antithrombotic therapy in patients undergoing coronary · 2019. 10. 14. · short title:...

Confidential: For Review OnlyAntithrombotic Therapy in Patients Undergoing Coronary Artery Bypass Graft Surgery: A Systematic Review and

Network Meta-Analysis

Journal: BMJ

Manuscript ID BMJ-2019-050568

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 06-May-2019

Complete List of Authors: Solo, Karla; Western UniversityLavi, Shahar; London Health Sciences Centre, MedicineBhatt, Deepak; VA Boston Healthcare System, Levine, Glenn; Department of Medicine, Baylor College of Medicine, Houston, Texas, Unites StatesKulik, Alexander; Lynn Heart and Vascular Institute, Boca Raton Regional Hospital, and Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida, Unites StatesJohn-Baptiste, Ava; Western UniversityKabali, Conrad; McMaster University, Martin, Janet; London Health Sciences Centre, AnesthesiaEikelboom, John; McMaster University, MedicineFremes, Stephen; Sunnybrook Health Science Centre, Department of Surgery, Division of Cardiac and Vascular SurgeryRuel, Marc; University of Ottawa Heart Institute, MedicineHuitema, Ashlay; London Health Sciences Centre, Medicine, Division of CardiologyChoudhury, Tawfiq; London Health Sciences Centre, Medicine, Division of CardiologyTzemos, Nikolaos; London Health Sciences Centre, Medicine, Division of Cardiologymamas, mamas; manchester heart centreBagur, Rodrigo; London Health Sciences Centre, Medicine, Division of Cardiology

Keywords: aspirin, clopidogrel, ticagrelor, warfarin, network meta-analysis, coronary artery bypass graft, antithrombotic, rivaroxaban

https://mc.manuscriptcentral.com/bmj

BMJ

Confidential: For Review Only

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Antithrombotic Therapy in Patients Undergoing Coronary Artery Bypass

Graft Surgery: A Systematic Review and Network Meta-Analysis

Karla Solo,1 BMSc; Shahar Lavi,2 MD; Deepak L. Bhatt,3 MD, MPH; Glenn N. Levine,4 MD;

Alexander Kulik,5 MD; Ava A. John-Baptiste,1,6,7 PhD; Conrad Kabali,8 MSc, PhD; Janet Martin,1,6

PharmD, MSc (HTA&M); John W. Eikelboom,9 MBBS; Stephen E. Fremes,10,11 MD, MSc; Marc

Ruel,12 MD, MPH; Ashlay A. Huitema,2 MD; Tawfiq Choudhury,2 MBBS, MD (Res); Nikolaos

Tzemos,2 MD; Mamas A. Mamas,13 BMBCh, DPhil; Rodrigo Bagur,1,2,13 MD, PhD

1Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.Trent, United Kingdom.2London Health Sciences Centre, London, Ontario, Canada.3Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Unites States.4Department of Medicine, Baylor College of Medicine, Houston, Texas, Unites States.5Lynn Heart and Vascular Institute, Boca Raton Regional Hospital, and Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida, Unites States.6Department of Anesthesia & Perioperative Medicine and Centre for Medical Evidence, Decision Integrity & Clinical Impact (MEDICI), Western University, London, Ontario, Canada.7Interfaculty Program in Public Health, Western University, London, Ontario, Canada.8Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.9Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.10Schulich Heart Centre, Sunnybrook Health Science University of Toronto, Toronto, Ontario, Canada. 11Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Ontario, Canada.12University of Ottawa Heart Institute, Ottawa, Ontario, Canada.13Keele Cardiovascular Research Group, Institute for Applied Clinical Science and Centre for Prognosis Research, Institute of Primary Care and Health Sciences, University of Keele, Stoke-on-Trent, United Kingdom.

Short title: Antithrombotic therapy after CABG

Keywords: coronary artery bypass graft, antithrombotic therapy, saphenous vein graft failure, systematic review, network meta-analysis

Word count: 3460

Corresponding authorRodrigo Bagur, MD, PhD, FAHAUniversity Hospital, London Health Sciences Centre339 Windermere Road, N6A 5A5, London, Ontario, CanadaPhone: 519-663-3997 - FAX: 519-434-3278E-mail: [email protected]

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Aspirin monotherapy is considered the preferred antiplatelet agent to prevent saphenous vein

graft failure after coronary artery bypass surgery, although at a cost of increasing the risk of

bleeding

Uncertainty remains regarding the benefits of adding a P2Y12 inhibitor or oral anticoagulant to

aspirin monotherapy after bypass surgery, and this combination has not been directly compared

with other antithrombotic therapies in randomized controlled trials

WHAT THIS STUDY ADDS

In this systematic review and network meta-analysis of randomized trials, one-year dual-

antiplatelet therapy with either aspirin plus clopidogrel or ticagrelor were the most efficacious

treatment compared to aspirin monotherapy in reducing saphenous vein graft failure after

coronary artery bypass surgery

We found no strong evidence of difference among different antithrombotics with regard to major

bleeding, myocardial infarction and death compared to aspirin monotherapy

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ABSTRACT

Objective: To assess the effects of different oral antithrombotic agents for the prevention of

saphenous vein graft failure (SVGF) in patients undergoing coronary artery bypass graft (CABG)

surgery.

Design: Systematic review of randomized controlled trials (RCTs). Frequentist network meta-

analysis conducted with random effects model allowed pharmacological interventions to be ranked

for effectiveness for each outcome measure. Effect size reported as odds ratio and 95% confidence

interval. Certainty of evidence of the network estimates was assessed using GRADE system. This

study is registered with PROSPERO (CRD42017065678) and the protocol has been peer-reviewed

and published.

Data Sources: We searched MEDLINE, EMBASE, Web of Science, CINAHL, and Cochrane

Library to identify RCTs published up to January 25, 2019.

Eligibility criteria: Randomised controlled trials including adult participants (aged ≥18) receiving

oral antithrombotic agents (antiplatelets or anticoagulants) for the prevention of SVGF after CABG

surgery.

Data abstraction methods: This study is reported using the Preferred Reporting Items for

Systematic reviews and Meta-analyses (PRISMA) extension statement for network meta-analysis.

Two investigators independently screened articles by title, abstract and full-text according to pre-

specified inclusion criteria. The full-text reports of potentially relevant studies were retrieved, and

data on study and patient characteristics, treatment strategies, and results of all included studies

were then independently extracted. Any discrepancies were resolved by consensus after consulting

a third investigator.

Main outcome measures: The primary efficacy endpoint was SVGF and major bleeding was the

primary safety endpoint. Secondary endpoints included myocardial infarction and death.

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Results: The review identified 3266 citations, and 21 articles related to 20 unique RCTs

comprising 4803 patients and 9 pharmacological interventions were included in the network meta-

analysis. Moderate-certainty evidence supports the use of one-year dual-antiplatelet therapy

(DAPT) with either aspirin plus ticagrelor (OR: 0.50; 95% CI: 0.31-0.79) or clopidogrel (OR: 0.60;

95% CI: 0.42-0.86) compared to aspirin monotherapy in reducing SVGF. We found no strong

evidence of difference among different antithrombotics with regard to major bleeding, myocardial

infarction and death compared to aspirin monotherapy. While we could not rule out the possibility

of intransitivity, between-trial heterogeneity and incoherence were low in all included analyses.

Sensitivity analysis using per-graft data did not change the effect estimates.

Conclusions: One-year DAPT with aspirin and clopidogrel or ticagrelor should be the preferred

antithrombotic strategy to prevent SVGF after CABG. Based on the individual risk-benefit profile,

the risk of major bleeding should be considered when planning DAPT for the prevention of SVGF.

Ascertaining the impact of long-term DAPT to inform recommendations for patients undergoing

CABG will require studies including a large number of patients with longer follow-up. Our results

may support future guideline updates for the optimal antithrombotic management of patients

undergoing CABG.

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INTRODUCTION

Coronary artery bypass grafting (CABG) is the preferred treatment for many patients with multi

vessel coronary artery disease (CAD).1 2 Nonetheless, patients undergoing CABG remain at risk

for subsequent major adverse cardiovascular events (MACE), mainly due to saphenous vein graft

failure (SVGF)3-6 or progression of the underlying CAD.6 Importantly, previous studies have

shown rates of SVGF of up to 30% in the first year7 and 30-70% beyond 10 years after CABG

surgery.7-11 However, despite its relatively high early failure rates, SVGs remain the most

commonly used graft during CABG.

Aspirin monotherapy is considered the preferred antiplatelet agent to prevent SVGF after

CABG (Class I, Level of Evidence A),12 and updated meta-analyses support this recommendation,

although at a cost of increasing the risk of bleeding.13-15 Uncertainty remains regarding the benefits

of adding a P2Y12 inhibitor or oral anticoagulant to aspirin monotherapy. Despite emerging

evidence on potential benefits of dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel

after CABG, this combination has not been directly compared with other antithrombotic therapies

in randomized controlled trials (RCTs), and no studies have been published to compare the effects

of all available oral antithrombotic (antiplatelets and anticoagulants) agents for the prevention of

SVGF after CABG within a single analytical framework. Therefore, the aims of this study were to

systematically review RCTs that assessed the effects of oral antithrombotic agents for the

prevention of SVGF in patients undergoing CABG and to evaluate the comparative efficacy and

harms of these medications using network meta-analysis.

METHODS

Literature search

This systematic review and network meta-analysis is reported using the Preferred Reporting Items

for Systematic reviews and Meta-analyses (PRISMA) extension statement for network meta-

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analysis16 (Supplementary Figure 1). This study is registered with PROSPERO

(CRD42017065678) and the protocol has been peer-reviewed and in BMJ Open.17

We conducted a search of MEDLINE, EMBASE, Web of Science, CINAHL, and Cochrane

Library, from inception to January 25th, 2019. We also performed a grey literature search and

checked reference lists of relevant reviews and eligible RCTs to ensure a comprehensive search.17

The full search strategy has been published in the protocol.17

Data selection

Studies were eligible for inclusion if they: 1) involved patients (≥18 years) undergoing CABG with

at least one SVG, 2) compared oral antithrombotic regimens with each other or placebo and, 3)

evaluated SVGF, regardless of unit of analysis and drug regimens. Antithrombotic therapies

included in this study were aspirin, clopidogrel, ticagrelor, vitamin K antagonists (warfarin,

acenocoumarol, phenprocoumon), rivaroxaban; DAPT included aspirin plus clopidogrel or

ticagrelor, and dual-therapy included aspirin plus rivaroxaban. We did not include aspirin plus

dipyridamole as this combination is not regularly used in clinical practice for patients with CAD.

We considered aspirin monotherapy as a single intervention regardless of whether aspirin was

interrupted or continuously administered before CABG as a recent meta-analysis showed no

difference between these two approaches.15

Data identification and extraction

Two investigators (KS and AAH) independently screened articles by title, abstract and full-text

according to pre-specified inclusion criteria. The full-text reports of potentially relevant studies

were retrieved, and data on study and patient characteristics, treatment strategies, and results of all

included studies were then independently extracted (KS and AAH/TC) using a data extraction

form. Any discrepancies were resolved by consensus after consulting a third investigator (RB).

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Outcomes measures

The primary efficacy outcome was the incidence of SVGF, defined as participants with at least one

occluded SVG as assessed by either invasive angiogram or computed tomography (Table 1). Since

not all the included studies expressed SVGF on a per-patient basis, studies reporting per-graft data

were also included in our base-case analysis to increase the totality of evidence. The decision about

combining per-patient and per-graft data was made after comparing results from per-patient18-33

and per-graft18-31 33-38 (to account for clustering effects) meta-analyses, which showed consistency

in terms of magnitude and direction of effect estimates and with large overlapping 95% confidence

intervals (CI) of effect sizes in most comparisons. Because sensitivity analysis comparing between

the per-graft network meta-analysis and the case-base network meta-analysis did not differ

substantially, the inference for our base-case analysis was made at the patient level, which is

clinically preferable given that treatments are naturally applied to patients (and not grafts).

Regarding per-graft data, we calculated and used effective sample size (ESS) instead of

originally reported outcome data to account for clustering effects.39-41 The intra-cluster correlation

(ICC) needed to calculate the ESS was obtained from an external source.41 42 The size of the ICC

and the number of observations sampled within each cluster influence the power of the study,41 and

our ICC was 0.177. Additionally, if studies reported the incidence of SVGF at multiple time-points,

the longest available follow-up period was included in our base-case analysis.

The primary safety outcome was the incidence of major bleeding. Secondary outcomes were

all-cause mortality and myocardial infarction. These outcomes were binary and defined as per-

study author’s definitions. Data on major adverse cardiac and cerebrovascular events, heart failure,

minor bleeding, red blood cell transfusion, and admission to hospital due to cardiovascular cause

were collected, but not reported due to sparse data.

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Risk of bias and certainty assessment

We assessed study risk of bias using the Cochrane Collaboration tool for randomized trials 2.043

for each outcome, and graded the certainty of direct and network evidence using the Grade of

Recommendations Assessment, Development, and Evaluation (GRADE) for network meta-

analysis.44

Statistical analysis

We performed a frequentist network meta-analysis, stratified by study, to obtain network estimates

for outcomes of interest. The model framework used random-effects to allow for apparent

heterogeneity between studies in treatment comparison effects. A pairwise meta-analysis was

conducted to generate direct estimates for outcomes also using a random-effects model. The patient

and study characteristics were evaluated to assess whether these characteristics were sufficiently

similar across the studies and treatment comparisons. Additionally, incoherence assumption (the

statistical disagreement between direct and indirect evidence in a closed loop) was evaluated

locally using a loop-specific approach, and globally using a design-by-treatment interaction model.

To rank the intervention’s hierarchy in the network meta-analysis, we used the surface under

the cumulative ranking (SUCRA),45 and mean ranks were estimated. To explore the potential for

publication bias, we used the comparison-adjusted funnel plot.45

Sensitivity analyses were performed to assess the robustness of the model for the primary

outcomes by visually comparing the results between base-case analysis with per-graft analysis and

by excluding trials with off-pump CABG only and using in-trial data analysis. To explore the

impact of missing data we performed an “all-missing-failure” analysis, which assumes that all

missing patients had a negative event.46 All outcomes of interest were binary and the relative

treatment effects were reported as odds ratio (OR) with 95% CI. All analyses were done in Stata

version 14 using the network command.

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RESULTS

Data selection

The systematic search identified 3266 citations, of these, 21 articles18-38 related to 20 unique

parallel-group RCTs comprising 4803 patients and investigating 9 different interventions published

between 1979 and 2019 were included in this network meta-analysis (Supplementary Figure 1).

Of 20 RCTs, 3 were trials with 3 eligible arms and the remaining were trials with 2 eligible arms.19

33 38

The study sample size ranged from 20 to 1,448 patients, patient age ranged from 44 to 83

years, 83% were male and 83% underwent elective (stable CAD) surgery. The number of SVGs

ranged from 1.14 to 3.60 per patient, pharmacological interventions were initiated between 7 days

before CABG and 14 days after CABG. The duration of follow-up ranged from 1 month to 8 years.

Assessment of SVGF was performed by either invasive angiography or computed tomography

(Table 1).

Across comparisons, the distribution of baseline characteristics by treatment was generally

balanced, except for the type of CABG technique (on-pump versus off-pump CABG) and the

timing of drug initiation (Table 2). Information on antifibrinolytic use was not reported due to

limited data.

Mixed treatment meta-analyses

Primary efficacy outcome

The network of treatment comparisons for SVGF included 9 individual nodes (Figure 1-A). Each

of the nodes represent placebo or different pharmacological interventions, in which aspirin was the

most well-connected intervention with all other interventions directly linked to it, except for

clopidogrel monotherapy. Figure 2-A shows network estimates of treatment effect on SVGF for

different interventions compared to aspirin monotherapy. Network meta-analysis showed that

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DAPT with either aspirin plus ticagrelor (OR: 0.50; 95% CI: 0.31-0.79) or aspirin plus clopidogrel

(OR: 0.60; 95% CI: 0.42-0.86) was more efficacious than aspirin monotherapy to prevent SVGF.

Pooled effect sizes also suggested that all active interventions reduced SVGF when compared with

placebo. However, the evidence does not support the efficacy of clopidogrel monotherapy for the

reduction of SVGF when compared with placebo (Figure 3-A). According to SUCRA, the top two

ranked interventions for the reduction of SVGF were DAPT with aspirin plus ticagrelor (SUCRA:

94.4) and aspirin plus clopidogrel (SUCRA: 85.3), Table 2.

Sensitivity analyses using per-graft data, excluding off-pump only trials,29 30 and accounting

for missing outcome data, did not substantially change the study effect estimates (Supplementary

Table 1) and SUCRA values (Supplementary Table 2). One of the included studies in this

network meta-analysis reported post-trial34 (used in the base-case analysis) and in-trial32 data.

Sensitivity analysis to explore the legacy effect of pharmacologic intervention using in-trial data

did not substantially change effect estimates and SUCRA values compared to the base case analysis

(Supplementary Table 1 and Supplementary Table 2, respectively).

Primary safety outcome

Eleven RCTs19 24 26 27 29 31 33 34 36-38 representing 3,745 patients reported the incidence of major

bleeding. The network diagram of eligible treatment comparisons included 8 individual nodes

(Figure 1-B). Each of the nodes represents different active interventions or placebo, in which

aspirin monotherapy was the most well-connected intervention with all other interventions directly

linked to it. Figure 2-B shows network estimates of treatment effect on major bleeding for different

interventions compared to aspirin monotherapy. Network meta-analyses showed no evidence of

differences among all possible treatment comparisons. Pooled effect sizes also suggested that all

active interventions increased bleeding when compared with placebo, although without significant

evidence between antithrombotic strategies (Figure 3-B). According to SUCRA, after placebo

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(SUCRA: 84.4), the top ranked intervention associated with fewer major bleeding was DAPT with

aspirin plus clopidogrel (SUCRA: 66.5), Table 2.

Sensitivity analyses excluding 1 off-pump only trial,29 accounting for missing outcome data,

and using in-trial data, did not substantially change the study effect estimates (Supplementary

Table 3) and SUCRA values (Supplementary Table 4). When using in-trial data analysis, aspirin

monotherapy and its combination with rivaroxaban obtained a higher rank (Supplementary Table

4).

Secondary outcomes

Ten RCTs18 19 22-24 26 28 31 32 36 representing 1,921 patients reported all-cause mortality, and 12

RCTs19 24 26-29 31 33 34 36-38 representing 3,994 patients reported myocardial infarction. Figure 4

shows networks of treatment comparisons for secondary outcomes. Results for secondary

outcomes are summarized in Figure 5. Network meta-analyses showed no evidence of differences

among all possible comparisons for secondary outcomes (all-cause mortality and myocardial

infarction). Other pre-specified secondary outcomes were sparsely reported in the included RCTs;

therefore, network meta-analysis was not conducted for these outcomes.

Risk of bias and certainty of evidence

Two RCTs20 36 were judged to have a high risk of bias arising from the randomization process and

5 RCTs18 19 23 34 37 for bias due to missing outcome data (Supplementary Table 5). Five of the

trials19 22 30 35 36 had some concerns related to measurements of the outcome and 3 RCTs20 30 35

related bias from selective reporting of outcomes. Only 5 trials29 31-33 37 were judged to have a low

risk of bias due to deviation from intended interventions. Overall, 8 (40%) trials18-21 23 34 36 37 were

judged to have a high risk of bias, primarily due to failure to blind and missing outcome data. Of

trials reporting incomplete outcome data, 10 trials20 26 28 29 31-33 36 38 performed intention-to-treat

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analysis, and 2 of these20 33 clearly reported the use of intention-to-treat analysis with worst-case

assumptions for imputation of missing data. It was unclear how the remaining trials with

incomplete data handled missing outcome data.

The certainty of evidence of network estimates for SVGF is also provided within Figure 3-

A. Evidence certainty was downgraded to low or very-low for most comparisons mainly because

of study limitations due to incomplete outcome data, imprecision, indirectness, and the possibility

of intransitivity. Certainty of evidence for direct, indirect, and network estimates is summarized in

Supplementary Tables 6 and 7. The network evidence for DAPT with aspirin plus ticagrelor and

aspirin plus clopidogrel was of moderate certainty when compared with aspirin monotherapy. The

symmetrical comparison-adjusted funnel plot shows neither evidence of publication bias for

placebo-controlled trials nor small-study effects (Supplementary Figure 2).

The certainty of evidence for clinical outcomes, including major bleeding, myocardial

infarction, and mortality, was also downgraded to low or very-low for most comparisons (Figure

3-B, Figure 5 and Supplementary Tables 6 and 7). It should be noted, however, that comparisons

with moderate-certainty evidence should be interpreted with caution mainly due to inconsistency

and publication bias. Inconsistency could not be thoroughly assessed because many of the

comparisons consisted of a single study, and publication bias was not possible to assess for

secondary outcomes because this network meta-analysis was designed to exclude studies that did

not evaluate our primary efficacy outcome (SVGF), regardless of reported secondary outcomes

(Supplementary Tables 6 and 7).

Network assumptions

The distribution of potential effect modifiers was not balanced across comparisons; however, the

evidence of intransitivity was inconclusive due to missing data in several comparisons (Table 2).

While we could not rule out the possibility of intransitivity, between-trial heterogeneity (tau2) was

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low in all included analyses compared to the expected value as reported in the literature.47

Similarly, even with low between-trial heterogeneity, we also could not completely rule it out due

to missing data. Direct and indirect estimates as well as tau2 are showed in Supplementary Table

7. Loop-specific approach (Supplementary Table 8) and design-by-treatment interaction models

(Supplementary Table 9) showed no evidence of incoherence between direct and indirect

comparisons for all analyses.

DISCUSSION

This system review included 20 parallel-group RCTs and compared 8 active antithrombotic

interventions in a single framework for the assessment of SVGF in patients undergoing CABG.

The results of this network meta-analysis suggest that among active interventions and based on

moderate certainty evidence, DAPT with aspirin plus ticagrelor or clopidogrel were the most

efficacious treatment regimens for the prevention of SVGF as compared to aspirin monotherapy.

However, the trade-off was an increased risk of major bleeding, although without differences

amongst pharmacological therapies.

Strengths and weakness of the study

The strength of our analysis lies on its robust design and transparency. We prespecified the research

question and published a peer-review protocol17 for this systematic review of published RCTs of

pharmacologic interventions for the prevention of SVGF after CABG surgery. To increase the

totality of evidence, we accounted for cluster effects of data expressed on a per-patient and a per-

graft basis, and made an interference at a patient level, improving the applicability of the results in

light of newer P2Y12 inhibitor (ticagrelor) and direct oral anticoagulation (rivaroxaban). Our

analysis adds new data on the use of DAPT with aspirin plus ticagrelor and direct oral

anticoagulation with rivaroxaban, providing, therefore, a better understanding on the role of these

pharmacologic interventions for the prevention of SVGF after CABG. There weakness of our study

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is regarding clinical outcomes. The present network meta-analysis did not find statistically

significant differences among comparisons, nonetheless, these were not our pre-specified primary

outcome.

Comparison with previous data

Aspirin monotherapy is currently recommended for patients with stable CAD after CABG to

reduce SVGF.12 In contrast to patients presenting with acute coronary syndromes (ACS), when

DAPT is recommended following CABG, there is no evidence that DAPT is associated with a

decrease in thromboembolic complications or mortality in patients with stable CAD undergoing

CABG.48 Few data suggest that additional pharmacological intervention with DAPT reduces the

risk of SVGF (but not arterial occlusion) after on-pump CABG in patients with stable CAD;49 50

however, a recent network meta-analysis51 including only antiplatelet agents did not show a

statistically significant benefit in terms of SVGF with DAPT.

In this regard, the 2016 American guidelines,52 recommend that in patients with stable CAD,

aspirin 81 mg (75 mg to 100 mg) plus clopidogrel (initiated early postoperatively) for 12 months

after CABG may be reasonable to improve SVG patency (Class IIb, Level of Evidence B).

Conversely, the 2017 European guidelines state that there is insufficient evidence to generally

recommend DAPT to reduce SVGF.48 In order to mitigate the relative hypercoagulable state that

off-pump patients experience, the 2015 American Heart Association Scientific Statement12 gives a

Class I, Level of Evidence A, for the combination of aspirin and clopidogrel after off-pump CABG;

however, the European guidelines state that there is week evidence to support DAPT in this subset

of patients,48 and the American guidelines52 do not comment on this.

With regard to clinical outcomes, a previous pairwise meta-analysis of RCTs found no

significant differences in mortality, myocardial infarction, and major bleeding between DAPT with

aspirin plus clopidogrel and aspirin monotherapy after CABG.53 Although the occurrence of major

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bleeding with aspirin plus ticagrelor was not statistically significant compared to aspirin

monotherapy, the network estimates showed double odds, and wide CI compared to aspirin plus

clopidogrel. Hence, because major bleeding has been associated with increased morbidity and

mortality,54 55 the risk of bleeding should be carefully balanced against the benefits when planning

long-term (i.e. >12 months) DAPT in patients undergoing CABG.

Limitations

Our study also has several limitations. First, the quality of our analysis is limited by the inherent

limitations of individual included trials, notably, patient-level data was not available, precluding

adjustment for any differences in clinical setting such as stable CAD versus ACS, elective versus

urgent, on-pump versus off-pump CABG surgery and the inability to perform competing risk

analysis. Second, although we presented full details about the risk of bias of all included trials

(Supplementary Table 5), many trials did not report adequate information about allocation

sequence concealment, proportional and reasons for missing outcome data, and how trials handled

missing data which might lead to inaccurate interpretation of the certainty of evidence. Third,

different trials used different outcome definitions, which may threaten internal validity of our

network meta-analysis. Although sensitivity analysis showed no substantial differences in effect

estimates between per-graft and per-patient analyses for most comparisons, the credibility of this

data-driven approach remains unclear. Fourth, we combined aspirin and certain oral anticoagulants

with different doses in the same node, assuming that there would be no systematic differences in

treatment effects across doses. Fifth, the trials in which the majority of patients underwent off-

pump CABG,29 30 33 the dose of aspirin (monotherapy or DAPT) was 81-100 mg daily. However,

we are unable to compare and confirm the potential benefit of higher doses (i.e. 160-325 mg) of

aspirin in off-pump patients due to lack of off-pump trials using these doses of aspirin. Sixth, local

coherence could not be estimated for some of the treatments due to lack of data, but we assessed

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network coherence globally using the design-by-treatment interaction model. Seventh, the present

network meta-analysis included trials published over a 39-year period; therefore, patient

characteristics, surgical techniques (i.e. off-pump CABG), and drug regimens (earliest trials more

likely to compare versus placebo and later trials more likely to be active-comparator trials) may

not reflect the current clinical practice; hence, changes over time could potentially affect treatment

estimates. Post-hoc meta-regression analysis did not show evidence of association between

treatment effect and year of publication for some treatments, but it was not possible to estimate the

effect of publication year for all treatments due to multicollinearity and missing linkage

(Supplementary Table 10). Finally, legacy effect was explored because of one study reported

SVGF at 1 and 8 years,32 34 but sensitivity analysis did not change the effect estimates.

Unanswered questions and future research

We did not have enough power to detect significance for clinical outcomes because we restricted

the inclusion to trials that reported SVGF (our primary outcome), hence, reducing statistical power

in this regard. However, the eligibility criteria were purposefully made stringent to reduce

heterogeneity and risk of bias. Further research is needed with studies of adequate duration and

sample size to inform SVGF at different time-points to ascertain the potential legacy effect of

DAPT during the first year after CABG, and long-term (i.e. 5 or 10 years) incidence of SVGF or,

as above-mentioned, patient-important outcomes (mortality, ischemic or bleeding events).

Ascertaining the impact of long-term (beyond 12 months) DAPT to inform recommendations will

require studies including a large number of patients with longer follow-up (i.e. >5 or 10 years).

Hence, although further RCTs may help determine the ideal antithrombotic strategy after CABG,

these might be difficult to undertake using a mixed treatment comparison design.

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CONCLUSION

This study represents the most comprehensive synthesis of evidence available to date for

contemporary antithrombotic agents for the prevention of SVGF after CABG. The results of this

network meta-analysis suggest that one-year DAPT with aspirin in combination with clopidogrel

or ticagrelor should be considered the preferred antithrombotic strategy to reduce SVGF after

CABG. The decision to continue with DAPT after CABG should be an individualized decision for

each patient, balancing the safety-efficacy profile of these pharmacologic interventions.

Meanwhile, our results may support future guideline updates for the optimal antithrombotic

management of patients undergoing CABG.

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Contributors

KS and RB conceived and designed the study. KS, AAH and TC performed literature search, screen

articles for inclusion, and extracted data. KS and RB analyzed, interpreted the data and drafted the

first version of the manuscript. All authors have interpreted the data, critically revised, provided

intellectual contributions and approved the final version of the manuscript. RB is the guarantor.

Funding: This research received no specific grant from any funding agency in the public,

commercial or not-for-profit sectors.

Patient consent: Not required.

Provenance and peer review: Not commissioned; externally peer reviewed.

Competing interests: All authors read and met the ICMJE criteria for authorship and agree with

the results and conclusions of this article. Dr John W. Eikelboom has received honoraria and/or

research support from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-

Sankyo, Janssen, Pfizer, and Sanofi. The remaining author have nothing to disclose.

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Figure legends

Figure 1. Network of treatment comparisons for (A) saphenous vein graft failure (primary

efficacy outcome) and (B) major bleeding (primary safety outcome). Each node represents

different active interventions or placebo. The size of nodes is proportional to the number of studies

evaluating that particular intervention. The increasing thickness of lines between nodes is

proportional to the number of randomly assigned patients contributing to direct comparisons. Vit-

K A: vitamin-K antagonist.

Figure 2. Network estimates of the treatment effects for (A) saphenous vein graft failure

(primary efficacy outcome) and (B) major bleeding (primary safety outcome). All active

interventions and placebo were compared with aspirin monotherapy. OR: odds ratio. 95% CI:

confidence interval.

Figure 3. Network meta-analysis and certainty of evidence for (A) saphenous vein graft

failure (primary efficacy outcome) and (B) major bleeding (primary safety outcome). Results

are the odds ratio and (95% confidence intervals) from the network meta-analysis between the

column-defining intervention and the row-defining intervention. Significant results are in bold. The

certainty of evidence is also incorporated within this figure. Notably, green represents moderate-

certainty evidence, yellow represents low-certainty evidence, and red represents very-low certainty

evidence.

Figure 4. Network of treatment comparisons for secondary outcomes (A) all-cause mortality

and (B) myocardial infarction. Each node represents different active interventions or placebo.

The size of nodes is proportional to the number of studies evaluating that particular intervention.

The increasing thickness of lines between nodes is proportional to the number of randomly assigned

patients contributing to direct comparisons. Vit-K A: vitamin-K antagonist.

Figure 5. Network meta-analysis and certainty of evidence for secondary outcomes (A) all-

cause mortality and (B) myocardial infarction. Results are the odds ratio and (95% confidence

intervals) from the network meta-analysis between the column-defining intervention and the row-

defining intervention. The certainty of evidence is also incorporated within this figure. Notably,

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green represents moderate-certainty evidence, yellow represents low-certainty evidence, and red

represents very-low certainty evidence.

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Table 1. Characteristics of the included randomised controlled trials

Study, Year Overall n; RoB

Time of drug initiation post-

CABG

Treatment duration

SVG Patency assessment method (unit of analysis)

Time from random to patency assessment

Relevant study armsNo. of any graft/vein

per patient†

Age (years)

Male (%)

Angiography (per patient+per graft) Vit-K Antag: Warfarin (INR target: NR) 2.85/2.85 56±8 69.2Pantely, 1979 47;

High+3

days6

months 6 months Control: No study medication 2.54/2.54 52±8 83.3Vit-K Antag: Warfarin (INR target: 1.5-2) 1.91/1.91 - 92.9Aspirin: 600 mg BID 2.03/2.03 - 82.0McEnany, 1982 216;

High+3 to 4

days12

monthsAngiography (per patient+per graft)21.5 months (range: 1 to 47 month)

Control: Matching placebo 2.00/2.00 - 87.3Angiography (per patient+per graft) Aspirin: 325 mg TID 2.20/2.20 - 100

Sharma, 1983 116;High

+3 to 5 days

12 months 12 months Control: No study medication 2.20/2.20 - 100

Angiography (per patient+per graft) Aspirin: 100 mg OD 1.90/1.90 55±10 82.8Lorenz, 1984 60;

High+24

hours4

months 4 months Control: Matching placebo 2.23/2.23 55±6 90.3Angiography (per patient+per graft) Aspirin: 325 mg TID 3.10/3.10 - -

Brown, 198598; Someconcerns +67 ± 27 hours 12

months 12 months Control: Matching placebo 3.30/3.30 - -Angiography (per graft) Aspirin: 325 mg OD -/3.20 59±8 100

Goldman, 198998; Someconcerns

-12 hours

12 months 12 months (range: 62 to 527 days) Control: Matching placebo 58±8 100

Angiography (per patient+per graft) Aspirin: 324 mg OD -/3.40 56±8 86.6Gavaghan 1991 237; Some

concerns+1

hours12

months 12 months (range: 222 to 430 days) Control: Matching placebo -/3.60 56±7 83.6Vit-K A: 4 mg Acenocoumarol or 6 mg Phenprocoumon (INR Target: 2.8-4.8) -/3.10 58±8 88.0

Van der Meer, 1993 635; Someconcerns

-12 hours;24 hours

12 months

Angiography (per patient+per graft)12 months Aspirin: 50 mg OD -/2.80 58±8 87.0

Angiography (per patient) Aspirin: 100 mg OD 3.14/2.56 60±9 94.0Hockings, 1993 140;

High-7

days6

months 6 months Control: Matching placebo 3.52/2.79 60±9 92.3Aspirin + Clopidogrel: 100 and 75 mg OD, respectively 2.9/2.9 58±8.5 -

Mujanovic, 2009 20; Someconcerns

Immediately post-op

3months

Angiography (per graft)3 months Aspirin: 100 mg OD 2.7/2.7 60±8.5 -

Aspirin + Clopidogrel: 100 and 75 mg OD, respectively 2.66/1.71 61±10 82.1

Gao, 2009 197; Someconcerns

+1 day Unclear 64-MSCTA (per graft)

12 months Clopidogrel: 75 mg OD 2.49/1.51 62±9.9 83.3Aspirin + Clopidogrel: 162 and 75 mg OD, respectively 3.6/2.30 65±7.5 91.1

Kulik, 2010 113; Low 0 day

12 months

Angiography (per patient+per graft)12 months Aspirin: 162 mg OD and matching placebo 3.4/2.24 68±7.4 87.7

Aspirin + Clopidogrel: 100 and 75 mg OD, respectively 3.18/2.14 58±8.3 82.3

Gao, 2010 249; Someconcerns

≤ +48 hours

3 months

MSCTA (per graft)3 months Aspirin: 100 mg OD 3.11/2.10 60±7.9 83.8

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30Aspirin + Clopidogrel: 81 and 75 mg OD, respectively 4.03/2.35 66±9.4 93.9

Sun, 2010 99; Someconcerns

+6 to 48 hours

1month

MSCTA (per patient)50 days Aspirin: 81 mg OD 3.95/2.30 65±9.3 86.0

Aspirin + Clopidogrel: 100 and 75 mg OD, respectively 3.1/1.78 59±7.7 73.3

Mannacio, 2012 300; Someconcerns +28 ± 12 hours 12

months64-MSCTA (per graft)

12 months Aspirin: 100 mg OD 3.2/1.87 59±8.3 75.3Aspirin & Ticagrelor: 81 mg OD and 90 mg BID, respectively 2.49/1.14 62±7.5 85.7

Saw, 2016 70; High

+58 to 59 hours

3 months

128/320-MSCTA (per graft)12 months Aspirin: 81 mg OD and matching placebo 3.43/1.69 63±9.7 88.6

Aspirin + Clopidogrel: 81 and 75 mg OD, respectively 3.00/2.00 - -

Slim, 2016 20; Someconcerns

+6 hours

8 months

128-MSCTA (per graft)12 months Aspirin: 81 mg OD and matching placebo 3.38/2.38 - -

Aspirin + Ticagrelor: 100 mg OD and 90 mg BID, respectively 3.76/2.90 64±8.2 79.8

Ticagrelor: 90 BID 3.83/2.94 63±8.3 80.7Zhao, 2018 500; Low +0 to 24 hours 12

monthsMSCTA (per graft)

12 monthsAspirin: 100 OD 3.76/2.92 64±8.1 84.9Aspirin + Ticagrelor: 100 mg OD and 90 mg BID, respectively -/2.51 59±8.9 77.1

Xu, 2018 140; High NR 1

monthMSCTA (per graft)

1 month Aspirin & Clopidogrel: 100 mg OD and 75 mg OD, respectively -/2.59 60±7.5 72.9

Aspirin + Rivaroxaban: 100 mg OD and 2.5 mg BID, respectively -/2.00 66±7.8 78.3MSCTA (per graft)

12 months Rivaroxaban: 5 mg BID -/2.00 65±7.9 81.2Lamy, 2018 1448; Someconcerns

+4 to 14 days NR

Aspirin: 100 mg OD -/2.00 66±8.5 82.3

Values are presented as mean ± standard deviation or n (%) unless otherwise noted. †Data that were not reported in the original studies were calculated from total number of grafts/number of patients enrolled. INR: international normalized ratio. n: sample size. NR: Not reported. OAC: oral anticoagulation. OD: once a day. BID: twice a day. TID: three times a day. RoB: Risk of bias rating for saphenous vein graft failure. Vit-K Antag: Vitamin-K Antagonists. MSCT: multislice computed tomography angiography.

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Table 2. Summary of baseline and procedural characteristics of patients across different treatment comparisons

Characte-ristics

Number of

RCTs*

Aspirin vs

Placebon=7

RCTs

Vit-K Antag vs Control

n=2 RCTs

Vit-K Antag vs Aspirin

n=2 RCTs

Ticagrelor vs Aspirinn=1 RCT

Riva vs Aspirin

n=1 RCT

ASA+Riva vs Aspirinn=1 RCT

ASA+Riva vs Riva

n=1 RCT

ASA+Clopi vs Aspirinn=6 RCTs

ASA+Clopi vs Clopi

n=1 RCT

ASA+Tica vs Aspirinn=2 RCTs

ASA+Clopi vs

ASA+Tican= 1 RCT

ASA+Tica vs Tica

n=1 RCT

Age 17 58±7.7 53±8 58±8 64±8.2 65±8.2 66±8.1 66±7.8 61±8.16 62±9.94 63±8.24 60±8.2 64±8.3

Male 161212/127

8(95)

129/148(87)

632/722(88)

275/332(83)

773/946 (82)

774/965 (80)

785/985 (80)

599/736(81)

163/197(83)

336/404 (83)

105/140(75)

183/217(84)

Diabetes 14 45/560(8)

18/111(16)

74/722(10)

142/332 (43)

412/946(44)

413/965(43)

393/985(40)

168/756(22)

108/197(55)

163/404 (40)

94/140(67)

124/217(57)

Hypertension 15 528/1218

(43)20/111

(18)250/722

(35)242/332

(73) NR NR NR 417/756(55)

125/197(64)

301/404 (75)

92/140(66)

176/217(81)

Dyslipi-demia 9 27/116

(23) NR 271/616(44)

243/332 (73) NR NR NR 426/736

(58)41/197

(21)299/404

(74) NR 245/292(84)

Prior MI 13 703/1076(65)

74/111(67)

401/722(56)

103/332 (31)

351/946(37)

350/965(36)

355/985(36)

253/623(41)

105/197(53)

108/404 (27)

53/140(38)

102/217(47)

Prior PCI 5 NR NR NR NR NR NR NR 77/524(15)

24/197(12)

8/70 (11)

18/140(13) NR

Prior CVA 3 NR NR NR 35/332

(11)29/946(3.1)

36/965(4.0)

37/985(3.8)

16/436(3.7) NR 48/334

(14) NR 75/217(35)

OPCABG 16 862/862(100)

37/37(100)

616/616(100)

82/332(25)

235/946(25)

228/965(24)

245/985(25)

321/776(41)

124/197(63)

85/334(25)

26/140(19)

88/217(41)

Elective surgery 16 932/1006

(93)73/145

(50)695/755

(92)332/332

(100)582/946

(61)599/965

(62)601/985

(61)776/776

(100)186/197

(94)381/404

(94)140/140

(100)217/217

(100)Time of

drug initiation (range)

20

14 preop to 5

postop days

3 to 4 postop days

12 preop hours to 4

postop days

Within 24 postop hours

4 to 14 postop days

4 to 14 postop days

4 to 14 postop days

Immediately postop to 48

hours1 day

Within 24-59 postop

hoursNR

Within 24 postop hours

Values presented as mean ± standard deviation or n/N (%) unless otherwise noted. RCT: randomized-controlled trial/s. *Number of RCTs reporting data. ASA: aspirin. Clopi: clopidogrel. Tica: ticagrelor. Riva: rivaroxaban. Vit-K Antag: vitamin-K antagonists. ASA+Clopi: dual-antiplatelet therapy with aspirin plus clopidogrel. ASA+Tica: dual-antiplatelet therapy with aspirin plus ticagrelor. ASA+Riva: dual therapy with aspirin plus rivaroxaban. MI: myocardial infarction. PCI: percutaneous coronary intervention. CVA: cerebrovascular accident. OPCABG: off-pump coronary artery bypass graft. Preop: preoperative. Postop: postoperative. NR: Not reported.

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Table 3: Treatment rankings according to Surface Under the Cumulative Ranking (SUCRA) values

Treatment by outcome SUCRA

Primary Efficacy Outcome: SVGF (Base case analysis)

Aspirin + Ticagrelor 94.4

Aspirin + Clopidogrel 85.3

Aspirin + Rivaroxaban 32.9

Ticagrelor 61.3

Rivaroxaban 58.3

Vitamin-K Antagonist 39.7

Aspirin 38.5

Clopidogrel 36.2

Placebo 3.3

SVGF (Per graft analysis)



Ticagrelor 70.7


Rivaroxaban 53.5


Aspirin 33.2

Clopidogrel 34.8

Placebo 3.5

Primary Safety Outcome: Major Bleeding (no Clopidogrel monotherapy)

Placebo 84.4


Aspirin 61.5


Rivaroxaban 33.6

Ticagrelor 38.6



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Secondary Outcome: All-cause Mortality (no Clopidogrel monotherapy)

Placebo 61.0




Aspirin 29.0

Secondary Outcome: Myocardial Infarction (no Clopidogrel monotherapy)



Rivaroxaban 44.0

Ticagrelor 59.5



Aspirin 39.5

Placebo 14.9

Larger SUCRA values indicates better interventions and higher hierarchy ranks are in bold.

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Confidential: For Review OnlySupplementary Figure 1. PRISMA (Preferred Reporting Items for Systematic Reviews andMeta-Analyses) flow diagram

Records excludedn = 1,179

Full-text articlesexcluded, with reasons

n =105- Duplicate- Wrong outcome- Wrong study design- Wrong intervention- Wrong patient

population- Wrong setting- Non-extractable data- Non-English- Ongoing trials

Studies included inquantitative synthesis

(meta-analysis)n = 20 unique RCTs

Reported in 21 manuscripts

Records screenedn = 1,307

Records after duplicates removedn = 1,307

Iden

tific

atio

nSc

reen

ing

Elig

ibili

tyIn

clud

edRecords identified through

database searchingn = 3,266

Studies included inqualitative synthesis

n = 23

Full-text articles assessedfor eligibility

n = 128

RCT: randomized controlled trials.

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Confidential: For Review OnlySupplementary Figure 2. Comparison-adjusted funnel plot for primary efficacy and safety outcomes

A

B

Saphenous Vein Graft Failure

Major Bleeding

Panel A. Primary efficacy outcome. 1 versus 6: aspirin monotherapy versus placebo. 4 versus 6:

vitamin-K antagonist versus placebo.

Panel B. Primary safety outcome. 1 versus 5: aspirin monotherapy versus placebo. 4 versus 5:

vitamin-K antagonist versus placebo.

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Supplementary Table 1. Sensitivity analyses: Effect estimates for saphenous vein graft failure

Network meta-analysis - OR (95% CI)

Treatment Comparator PairwiseOR (95% CI) Base Case

analysis

Without OPCABG only

studies*

Imputation analysis

Per graft analysis

In-trial analysis†

ASA+Clopi Placebo - 0.34 (0.21-0.54) 0.38 (0.22-0.66) 0.35 (0.23-0.53) 0.35 (0.22-0.55) 0.33 (0.21-0.53)ASA+Riva Placebo - 0.60 (0.38-0.98) 0.60 (0.38-0.49) 0.69 (0.49-0.97) 0.63 (0.41-0.98) 0.60 (0.38-0.94)ASA+Tica Placebo - 0.28 (0.16-0.48) 0.29 (0.16-0.49) 0.32 (0.19-0.54) 0.29 (0.18-0.47) 0.28 (0.16-0.48)

Rivaroxaban Placebo - 0.48 (0.30-0.77) 0.48 (0.30-0.77) 0.74 (0.53-1.04) 0.51 (0.32-0.80) 0.48 (0.30-0.77)Ticagrelor Placebo - 0.45 (0.26-0.79) 0.45 (0.26-0.80) 0.52 (0.30-0.90) 0.41 (0.26-0.66) 0.45 (0.25-0.79)

Vit-K Antag Placebo 0.68 (0.30-1.51) 0.56 (0.37-0.86) 0.56 (0.37-0.86) 0.75 (0.52-1.06) 0.54 (0.37-0.78) 0.56 (0.37-0.86)Aspirin Placebo 0.55 (0.39-0.78) 0.56 (0.42-0.76) 0.56 (0.42-0.76) 0.66 (0.51-0.85) 0.60 (0.46-0.78) 0.56 (0.42-0.76)

Clopidogrel Placebo - 0.64 (0.19-2.16) 0.73 (0.21-2.54) 0.67 (0.20-2.21) 0.67 (0.20-2.23) 0.63 (0.19-2.11)ASA+Clopi Aspirin 0.62 (0.43-0.90) 0.60 (0.42-0.86) 0.68 (0.43-1.07) 0.53 (0.39-0.73) 0.59 (0.41-0.84) 0.58 (0.41-0.84)ASA+Riva Aspirin 1.06 (0.75-1.50) 1.06 (0.75-1.50) 1.06 (0.75-1.50) 1.05 (0.84-1.31) 1.06 (0.75-1.50) 1.06 (0.75-1.50)ASA+Tica Aspirin 0.46 (0.28-0.76) 0.50 (0.31-0.79) 0.51 (0.32-0.80) 0.49 (0.31-0.78) 0.49 (0.33-0.72) 0.49 (0.31-0.78)

Rivaroxaban Aspirin 0.85 (0.59-1.23) 0.85 (0.59-1.23) 0.85 (0.59-1.23) 1.13 (0.91-1.41) 0.85 (0.59-1.23) 0.85 (0.59-1.23)Ticagrelor Aspirin 0.78 (0.48-1.27) 0.80 (0.49-1.29) 0.80 (0.50-1.30) 0.79 (0.49-1.29) 0.69 (0.47-1.02) 0.80 (0.49-1.29)

Vit-K Antag Aspirin 0.94 (0.66-1.35) 1.00 (0.71-1.41) 1.00 (0.71-1.41) 1.14 (0.86-1.51) 0.90 (0.66-1.21) 1.00 (0.71-1.41)Aspirin Clopidogrel - 0.88 (0.27-2.84) 0.77 (0.23-2.58) 0.98 (0.31-3.14) 0.89 (0.28-2.90) 0.90 (0.28-2.91)

ASA+Clopi Clopidogrel 0.52 (0.17-1.60) 0.52 (0.17-1.60) 0.52 (0.17-1.60) 0.52 (0.17-1.61) 0.52 (0.17-1.60) 0.52 (0.17-1.60)ASA+Riva Clopidogrel - 0.93 (0.27-3.16) 0.82 (0.23-2.87) 1.03 (0.32-3.37) 0.95 (0.28-3.22) 0.95 (0.28-3.23)ASA+Tica Clopidogrel - 0.44 (0.13-1.52) 0.39 (0.11-1.39) 0.48 (0.14-1.66) 0.44 (0.13-1.50) 0.44 (0.13-1.54)

Rivaroxaban Clopidogrel - 0.75 (0.22-2.55) 0.66 (0.19-2.32) 1.11 (0.34-3.62) 0.76 (0.22-2.60) 0.76 (0.22-2.61)Ticagrelor Clopidogrel - 0.70 (0.20-2.47) 0.62 (0.17-2.25) 0.78 (0.22-2.73) 0.62 (0.18-2.12) 0.71 (0.20-2.53)

Vit-K Antag Clopidogrel - 0.88 (0.26-2.98) 0.77 (0.22-2.71) 1.11 (0.34-3.69) 0.80 (0.24-2.70) 0.90 (0.26-3.05)ASA+Clopi Vit-K Antag - 0.60 (0.36-0.98) 0.68 (0.38-1.20) 0.47 (0.31-0.72) 0.65 (0.41-1.04) 0.58 (0.36-0.96)ASA+Riva Vit-K Antag - 1.06 (0.65-1.73) 1.06 (0.65-1.73) 0.93 (0.65-1.33) 1.18 (0.75-1.87) 1.06 (0.65-1.73)ASA+Tica Vit-K Antag - 0.50 (0.28-0.88) 0.51 (0.28-0.90) 0.43 (0.25-0.74) 0.55 (0.34-0.89) 0.50 (0.28-0.88)

Rivaroxaban Vit-K Antag - 0.85 (0.51-1.41) 0.85 (0.51-1.41) 0.99 (0.69-1.42) 0.95 (0.59-1.52) 0.85 (0.51-1.41)

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Ticagrelor Vit-K Antag - 0.80 (0.44-1.44) 0.80 (0.45-1.45) 0.70 (0.40-1.22) 0.77 (0.47-1.26) 0.80 (0.44-1.44)ASA+Clopi Ticagrelor - 0.75 (0.42-1.35) 0.85 (0.44-1.61) 0.68 (0.38-1.19) 0.85 (0.51-1.43) 0.73 (0.41-1.32)ASA+Riva Ticagrelor - 1.33 (0.73-2.40) 1.32 (0.73-2.38) 1.33 (0.78-2.27) 1.53 (0.91-2.58) 1.33 (0.74-2.40)ASA+Tica Ticagrelor 0.60 (0.35-1.04) 0.62 (0.37-1.05) 0.63 (0.37-1.06) 0.62 (0.36-1.05) 0.71 (0.46-1.10) 0.62 (0.37-1.05)

Rivaroxaban Ticagrelor - 1.07 (0.58-1.95) 1.06 (0.58-1.94) 1.43 (0.84-2.43) 1.23 (0.72-2.10) 1.07 (0.58-1.96)ASA+Clopi Rivaroxaban - 0.70 (0.42-1.18) 0.80 (0.45-1.43) 0.47 (0.32-0.70) 0.69 (0.41-1.16) 0.69 (0.41-1.15)ASA+Riva Rivaroxaban 1.25 (0.87-1.78) 1.25 (0.87-1.78) 1.25 (0.87-1.78) 0.93 (0.75-1.16) 1.25 (0.87-1.78) 1.25 (0.87-1.78)ASA+Tica Rivaroxaban - 0.58 (0.32-1.05) 0.59 (0.33-1.07) 0.43 (0.26-0.72) 0.58 (0.34-0.99) 0.58 (0.32-1.05)ASA+Clopi ASA+Tica 0.81 (0.24-2.73) 1.20 (0.69-2.09) 1.34 (0.74-2.45) 1.09 (0.64-1.87) 1.19 (0.72-1.97) 1.18 (0.68-2.05)ASA+Tica ASA+Riva - 0.47 (0.26-0.83) 0.48 (0.27-0.85) 0.46 (0.28-0.77) 0.47 (0.28-0.78) 0.47 (0.26-0.83)ASA+Clopi ASA+Riva - 0.56 (0.34-0.93) 0.64 (0.36-1.14) 0.51 (0.35-0.75) 0.55 (0.34-0.91) 0.55 (0.33-0.91)

OR: odds ratio. CI: confident interval. Vit-K Antag: vitamin-K antagonists. ASA+Clopi: dual-antiplatelet therapy with aspirin plus clopidogrel. ASA+Tica: dual-antiplatelet therapy with aspirin plus ticagrelor. ASA+Riva: dual therapy with aspirin plus rivaroxaban. OPCABG: off-pump coronary artery bypass graft. *Excluding Mujanovic 2009 and Mannacio 2012 that included OPCABG only. †Sensitivity analysis to explore potential of legacy effect was done by replacing post-trial data (Hage 2017) with in-trial data (Kulik 2010). Significant results are in bold.

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Confidential: For Review OnlySupplementary Table 2. Sensitivity analysis: Surface Under the Cumulative Ranking (SUCRA) values for saphenous vein graft failure

Base case analysis

All Missing Failure

Without OPCAB only

studies*

Per graft analysis

In-trial analysis†Treatment by

outcomeSUCRA SUCRA SUCRA SUCRA SUCRA

ASA+Tica 94.4 93.3 95.6 94.4 94.1

ASA+Clopi 85.3 89.4 78.7 83.9 86.2

Vit-K Antag 39.7 31.2 41.8 47.0 39.5

Aspirin 38.5 50.4 40.2 33.2 38.3

Clopidogrel 36.2 43.6 30.6 34.8 37.2

Placebo 3.3 4.7 4.2 3.5 3.1

Ticagrelor 61.3 65.6 63.4 70.7 61.0

Rivaroxaban 58.3 30.1 60.9 53.5 57.9

ASA+Riva 32.9 41.7 34.6 29.0 32.7

ASA+Clopi: Dual-antiplatelet with aspirin and clopidogrel. ASA+Tica: Dual-antiplatelet therapy with

aspirin and ticagrelor. *Excluding Mujanovic 2009 and Mannacio 2012 that included OPCABG only.

†Replacing post-trial data (Hage 2017) with in-trial data (Kulik 2010). Vit-K Antag: vitamin-K antagonists.


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Supplementary Table 3. Sensitivity analyses: Effect estimates for major bleeding

Network meta-analysis - Odds Ratio (95% CI)

Treatment Comparator PairwiseOR (95% CI) Base Case

analysis

Without OPCABG only

studies*

Imputation analysis

In-trial analysis†

ASA+Clopi Placebo - 2.53 (0.21-29.98) 2.39 (0.19-30.52) 2.09 (0.20-22.45) 3.69 (0.31-44.68)ASA+Riva Placebo - 2.96 (0.28-31.78) 2.96 (0.28-31.78) 3.06 (0.29-32.66) 2.96 (0.28-31.78)ASA+Tica Placebo - 5.74 (0.31-106.01) 5.60 (0.30-104.60) 5.40 (0.30-97.95) 6.72 (0.36-124.57)

Rivaroxaban Placebo - 4.45 (0.42-47.02) 4.76 (0.19-117.30) 4.61 (0.44-48.33) 4.45 (0.42-47.02)Ticagrelor Placebo - 4.86 (0.20-118.93) 4.45 (0.42-47.02) 4.63 (0.19-111.71) 5.58 (0.23-136.83)

Vit-K Antag Placebo 10.8 (0.57-205) 5.31 (0.56-50.21) 5.31 (0.56-50.21) 5.14 (0.55-48.29) 5.31 (0.56-50.21)Aspirin Placebo 2.62 (0.11-65) 2.98 (0.31-28.18) 2.98 (0.31-28.18) 3.08 (0.33-28.96) 2.98 (0.31-28.18)

ASA+Clopi Aspirin 0.76 (0.25-2.31) 0.85 (0.30-2.37) 0.80 (0.24-2.66) 0.68 (0.31-1.48) 1.24 (0.42-3.65)ASA+Riva Aspirin 0.99 (0.46-2.14) 0.99 (0.46-2.14) 0.99 (0.46-2.14) 0.99 (0.46-2.14) 0.99 (0.46-2.14)ASA+Tica Aspirin 7.04 (0.36-137) 1.93 (0.30-12.36) 1.88 (0.29-12.28) 1.75 (0.28-11.01) 2.26 (0.35-14.55)

Rivaroxaban Aspirin 1.50 (0.73-3.04) 1.50 (0.73-3.04) 1.60 (0.16-15.70) 1.50 (0.73-3.04) 1.50 (0.73-3.04)Ticagrelor Aspirin 5.06 (0.24-106) 1.63 (0.17-15.86) 1.50 (0.73-3.04) 1.50 (0.16-14.42) 1.87 (0.19-18.27)

Vit-K Antag Aspirin 2.26 (0.56-9.12) 1.78 (0.95-3.34) 1.78 (0.95-3.34) 1.67 (0.98-2.84) 1.78 (0.95-3.34)ASA+Clopi Vit-K Antag - 0.48 (0.14-1.59) 0.45 (0.12-1.74) 0.41 (0.16-1.04) 0.69 (0.20-2.43)ASA+Riva Vit-K Antag - 0.56 (0.21-1.50) 0.56 (0.21-1.50) 0.59 (0.23-1.51) 0.56 (0.21-1.50)ASA+Tica Vit-K Antag - 1.08 (0.15-7.69) 1.05 (0.15-7.63) 1.05 (0.16-7.11) 1.26 (0.18-9.05)

Rivaroxaban Vit-K Antag - 0.84 (0.32-2.16) 0.90 (0.08-9.58) 0.90 (0.37-2.17) 0.84 (0.32-2.16)Ticagrelor Vit-K Antag - 0.91 (0.09-9.69) 0.84 (0.32-2.16) 0.90 (0.09-9.19) 1.05 (0.10-11.15)

ASA+Clopi Ticagrelor - 0.52 (0.05-5.39) 0.50 (0.05-5.36) 0.45 (0.05-4.50) 0.66 (0.06-6.91)ASA+Riva Ticagrelor - 0.61 (0.06-6.71) 0.62 (0.06-6.93) 0.66 (0.06-7.19) 0.53 (0.05-5.86)ASA+Tica Ticagrelor 1.49 (0.25-9.04) 1.18 (0.24-5.91) 1.18 (0.23-5.89) 1.17 (0.23-5.84) 1.20 (0.24-6.03)

Rivaroxaban Ticagrelor - 0.92 (0.08-9.93) 0.94 (0.09-10.26) 0.99 (0.09-10.64) 0.80 (0.07-8.68)ASA+Clopi Rivaroxaban - 0.57 (0.16-1.98) 0.54 (0.13-2.16) 0.45 (0.16-1.30) 0.83 (0.23-3.02)ASA+Riva Rivaroxaban 0.66 (0.33-1.33) 0.66 (0.33-1.33) 0.66 (0.33-1.33) 0.66 (0.33-1.33) 0.66 (0.33-1.33)ASA+Tica Rivaroxaban - 1.29 (0.18-9.42) 1.26 (0.17-9.35) 1.17 (0.16-8.41) 1.51 (0.21-11.09)

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ASA+Clopi ASA+Tica 1.00 (0.06-16.3) 0.44 (0.07-2.97) 0.43 (0.06-2.96) 0.39 (0.06-2.50) 0.55 (0.08-3.73)ASA+Tica ASA+Riva - 1.94 (0.26-14.48) 1.89 (0.25-14.37) 1.77 (0.24-12.93) 2.27 (0.30-17.04)ASA+Clopi ASA+Riva - 0.86 (0.24-3.08) 0.81 (0.19-3.35) 0.68 (0.23-2.04) 1.25 (0.33-4.69)

CI: confident interval. OPCABG: off-pump coronary artery bypass graft. ASA: aspirin. Clopi: clopidogrel. Tica: ticagrelor. Riva: rivaroxaban. Vit-K Antag: vitamin-K antagonists. ASA+Clopi: dual-antiplatelet therapy with aspirin plus clopidogrel. ASA+Tica: dual-antiplatelet therapy with aspirin plus ticagrelor. ASA+Riva: dual therapy with aspirin plus rivaroxaban. *Excluding Mannacio 2012 that included OPCABG only. †Sensitivity analysis to explore potential of legacy effect was done by replacing post-trial data (Hage 2017) with in-trial data (Kulik 2010).

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Confidential: For Review OnlySupplementary Table 4. Sensitivity analysis: Surface Under the Cumulative Ranking (SUCRA) values for major bleeding

Base case analysis

All Missing Failure

Without OPCABG

only studies*

In-trial analysis†Treatment by

outcomeSUCRA SUCRA SUCRA SUCRA

Placebo 84.4 83.9 84.0 86.1

ASA+Clopi 66.5 76.5 67.4 51.0

Aspirin 61.5 57.7 61.0 66.7

ASA+Riva 61.1 57.7 60.5 65.5

Rivaroxaban 33.6 30.3 33.4 37.9

Ticagrelor 38.6 39.2 39.0 37.0

ASA+Tica 29.8 31.0 30.5 27.4

Vit-K Antag 24.4 23.8 24.3 28.4

ASA+Clopi: dual-antiplatelet with aspirin plus clopidogrel. ASA+Tica: dual-antiplatelet therapy with

aspirin plus ticagrelor. ASA+Riva: dual therapy aspirin plus rivaroxaban. Vit-K Antag: vitamin-K

antagonists. OPCABG: off-pump coronary artery bypass graft. *Excluding Mujanovic 2009 and Mannacio

2012 that included OPCABG only. †Replacing post-trial data (Hage 2017) with in-trial data (Kulik 2010).


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Confidential: For Review OnlySupplementary Table 5: Study-specific risk of bias

Study ID

Bias arising from the

randomization process

Bias due to deviation

from intended

interventions

Bias due to

missing outcome

data

Bias in measurement

of the outcome

Bias in selection

of the reported

result

Overall (SVGF/clinical

outcomes*)

Pantely, 1979 Low risk some

concerns High risk Low risk Low risk High/Some concerns

McEnany, 1982 Some concerns Some

concerns High risk Some concern Low risk High/Some concerns

Sharma, 1983 Some concerns Some

concerns High risk Low risk Low risk High/Some concerns

Lorenz,1984 High risk Some

concerns Low risk Low risk Some concerns High/High

Brown, 1985 Some concerns Some

concerns Low risk Some concerns Low risk

Some concerns/

Some concerns

Goldman, 1989 Some concerns Some

concerns Low risk Low risk Low risk

Some concerns/

Some concerns

Gavaghan, 1991 Some concerns Some


Some concerns/

Some concerns

Van der Meer, 1993 Low risk Some


Some concerns/

Some concerns

Hockings, 1993 Some concerns Some

concernsSome

concerns Low risk High risk High/High

Mujanovic, 2009 Some concerns Some

concerns Low risk Some concerns

Some concerns

Some concerns/

Some concerns

Gao, 2009 Some concerns Some

concerns Low risk Some concerns

Some concerns

Some concerns/

Some concerns

Kulik, 2010 Low risk Low risk Low risk Low risk Low risk Low/Low

Hage, 2017* Low risk Low risk High risk Low risk Low risk High/Low

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Confidential: For Review OnlyGao,2010 Some concerns Some


Some concerns/

Some concerns

Sun,2010 Low risk Low risk Some

concerns Low risk Low riskSome

concerns/Low

Mannacio, 2012 Some concerns Low risk Low risk Low risk Low risk

Some concerns/

Some concerns

Saw, 2016 Low risk Low risk High risk Low risk Low risk High /

Low

Slim, 2016 Some concerns Some


Some concerns/

Some concerns

Zhao, 2018 Low risk Low risk Low risk Low risk Low risk Low/

Low

Xu, 2018 High risk Some

concerns Low risk Some concerns Low risk High risk/

High risk

Lamy, 2019 Low risk Some


Some concerns/

Some concerns

SVGF: saphenous vein graft failure. *Clinical outcomes include major bleeding, mortality and myocardial

infarction.

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Supplementary Table 6. Certainty of direct evidence assessment

Comparison No. of RCTs Risk of bias Inconsistency Indirectness Publication

biasOdds Ratio(95% CI)

Certainty of evidence

Saphenous vein graft failure (Base case analysis)

Aspirin vs Placebo 7 Not Serious Not Serious Serious2 Unclear3 0.55 (0.39-0.78) Moderate

Vit-K Antag vs Placebo 2 Serious4 Not Serious Serious2 Unclear3 0.68 (0.30-1.51) Low

Vit-K Antag vs Aspirin 2 Serious5 Not Serious Serious2 Unclear3 0.94 (0.66-1.35) Low

ASA+Clopi vs Aspirin 6 Not Serious Not Serious Serious2 Unclear3 0.62 (0.43-0.90) Moderate

ASA+Clopi vs Clopi 1 Not Serious NA6 Serious2 Unclear3 0.52 (0.17-1.60) Moderate

ASA+Clopi vs ASA+Tica 1 Serious1 NA6 Serious2 Unclear3 0.81 (0.24-2.73) Low

ASA+Tica vs Aspirin 2 Not Serious Not Serious Serious2 Unclear3 0.46 (0.28-0.76) Moderate

ASA+Riva vs Aspirin 1 Not Serious NA6 Serious2 Unclear3 1.06 (0.75-1.50) Moderate

ASA+Riva vs Riva 1 Not Serious NA6 Serious2 Unclear3 1.25 (0.87-1.78) Moderate

Riva vs Aspirin 1 Not Serious NA6 Serious2 Unclear3 0.85 (0.59-1.23) Moderate

ASA+Tica vs Ticagrelor 1 Not Serious NA6 Serious2 Unclear3 0.60 (0.35-1.04) Moderate

Ticagrelor vs Aspirin 1 Not Serious NA6 Serious2 Unclear3 0.78 (0.48-1.27) Moderate

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Major bleeding

Aspirin vs Placebo 2 Not Serious NA6 Serious2 NA7 2.62 (0.11-65) Moderate

Vit-K Antag vs Placebo 1 Serious1 NA6 Not Serious NA7 10.81 (0.57-204) Moderate

Vit-K Antag vs Aspirin 2 Serious1 Not Serious Serious2 NA7 2.26 (0.56-9.12) Low

ASA+Clopi vs Aspirin 4 Not Serious Not Serious Serious2 NA7 0.76 (0.25-2.31) Moderate

ASA+Clopi vs ASA+Tica 1 Serious1 NA6 Not Serious NA7 1.00 (0.06-16.31) Moderate

ASA+Tica vs Aspirin 2 Not Serious NA6 Not Serious NA7 7.04 (0.36-137) High

ASA+Riva vs Aspirin 1 Not Serious NA6 Not Serious NA7 0.99 (0.46-2.14) High

ASA+Riva vs Riva 1 Not Serious NA6 Not Serious NA7 0.66 (0.33-1.33) High

Riva vs Aspirin 1 Not Serious NA6 Not Serious NA7 1.50 (0.73-3.04) High

ASA+Tica vs Ticagrelor 1 Not Serious NA6 Not Serious NA7 1.49 (0.25-9.04) High

Ticagrelor vs Aspirin 1 Not Serious NA6 Not Serious NA7 5.06 (0.24-106) High

Mortality

Aspirin vs Placebo 4 Not Serious Not Serious Serious2 NA7 1.54 (0.36-6.66) Moderate

Vit-K Antag vs Placebo 2 Serious1 NA6 Not Serious NA7 3.44 (0.14-85.9) Moderate


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ASA+Clopi vs ASA+Tica 1 Serious1 NA6 Not Serious NA7 Not estimable Moderate

Myocardial infarction

Aspirin vs Placebo 2 Not Serious Not Serious Serious2 NA7 0.97 (0.03-27.4) Moderate

Vit-K Antag vs Placebo 1 Serious1 NA6 Not Serious NA7 0.21 (0.02-1.89) Moderate



ASA+Clopi vs ASA+Tica 1 Serious1 NA6 Not Serious NA7 Not estimable Moderate

ASA+Tica vs Aspirin 2 Not Serious NA6 Not Serious NA7 0.65 (0.11-3.97) High

ASA+Riva vs Aspirin 1 Not Serious NA6 Not Serious NA7 0.52 (0.15-1.80) High

ASA+Riva vs Riva 1 Not Serious NA6 Not Serious NA7 0.55 (0.16-1.88) High

Riva vs Aspirin 1 Not Serious NA6 Not Serious NA7 0.96 (0.33-2.75) High

ASA+Tica vs Ticagrelor 1 Not Serious NA6 Not Serious NA7 0.99 (0.14-7.10) High

Ticagrelor vs Aspirin 1 Not Serious NA6 Not Serious NA7 0.66 (0.11-4.02) High

NA: Not applicable. RCT: randomised-controlled trial. CI: confidence interval. ASA: aspirin. Clopi: clopidogrel. Tica: ticagrelor. Riva: rivaroxaban. Vit-K Antag: vitamin-K antagonists. ASA+Clopi: dual-antiplatelet therapy with aspirin plus clopidogrel. ASA+Tica: dual-antiplatelet therapy with aspirin plus ticagrelor. ASA+Riva: dual therapy with aspirin plus rivaroxaban. Imprecision is not included in the assessment.1All studies failed to blind patients and personnel completely

2At least one study used aspirin at doses higher than those that are currently used (75-100 mg/day) and/or saphenous vein graft failure (SVGF) is a surrogate outcome as well as the short duration of treatment and follow-up for SVGF are not very applicable to the real-world situation.

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3As per protocol, the funnel plot or Egger’s test was not performed because of insufficient information (<10 studies).4No blinding in one study and incomplete blinding in another study. Both studies have incomplete patency data (range: 21% to 48.6%), and the proportion of missing data was not balanced between arms in one study.5Both studies failed to blind patients and personnel and had incomplete patency data (range: 15.9% to 48.6%). The proportion of missing data was not balanced between arms in one study.6Unable to assess because there are <2 studies available with non-zero events in both arms.7This NMA was designed to include studies that evaluated SVGF. Many studies reporting only clinical outcomes were excluded as a result of the design. Therefore, it is not possible to explore the impact of publication bias for clinical outcomes.

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Supplementary Table 7. Certainty of network evidence assessment

Direct Evidence Indirect Evidence Network Meta-Analysis*Comparison

OR (95% CI) Certainty of Evidence OR (95% CI) Certainty of Evidence OR (95% CI) Certainty of EvidenceSVGF (Base case analysis)

ASA+Clopi vs Placebo - - 0.34 (0.21-0.54) Moderate1,2,3 0.34 (0.21-0.54) ModerateASA+Riva vs Placebo - - 0.60 (0.38-0.98) Low1,4 0.60 (0.38-0.98) LowASA+Tica vs Placebo - - 0.28 (0.16-0.48) Moderate1,2,3 0.28 (0.16-0.48) Moderate

Riva vs Placebo - - 0.48 (0.30-0.77) Moderate1,2,3 0.48 (0.30-0.77) ModerateTicagrelor vs Placebo - - 0.45 (0.26-0.79) Moderate1,2,3 0.45 (0.26-0.79) Moderate

Vit-K Antag vs Placebo 0.68 (0.30-1.51) Low 0.52 (0.31-0.86) Very Low1,5 0.56 (0.37-0.86) LowClopidogrel vs Placebo - - 0.64 (0.19-2.16) Low1,3 0.64 (0.19-2.16) Very Low6

Aspirin vs Placebo 0.55 (0.39-0.78) Moderate 0.74 (0.22-2.47) Very Low1,4 0.56 (0.42-0.76) ModerateASA+Clopi vs Aspirin 0.62 (0.43-0.90) Moderate 0.38 (0.10-1.40) Very Low1,5 0.60 (0.42-0.86) ModerateASA+Riva vs Aspirin 1.06 (0.75-1.50) Moderate Not estimable NA 1.06 (0.75-1.50) Low 6

ASA+Tica vs Aspirin 0.46 (0.28-0.76) Moderate Not estimable NA 0.50 (0.31-0.79) ModerateRiva vs Aspirin 0.85 (0.59-1.23) Moderate Not estimable NA 0.85 (0.59-1.23) Low 6

Ticagrelor vs Aspirin 0.78 (0.48-1.27) Moderate Not estimable NA 0.80 (0.49-1.29) Low 6

Vit-K Antag vs Aspirin 0.94 (0.66-1.35) Low 1.81 (0.57-5.74) Very Low1,5 1.00 (0.71-1.41) Very Low6

Aspirin vs Clopidogrel - - 0.88 (0.27-2.84) Low1,3 0.88 (0.27-2.84) Very Low6

ASA+Clopi vs Clopidogrel 0.52 (0.17-1.60) Moderate Not estimable NA 0.52 (0.17-1.60) Low6

ASA+Riva vs Clopidogrel - - 0.93 (0.27-3.16) Low1,3 0.93 (0.27-3.16) Very Low6

ASA+Tica vs Clopidogrel - - 0.44 (0.13-1.52) Very Low1,5 0.44 (0.13-1.52) Very Low6

Riva vs Clopidogrel - - 0.75 (0.22-2.55) Low1,3 0.75 (0.22-2.55) Very Low6

Ticagrelor vs Clopidogrel - - 0.70 (0.20-2.47) Low1,3 0.70 (0.20-2.47) Very Low6

Vit-K Antag vs Clopidogrel - - 0.88 (0.26-2.98) Very Low1,5 0.88 (0.26-2.98) Very Low6

ASA+Clopi vs Vit-K Antag - - 0.60 (0.36-0.98) Very Low1,5 0.60 (0.36-0.98) Very LowASA+Riva vs Vit-K Antag - - 1.06 (0.65-1.73) Very Low1,5 1.06 (0.65-1.73) Very Low6

ASA+Tica vs Vit-K Antag - - 0.50 (0.28-0.88) Very Low1,5 0.50 (0.28-0.88) Very LowRiva vs Vit-K Antag - - 0.85 (0.51-1.41) Very Low1,5 0.85 (0.51-1.41) Very Low6

Ticagrelor vs Vit-K Antag - - 0.80 (0.44-1.44) Very Low1,5 0.80 (0.44-1.44) Very Low6

ASA+Clopi vs Ticagrelor - - 0.75 (0.42-1.35) Low1,3 0.75 (0.42-1.35) Very Low6

ASA+Riva vs Ticagrelor - - 1.33 (0.73-2.40) Low1,3 1.33 (0.73-2.40) Very Low6

ASA+Tica vs Ticagrelor 0.60 (0.35-1.04) Moderate Not estimable NA 0.62 (0.37-1.05) Low6

Riva vs Ticagrelor - - 1.07 (0.58-1.95) Low1,3 1.07 (0.58-1.95) Very Low6

ASA+Clopi vs Riva - - 0.70 (0.42-1.18) Low1,3 0.70 (0.42-1.18) Very Low6

ASA+Riva vs Riva 1.25 (0.87-1.78) Moderate Not estimable NA 1.25 (0.87-1.78) Low6

ASA+Tica vs Riva - - 0.58 (0.32-1.05) Very Low1,5 0.58 (0.32-1.05) Very LowASA+Clopi vs ASA+Tica 0.81 (0.24-2.73) Low 1.33 (0.72-2.48) Low1,3 1.20 (0.69-2.09) Very Low6

ASA+Tica vs ASA+Riva - - 0.47 (0.26-0.83) Moderate1,2,3 0.47 (0.26-0.83) Moderate

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ASA+Clopi vs ASA+Riva - - 0.56 (0.34-0.93) Low1,3 0.56 (0.34-0.93) LowThe estimated common between-study variance (tau2) = (1.03×10-10)2 = 1.06×10-20

Major BleedingASA+Clopi vs Placebo - - 2.53 (0.21-29.98) Low1,3 2.53 (0.21-29.98) Very Low6

ASA+Riva vs Placebo - - 2.96 (0.28-31.78) Low1,7 2.96 (0.28-31.78) Very Low6

ASA+Tica vs Placebo - - 5.74 (0.31-106.01) Low1,7 5.74 (0.31-106.01) Very Low6

Riva vs Placebo - - 4.45 (0.42-47.02) Low1,7 4.45 (0.42-47.02) Very Low6

Ticagrelor vs Placebo - - 4.86 (0.20-118.93) Low1,7 4.86 (0.20-118.93) Very Low6

Vit-K Antag vs Placebo 10.81 (0.57-204) Moderate 1.77 (0.08-39.2) Very Low1,5 5.31 (0.56-50.21) Low6

Aspirin vs Placebo 2.62 (0.11-65) Moderate Not estimable NA 2.98 (0.31-28.18) Low6

ASA+Clopi vs Aspirin 0.76 (0.25-2.31) Moderate 3.45 (0.09-136) Low1,7 0.85 (0.30-2.37) Low6

ASA+Riva vs Aspirin 0.99 (0.46-2.14) High Not estimable NA 0.99 (0.46-2.14) Moderate6

ASA+Tica vs Aspirin 7.04 (0.36-137) High Not estimable NA 1.93 (0.30-12.36) Moderate6

Riva vs Aspirin 1.50 (0.73-3.04) High Not estimable NA 1.50 (0.73-3.04) Moderate6

Ticagrelor vs Aspirin 5.06 (0.24-106) High Not estimable NA 1.63 (0.17-15.86) Moderate6

Vit-K Antag vs Aspirin 2.26 (0.56-9.12) Low Not estimable NA 1.78 (0.95-3.34) Very Low6

ASA+Clopi vs Vit-K Antag - - 0.48 (0.14-1.59) Very Low1,5 0.48 (0.14-1.59) Very Low6

ASA+Riva vs Vit-K Antag - - 0.56 (0.21-1.50) Very Low1,5 0.56 (0.21-1.50) Very Low6

ASA+Tica vs Vit-K Antag - - 1.08 (0.15-7.69) Very Low1,5 1.08 (0.15-7.69) Very Low6

Riva vs Vit-K Antag - - 0.84 (0.32-2.16) Very Low1,5 0.84 (0.32-2.16) Very Low6



ASA+Riva vs Ticagrelor - - 0.61 (0.06-6.71) Moderate1,8 0.61 (0.06-6.71) Low6

ASA+Tica vs Ticagrelor 1.49 (0.25-9.04) High Not estimable NA 1.18 (0.24-5.91) Moderate6

Riva vs Ticagrelor - - 0.92 (0.08-9.93) Moderate1,8 0.92 (0.08-9.93) Low6


ASA+Riva vs Riva 0.66 (0.33-1.33) High Not estimable NA 0.66 (0.33-1.33) Moderate6

ASA+Tica vs Riva - - 1.29 (0.18-9.42) Moderate1,8 1.29 (0.18-9.42) Low6

ASA+Clopi vs ASA+Tica 1.00 (0.06-16.3) Moderate 4.61 (0.34-62.3) Low1,7 0.44 (0.07-2.97) Low6

ASA+Tica vs ASA+Riva - - 1.94 (0.26-14.48) Moderate1,8 1.94 (0.26-14.48) Low6

ASA+Clopi vs ASA+Riva - - 0.86 (0.24-3.08) Low1,7 0.86 (0.24-3.08) Very Low6

The estimated common between-study variance (tau2) = (2.95×10-7)2 = 8.70×10-14

MortalityASA+Clopi vs Placebo - - 1.24 (0.13-11.45) Low1,3 1.24 (0.13-11.5) Very Low6

ASA+Tica vs Placebo - - 1.24 (0.01-114) Low1,3 1.24 (0.01-114) Very Low6

Vit-K Antag vs Placebo 3.44 (0.14-85.9) Moderate 0.53 (0.08-3.57) Very Low1,5 1.04 (0.23-4.72) Low6

Aspirin vs Placebo 1.54 (0.36-6.66) Moderate 11.99 (0.32-446) Very Low1,5 1.77 (0.52-5.99) Low6

ASA+Clopi vs Aspirin 0.70 (0.11-4.50) Moderate Not estimable NA 0.70 (0.11-4.50) Low6

ASA+Tica vs Aspirin 0.70 (0.01-54.3) Low1,3 0.70 (0.01-54.3) Low6

Vit-K Antag vs Aspirin 0.52 (0.15-1.8)^ Low 1.74 (0.04-76.1) Low1,3 0.59 (0.19-1.87) Very Low6

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ASA+Tica vs Vit-K Antag - - 1.19 (0.01-107) Very Low1,5 1.19 (0.01-107) Very Low6

ASA+Clopi vs ASA+Tica Not estimable Moderate Not estimable NA 1.00 (0.02-51.1) Low6


Myocardial InfarctionASA+Clopi vs Placebo - - 0.34 (0.06-2.05) Low1,3 0.34 (0.06-2.05) Very Low6

ASA+Riva vs Placebo - - 0.25 (0.04-1.73) Low1,7 0.25 (0.04-1.73) Very Low6

ASA+Tica vs Placebo - - 0.34 (0.04-2.84) Low1,7 0.34 (0.04-2.84) Very Low6

Riva vs Placebo - - 0.47 (0.08-2.84) Low1,7 0.47 (0.08-2.84) Very Low6

Ticagrelor vs Placebo - - 0.33 (0.03-3.28) Low1,7 0.33 (0.03-3.28) Very Low6

Vit-K Antag vs Placebo 0.21 (0.02-1.89) Moderate 2.19 (0.16-29.3) Very Low1,5 0.45 (0.10-2.00) Low6

Aspirin vs Placebo 0.97 (0.03-27.4) Moderate Not estimable NA 0.49 (0.11-2.11) Low6

ASA+Clopi vs Aspirin 0.69 (0.23-2.04) Moderate 0.70 (0.01-49.9) Low1,7 0.71 (0.26-1.96) Low6

ASA+Riva vs Aspirin 0.52 (0.15-1.80) High Not estimable NA 0.52 (0.15-1.80) Moderate6

ASA+Tica vs Aspirin 0.65 (0.11-3.97) High Not estimable NA 0.70 (0.15-3.22) Moderate6

Riva vs Aspirin 0.96 (0.33-2.75) High Not estimable NA 0.96 (0.33-2.75) Moderate6

Ticagrelor vs Aspirin 0.66 (0.11-4.02) High Not estimable NA 0.68 (0.12-3.97) Moderate6

Vit-K Antag vs Aspirin 0.97 (0.55-1.71) Low Not estimable NA 0.92 (0.52-1.63) Very Low6


ASA+Riva vs Vit-K Antag - - 0.57 (0.15-2.21) Very Low1,5 0.57 (0.15-2.21) Very Low6

ASA+Tica vs Vit-K Antag - - 0.76 (0.15-3.88) Very Low1,5 0.76 (0.15-3.88) Very Low6

Riva vs Vit-K Antag - - 1.04 (0.31-3.45) Very Low1,5 1.04 (0.31-3.45) Very Low6



ASA+Riva vs Ticagrelor - - 0.77 (0.09-6.58) Moderate1,8 0.77 (0.09-6.58) Low6

ASA+Tica vs Ticagrelor 0.99 (0.14-7.10) High Not estimable NA 1.03 (0.16-6.80) Moderate6

Riva vs Ticagrelor - - 1.40 (0.18-10.93) Moderate1,8 1.40 (0.18-10.93) Low6


ASA+Riva vs Riva 0.55 (0.16-1.88) High Not estimable NA 0.55 (0.16-1.88) Moderate6

ASA+Tica vs Riva - - 0.74 (0.12-4.68) Low1,7 0.74 (0.12-4.68) Very Low6

ASA+Clopi vs ASA+Tica Not estimable Moderate 1.00 (0.14-6.95) Low1,7 1.00 (0.18-5.74) Low6

ASA+Tica vs ASA+Riva - - 1.35 (0.19-9.55) Moderate1,8 1.35 (0.19-9.55) Low6

ASA+Clopi vs ASA+Riva - - 1.35 (0.27-6.70) Low1,7 1.35 (0.27-6.70) Very Low6


SVGF: saphenous vein graft failure. OR: odds ratio. CI: confidence interval. ASA: aspirin. Clopi: clopidogrel. Tica: ticagrelor. Riva: rivaroxaban. Vit-K Antag: vitamin-K antagonists. ASA+Clopi: dual-antiplatelet therapy with aspirin plus clopidogrel. ASA+Tica: dual-antiplatelet therapy with aspirin plus ticagrelor. ASA+Riva: dual therapy with aspirin plus rivaroxaban. Not estimable because of zero events in all study arms or because a second direct comparison needed to contribute to that specific indirect comparison is not available. Significant results are in bold. ^ and indirect estimates were obtained using the node-splitting approach. * <50% quantiles of the empirical distribution (i.e.- low heterogeneity) and lack of evidence of incoherence.𝜏2

𝑁𝑀𝐴

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1. Probable intransitivity (more on-pump coronary artery bypass graft patients, more urgent patients, and/or earlier drug administration in one of the direct comparisons).2. Effect size is <0.5 and statistically significant.3. The confidence ratings for both direct comparisons are moderate.4. The confidence ratings for both direct comparisons are low.5. The lower confidence rating of the two direct comparisons is low.6. Imprecise (wide 95% CI).7. The lower confidence rating of the two direct comparisons is moderate.8. The confidence ratings for both direct comparisons are high.

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Confidential: For Review OnlySupplementary Table 8. Local inconsistency tests assuming a common loop-specific heterogeneity estimated using the method of moments

Closed loop of evidence Inconsistency factor (IF - 95% CI)

Loop heterogeneity-tau2

SVGF (Base case analysis)

Aspirin-ASA+Clopi-ASA+Tica 0.49 (0.00-1.85) 0.000

Aspirin-Vit-K Antag-Placebo 0.33 (0.00-1.32) 0.018

Aspirin-ASA+Tica-Tica 0.03 (0.00-1.47) 0.000

SVGF (Per graft analysis)



Aspirin-ASA+Tica-Tic 0.04 (0.00-1.41) 0.000

Major Bleeding



Mortality


Myocardial Infarction


ASA+Clopi: dual-antiplatelet with aspirin plus clopidogrel. ASA+Tica: dual-antiplatelet therapy with

aspirin plus ticagrelor. Vit-K Antag: vitamin-K antagonists. If the 95% confidence interval (CI) excludes

zero-incoherence is detected statistically.

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Confidential: For Review OnlySupplementary Table 9. Global inconsistency using the design-by-treatment interaction model

Outcomes of interest Chi-square Global inconsistency P-value

SVGF (Base case analysis) 2.01 (df=5) 0.8473

SVGF (Per graft analysis) 2.68 (df=5) 0.7487

Major bleeding 2.58 (df=4) 0.6298

Mortality 1.92 (df=3) 0.5899

Myocardial infarction 3.77 (df=4) 0.4385

SVGF: saphenous vein graft failure.

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Confidential: For Review OnlySupplementary Table 10: Meta-regression of treatment effect and year of publication relative to the reference therapy (Aspirin)

Log odds ratio* 95% CI P-value

Aspirin + Clopidogrel year of publication 0.04 -0.09 to 0.169 0.552

Aspirin + Ticagrelor year of publication 0.07 -0.668 to 0.806 0.854

Vitamin K antagonist year of publication 0.01 -0.065 to 0.093 0.727

Placebo year of publication 0.06 -0.026 to 0.143 0.173

CI: confidence interval. *Log odds ratio is the strength of association between the treatment effect and

year of publication relative to the reference therapy (aspirin).

Estimates of the effect of year of publication on clopidogrel, aspirin + rivaroxaban, ticagrelor and

rivaroxaban, compared to the reference therapy aspirin, could not be obtained due to collinearity and missing

linkage.

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Figure 1. Network of treatment comparisons for (A) saphenous vein graft failure (primary efficacy outcome) and (B) major bleeding (primary safety outcome). Each node represents different active interventions or

placebo. The size of nodes is proportional to the number of studies evaluating that particular intervention. The increasing thickness of lines between nodes is proportional to the number of randomly assigned patients

contributing to direct comparisons. Vit-K A: vitamin-K antagonist.

177x251mm (300 x 300 DPI)

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Figure 2. Network estimates of the treatment effects for (A) saphenous vein graft failure (primary efficacy outcome) and (B) major bleeding (primary safety outcome). All active interventions and placebo were

compared with aspirin monotherapy. OR: odds ratio. 95% CI: confidence interval.

177x221mm (300 x 300 DPI)

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Figure 3. Network meta-analysis and certainty of evidence for (A) saphenous vein graft failure (primary efficacy outcome) and (B) major bleeding (primary safety outcome). Results are the odds ratio and (95% confidence intervals) from the network meta-analysis between the column-defining intervention and the row-defining intervention. Significant results are in bold. The certainty of evidence is also incorporated

within this figure. Notably, green represents moderate-certainty evidence, yellow represents low-certainty evidence, and red represents very-low certainty evidence.

177x229mm (300 x 300 DPI)

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Figure 4. Network of treatment comparisons for secondary outcomes (A) all-cause mortality and (B) myocardial infarction. Each node represents different active interventions or placebo. The size of nodes is proportional to the number of studies evaluating that particular intervention. The increasing thickness of lines between nodes is proportional to the number of randomly assigned patients contributing to direct

comparisons. Vit-K A: vitamin-K antagonist.

128x177mm (300 x 300 DPI)

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Figure 5. Network meta-analysis and certainty of evidence for secondary outcomes (A) all-cause mortality and (B) myocardial infarction. Results are the odds ratio and (95% confidence intervals) from the network meta-analysis between the column-defining intervention and the row-defining intervention. The certainty of

evidence is also incorporated within this figure. Notably, green represents moderate-certainty evidence, yellow represents low-certainty evidence, and red represents very-low certainty evidence.

254x272mm (300 x 300 DPI)

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antithrombotic therapy in patients undergoing coronary · 2019. 10. 14. · short title:...

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