonstrated numerically lower risk of ischemic events and NACE compared to shorter duration P2Y₁₂. Conversely, among low DAPT score patients, there was no numerical reduction in ischemic events and a greater than 2-fold increase in bleeding with longer P2Y₁₂ inhibitor duration. These findings were underpowered, however, given the limited number of trials. In addition, trial treatment strategies were heterogeneous. The GLOBAL LEADERS trial, for example, randomized patients to two distinct DAPT strategies: DAPT for one-year followed by aspirin monotherapy for one-year compared to DAPT for one-month followed by ticagrelor monotherapy for 23-months (34). As the DAPT score analysis only included patients event-free at 12-months, GLOBAL LEADERS incorporated the DAPT score as an assessment of aspirin versus ticagrelor monotherapy on bleeding and ischemic risk (30). This distinct strategy could explain GLOBAL LEADERS’ outlier position, particularly with regards to the decreased ischemic risk without a bleeding cost observed in low DAPT score patients with ticagrelor monotherapy. P2Y₁₂ inhibitor monotherapy may perhaps strike a balance between DAPT and aspirin monotherapy in terms of bleeding and ischemic risk. Despite the novel antiplatelet strategy, the GLOBAL LEADERS validation fundamentally underscores the DAPT score’s ability to discern a treatment effect between more intense and less intense P2Y₁₂ inhibition. Ultimately, a prospective trial will be needed to validate the DAPT score’s ability to identify those patients who might derive the greatest benefit from prolonged DAPT or perhaps even prolonged P2Y₁₂ inhibitor monotherapy.

This analysis leverages a large and heterogeneous patient population derived from both randomized and registry based clinical trials to support the utilization of the DAPT score as a clinical risk tool to identify patients with discordant ischemic and bleeding risk profiles to help guide antiplatelet regimens. Limited by a small number of trials comparing different DAPT durations/intensity, this analysis did not discern a statistically significant differences in treatment response to different DAPT regimens based on DAPT score. Our findings both compliment the recent meta-analysis that also externally validated the DAPT score and add to the strength of its conclusions with the addition of the GLOBAL LEADERS validation study (35).

Our study has important limitations. First, the studies included in the meta-analysis are heterogeneous in design, patient and procedural characteristics, and ischemic and bleeding event definitions. Our results, in spite of this heterogeneity, can potentially underscore the generalizability of our findings across multiple datasets and patient populations. Second, while our analysis confirmed the overall power of the DAPT score to predict bleeding and ischemic events, the analysis of the DAPT score’s ability to discern the effect of DAPT duration were confined to a small subgroup of studies limited by variation in DAPT regimens and duration in each trial. Third, this analysis was limited to the published high and low DAPT score stratification of each of the original validation studies. Evaluation of the DAPT score in a continuous fashion could potentially further assess if the degree of ischemic benefit or bleeding harm correlates with DAPT score magnitude.

Conclusion:

In conclusion, DAPT score was able to successfully uncouple the risks of ischemia and bleeding among patients undergoing PCI in a comprehensive meta-analysis of external validation studies. Based on these findings, high DAPT score patients have higher than average ischemic risk and lower than average bleeding risk. Conversely, low DAPT score patients consistently have lower than average ischemic risk, but higher than average bleeding risk – and thus may warrant a lower intensity or duration of DAPT. The DAPT score did not discern an overall benefit versus harm of different DAPT durations that met statistical significance, although this assessment was underpowered. Additional prospective studies evaluating a strategy to guide DAPT duration based on DAPT score versus usual care are warranted, particularly with newer antiplatelet strategies.

What is known?

The DAPT score is among the first clinical risk scores to independently predict ischemic and bleeding risk following percutaneous coronary intervention. Smaller studies have attempted to validate the DAPT score in different patient populations.

What the study adds?

This study offers an aggregate meta-analysis of existing validation studies to affirm the DAPT score’s ability to uncouple ischemic and bleeding across a heterogeneous patient population.

Appendix Table 1.

PRISMA Checklist

Section/topic	#	Checklist item	Reported on page #
TITLE
Title	1	Identify the report as a systematic review, meta-analysis, or both.	1
ABSTRACT
Structured summary	2	Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.	2
INTRODUCTION
Rationale	3	Describe the rationale for the review in the context of what is already known.	4–5
Objectives	4	Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).	5
METHODS
Protocol and registration	5	Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.	N/A
Eligibility criteria	6	Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.	6, Figure 1, Table 1
Information sources	7	Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.	6
Search	8	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.	6
Study selection	9	State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).	6, Figure 1
Data collection process	10	Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.	6
Data items	11	List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.	6–7
Risk of bias in individual studies	12	Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.	8, Appendix Figure 1
Summary measures	13	State the principal summary measures (e.g., risk ratio, difference in means).	7
Synthesis of results	14	Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.	7–8
Risk of bias across studies	15	Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).	8, Appendix Figure 1
Additional analyses	16	Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.	7–8
RESULTS
Study selection	17	Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.	9
Study characteristics	18	For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.	9–10
Risk of bias within studies	19	Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).	8
Results of individual studies	20	For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.	10–11, Figure 3
Synthesis of results	21	Present results of each meta-analysis done, including confidence intervals and measures of consistency.	11–12, Figure 3
Risk of bias across studies	22	Present results of any assessment of risk of bias across studies (see Item 15).	8, Appendix Figure 1, 2
Additional analysis	23	Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).	Figure 4–6
DISCUSSION
Summary of evidence	24	Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).	12–16
Limitations	25	Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).	15–16
Conclusions	26	Provide a general interpretation of the results in the context of other evidence, and implications for future research.	16
FUNDING
Funding	27	Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.	17

PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Appendix Table 2:

Critical appraisal of included studies using the Newcastle-Ottawa Quality Assessment Scale

Study	Selection (max 4)	Comparability (max 2)	Outcome (max 3)	Total Score
Yeh, RW (2016)	4	1	3	8
Piccolo, R (2017)	4	1	3	8
Harada, Y (2017)	4	1	2	7
Ueda, P (2018)	4	1	3	8
Brener, SJ (2018)	4	1	2	7
Yoshikawa, Y (2018)	3	1	2	6
Witberg, G (2019)	4	1	3	8
Chichareon, P (2019)	4	1	3	8

Appendix Figure 1:

The Risk Of Bias In Non-randomized Studies – of Interventions (ROBINS-I) assessment (36)

Appendix Figure 2A:

Publication Bias Assessment by Funnel Plot for Bleeding

Appendix Figure 2B:

Publication Bias Assessment by Funnel Plot for Ischemia