Article Final Examination SN-27-Sep-2021

BMJ: first published as 10.1136/bmj.l5476 on 10 October 2019. Downloaded from http://www.bmj.
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RESEARCH
Antithrombotic treatment after coronary artery bypass graft

surgery: systematic review and network meta-analysis
Karla Solo,1,2 Shahar Lavi,3 Conrad Kabali,4 Glenn N Levine,5 Alexander Kulik,6
Ava A John-Baptiste,1,7,8 Stephen E Fremes,9,10 Janet Martin,1,7 John W Eikelboom,11
Marc Ruel,12 Ashlay A Huitema,3 Tawfiq Choudhury,3 Deepak L Bhatt,13 Nikolaos Tzemos,3
Mamas A Mamas,14 Rodrigo Bagur1,3,14
For numbered affiliations see ABSTRACT interval 0.31 to 0.79, number needed to treat 10) or
end of the article. OBJECTIVE aspirin plus clopidogrel (0.60, 0.42 to 0.86, 19) to
Correspondence to: R Bagur, To assess the effects of different oral antithrombotic reduce saphenous vein graft failure when compared
University Hospital, London
Health Sciences Centre,
drugs that prevent saphenous vein graft failure in with aspirin monotherapy. The study found no strong
London, ON, N6A 5A5, Canada patients undergoing coronary artery bypass graft evidence of differences in major bleeding, myocardial
rodrigobagur@yahoo.com surgery. infarction, and death among different antithrombotic
(or @rodrigobagur on Twitter;
DESIGN therapies. The possibility of intransitivity could not
ORCID 0000-0003-1888-9429)
Systematic review and network meta-analysis. be ruled out; however, between-trial heterogeneity
Additional material is published
online only. To view please visit and incoherence were low in all included analyses.
DATA SOURCES
the journal online. Sensitivity analysis using per graft data did not
Medline, Embase, Web of Science, CINAHL, and the
Cite this as: BMJ 2019;367:l5476 change the effect estimates.
http://dx.doi.org/10.1136/bmj.l5476 Cochrane Library from inception to 25 January 2019.
CONCLUSIONS
Accepted: 22 August 2019 ELIGIBILITY CRITERIA FOR SELECTING STUDIES
The results of this network meta-analysis suggest an
Randomised controlled trials of participants (aged
important absolute benefit of adding ticagrelor or
≥18) who received oral antithrombotic drugs
clopidogrel to aspirin to prevent saphenous vein graft
(antiplatelets or anticoagulants) to prevent saphenous
failure after coronary artery bypass graft surgery. Dual
vein graft failure after coronary artery bypass graft
antiplatelet therapy after surgery should be tailored to
surgery.
the patient by balancing the safety and efficacy profile
MAIN OUTCOME MEASURES of the drug intervention against important patient
The primary efficacy endpoint was saphenous vein outcomes.
graft failure and the primary safety endpoint was
STUDY REGISTRATION
major bleeding. Secondary endpoints were myocardial
PROSPERO registration number CRD42017065678.
infarction and death.
RESULTS
This review identified 3266 citations, and 21 articles Introduction
that related to 20 randomised controlled trials were Coronary artery bypass graft surgery is the preferred
included in the network meta-analysis. These 20 treatment for many patients with multivessel coronary
trials comprised 4803 participants and investigated artery disease.1 2 However, patients undergoing this
nine different interventions (eight active and one procedure remain at risk of subsequent major adverse
placebo). Moderate certainty evidence supports the cardiovascular events, mainly caused by associated
use of dual antiplatelet therapy with either aspirin progression of native coronary artery disease, vascular
plus ticagrelor (odds ratio 0.50, 95% confidence damage, or saphenous vein graft failure.3-7 Previous
studies have shown rates of saphenous vein graft
WHAT IS ALREADY KNOWN ON THIS TOPIC failure of up to 30-40% in the first year8 9 and up to
70% beyond 10 years after coronary artery bypass
Aspirin is considered the preferred antiplatelet drug to prevent saphenous vein
graft surgery.8 10-13 Despite its relatively high early
graft failure after coronary artery bypass surgery
failure rates, saphenous vein graft remains the most
Uncertainty remains about the benefits of adding a P2Y12 inhibitor or direct oral commonly used graft in contemporary coronary artery
anticoagulant to aspirin monotherapy after bypass surgery bypass graft trials.14-17
WHAT THIS STUDY ADDS Aspirin is considered the preferred antiplatelet
drug to prevent saphenous vein graft failure after
Dual antiplatelet therapy with either aspirin plus ticagrelor or aspirin plus
coronary artery bypass graft (class I, level of
clopidogrel was more efficacious than aspirin monotherapy in preventing
evidence A).18 Updated meta-analyses support this
saphenous vein graft failure after coronary artery bypass surgery
recommendation, but at a cost of increasing the
No strong evidence was found of differences in major bleeding, myocardial risk of bleeding.19-21 Uncertainty remains about
infarction, and death for different antithrombotics compared with aspirin the benefits of adding a P2Y12 inhibitor or oral
monotherapy anticoagulant to aspirin monotherapy. There is
Future guideline updates are needed to optimise antithrombotic management of emerging evidence on the potential benefits of dual
patients undergoing coronary artery bypass graft surgery antiplatelet therapy with aspirin and clopidogrel or
Dual antiplatelet therapy with aspirin plus ticagrelor or aspirin plus clopidogrel ticagrelor after coronary artery bypass graft surgery,
could be considered for most patients after surgery but these combinations have not been directly
the bmj | BMJ 2019;367:l5476 | doi: 10.1136/bmj.l5476 1

BMJ: first published as 10.1136/bmj.l5476 on 10 October 2019. Downloaded from http://www.bmj.com/ on 13 September 2021 at The Avudh Srisukri Building, 110. Protected by copyright.
RESEARCH
compared with other antithrombotic therapies in trials to ensure a comprehensive search.23 The full
randomised controlled trials. Additionally, no studies search strategy has been published in the protocol.23
have been published to compare the effects of all
available oral antithrombotic drugs (antiplatelets and Data selection
anticoagulants) for the prevention of saphenous vein Studies were eligible for inclusion if they consisted of
graft failure after coronary artery bypass graft surgery patients (≥18 years) who underwent coronary artery
within a single analytical framework. Therefore, bypass graft surgery with at least one saphenous vein
in this study we aimed to systematically review graft; if they compared oral antithrombotic regimens
randomised controlled trials that assessed the effects with each other or placebo; and if they evaluated
of oral antithrombotic drugs to prevent saphenous saphenous vein graft failure, regardless of unit of
vein graft failure in patients undergoing coronary analysis and drug regimens. Antithrombotic drugs
artery bypass graft surgery. We also evaluated the included in this review were aspirin, clopidogrel,
comparative efficacy and harms of these drugs by ticagrelor, vitamin K antagonists (warfarin, aceno-
using a network meta-analysis. coumarol, phenprocoumon), and rivaroxaban; dual
antiplatelet therapy included aspirin plus clopidogrel
Methods or aspirin plus ticagrelor; and dual therapy included
Literature search aspirin plus rivaroxaban. We did not include aspirin
This systematic review and network meta-analysis plus dipyridamole because this combination is no
is reported following the Preferred Reporting Items longer used in clinical practice for patients with
for Systematic reviews and Meta-analyses (PRISMA) coronary artery disease. We considered aspirin
extension statement for network meta-analysis22 monotherapy as a single intervention regardless of
(fig 1). This study is registered with PROSPERO whether aspirin was interrupted or continuously
(CRD42017065678) and the protocol has been peer administered before coronary artery bypass graft
reviewed and published in BMJ Open.23 surgery because a recent meta-analysis showed no
We conducted a search of Medline, Embase, Web difference between these two approaches.21
of Science, CINAHL, and the Cochrane Library from
their inception to 25 January 2019. We also performed Data identification and extraction
a grey literature search and checked reference lists of Two investigators (KS and AAH) independently
relevant reviews and eligible randomised controlled screened articles by title, abstract, and full text
3266
Records identified through database searching
1307
Records screened aer duplicates removed
1179
Records excluded
128
Full text articles assessed for eligibility
105
Full text articles excluded
46 Duplicate
13 Wrong outcome
4 Wrong study design
26 Wrong intervention
4 Wrong patient population
4 Non-extractable data
1 Non-English
7 Ongoing trials
23
Studies included in qualitative synthesis
20
Studies included in quantitative synthesis (meta-analysis), unique randomised controlled trials
Reported in 21 manuscripts
Fig 1 | PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram
2 doi: 10.1136/bmj.l5476 | BMJ 2019;367:l5476 | the bmj

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Table 1 | Characteristics of the included randomised controlled trials

SVG patency
assessment method
Time of (unit of analysis), time
drug from randomisation to Effect size
Study, year initiation Treatment SVG patency No of any graft/ for SVGF, OR
(sample size) after CABG duration assessment Relevant study arms SVG per patient* Age (years) Male (%) (95% CI)
Angiography VKA: warfarin
Pantely, 1979 VKA: 2.85/2.85; VKA: 56±8; VKA: 69.2; VKA v C: 1.04
+3 days 6 months (per patient and per (INR target: NR);
(n=47) C: 2.54/2.54 C: 52±8 C: 83.3 (0.26 to 4.18)
graft), 6 months C: no study medication
VKA v C: 0.55
Angiography VKA: warfarin
VKA: 1.91/1.91; VKA: 92.9; (0.20 to 1.46); VKA v
McEnany, 1982 +3 to (per patient and per (INR target: 1.5-2);
12 months ASA: 2.03/2.03; — ASA: 82.0; ASA: 0.69 (0.26 to 1.84);
(n=216) 4 days graft), 21.5 months ASA: 600 mg BID;
C: 2.00/2.00 C: 87.3 ASA v C: 0.79 (0.32 to
(range 1-47 months) C: matching placebo
1.96)
Sharma, 1983 +3 to Angiography (per patient ASA: 325 mg TID; ASA: 2.20/2.20; ASA: 100; ASA v C: 0.94
12 months —
(n=116) 5 days and per graft), 12 months C: no study medication C: 2.20/2.20 C: 100 (0.42 to 2.13)
Lorenz, 1984 Angiography (per patient ASA: 100 mg OD; ASA:1.90/1.90; ASA: 55±10; ASA: 82.8; ASA v C: 0.23
+24 hours 4 months
(n=60) and per graft), 4 months C: matching placebo C: 2.23/2.23 C: 55±6 C: 90.3 (0.06 to 0.79)
Brown, 1985 +67± Angiography (per patient ASA: 325 mg TID; ASA: 3.10/3.10; ASA v C: 0.52
12 months — —
(n=98) 27 hours and per graft), 12 months C: matching placebo C: 3.30/3.30 (0.20 to 1.32)
Angiography (per graft),
Goldman, 1989 ASA: 325 mg OD; ASA: 59±8; ASA: 100; ASA v C: 0.68
−12 hours 12 months 12 months Overall: -/3.20
(n=98) C: matching placebo C: 58±8 C: 100 (0.39 to 1.18)
(range 62-527 days)
Angiography (per patient
Gavaghan, 1991 ASA: 324 mg OD; ASA: -/3.40; ASA:56±8; ASA: 86.6; ASA v C: 0.31
+1 hours 12 months and per graft), 12 months
(n=237) C: matching placebo C: -/3.60 C: 56±7 C: 83.6 (0.15 to 0.63)
(range 222-430 days)
VKA: 4 mg acenocoumarol
Angiography
Van der Meer, −12 hours; or 6 mg phenprocoumon VKA: -/3.10; VKA: 58±8; VKA: 88.0; VKA v ASA: 0.99
12 months (per patient and
1993 (n=635) 24 hours (INR target: 2.8-4.8); ASA: ASA: -/2.80 ASA: 58±8 ASA: 87.0 (0.67 to 1.46)
per graft), 12 months
50 mg OD
Hockings, 1993 Angiography ASA: 100 mg OD; ASA: 3.14/2.56; ASA: 60±9; ASA: 94.0; ASA v C: 0.53
−7 days 6 months
(n=140) (per patient), 6 months C: matching placebo C: 3.52/2.79 C: 60±9 C: 92.3 (0.16 to 1.71)
ASA+clopi: 100 and 75 mg ASA+clopi:
Mujanovic, 2009 Immediately Angiography (per graft), ASA+clopi: 2.9/2.9; ASA+clopi v ASA:
3 months OD, respectively; ASA: 58±8.5; ASA: —
(n=20) postop 3 months ASA: 2.7/2.7 0.16 (0.03 to 0.98)
100 mg OD 60±8.5
ASA+clopi: 100 and 75 mg ASA+clopi: ASA+clopi: ASA+clopi:
Gao, 2009 64-MSCTA (per graft), ASA+clopi v clopi:
+1 day Unclear OD, respectively; clopi: 2.66/1.71; clopi: 61±10; clopi: 82.1;
(n=197) 12 months 0.52 (0.17 to 1.60)
75 mg OD 2.49/1.51 62±9.9 clopi: 83.3
ASA+clopi: 162 and
Angiography ASA+clopi: ASA+clopi: ASA+clopi:
Kulik, 2010 75 mg OD, respectively; ASA+clopi v ASA
0 day 12 months (per patient and 3.6/2.30; ASA: 65±7.5; ASA: 91.1;
(n=113) ASA: 162 mg OD and 1.34† (0.39 to 4.62)
per graft), 12 months 3.4/2.24 68±7.4 ASA: 87.7
matching placebo
Gao, 2010 ≤ +48 MSCTA (per graft), ASA+clopi v ASA:
3 months OD, respectively; ASA: 3.18/2.14; ASA: 58±8.3; ASA: 82.3;
(n=249) hours 3 months 0.55 (0.29 to 1.04)
100 mg OD 3.11/2.10 60±7.9 ASA: 83.8
Sun, 2010 +6 to MSCTA (per patient), ASA+clopi v ASA:
1 month OD, respectively; ASA: 4.03/2.35; ASA: 66±9.4; ASA: 93.9;
(n=99) 48 hours 50 days 1.20 (0.33 to 4.32)
81 mg OD 3.95/2.30 65±9.3 ASA: 86.0
Mannacio, 2012 +28± 64-MSCTA (per graft), ASA+clopi v ASA:
12 months OD, respectively; ASA: 3.1/1.78; ASA: 59±7.7; ASA: 73.3;
(n=300) 12 hours 12 months 0.55 (0.29 to 1.02)
100 mg OD 3.2/1.87 59±8.3 ASA: 75.3
ASA+tica: 81 mg OD and
ASA+tica: ASA+tica:
Saw, 2016 +58 to 128/320-MSCTA 90 mg BID, respectively; ASA+tica: 85.7; ASA+tica v ASA: 0.45
3 months 2.49/1.14; ASA: 62±7.5; ASA:
(n=70) 59 hours (per graft), 12 months ASA: 81 mg OD and ASA:88.6 (0.13 to 1.56)
3.43/1.69 63±9.7
matching placebo
ASA+clopi: 81 and 75 mg
ASA+clopi:
Slim, 2016 128-MSCTA (per graft), OD, respectively; ASA: ASA+clopi v ASA:
+6 hours 8 months 3.00/2.00; ASA: — —
(n=20) 12 months 81 mg OD and matching 0.76 (0.20 to 2.95)
3.38/2.38
placebo
ASA+tica v tica: 0.70
ASA+tica: ASA+tica:
ASA+tica: 100 mg OD and ASA+tica: 79.8; (0.44 to 1.09); ASA+tica
Zhao, 2018 +0 to MSCTA (per graft), 3.76/2.90; tica: 64±8.2; tica:
12 months 90 mg BID, respectively; tica: 80.7; v ASA: 0.47 (0.27 to
(n=500) 24 hours 12 months 3.83/2.94; 63±8.3; ASA:
tica: 90 BID; ASA: 100 OD ASA: 84.9 0.80); tica v ASA: 0.68
ASA: 3.76/2.92 64±8.1
(0.46 to 1.01)
ASA+tica: 100 mg OD and ASA+tica:
Xu, 2018 MSCTA (per graft), 90 mg BID, respectively; ASA+tica: -/2.51; 59±8.9; ASA+tica: 77.1; ASA+tica v ASA+clopi:
NR 1 month
(n=140) 1 month ASA+clopi: 100 mg OD and ASA+clopi: -/2.59 ASA+clopi: ASA+clopi: 72.9 0.81 (0.24 to 2.73)
75 mg OD, respectively 60±7.5
ASA+riva: v riva: 1.24
ASA+riva: 100 mg OD and ASA+riva:
ASA+riva: -/2.00; ASA+riva: 78.3;
(0.87 to 1.78); ASA+riva
Lamy, 2018 +4 to MSCTA (per graft), 2.5 mg BID, respectively; 66±7.8; riva:
NR riva: -/2.00; riva: 81.2; v ASA: 1.13 (0.80 to
(n=1448) 14 days 12 months riva: 5 mg BID; 65±7.9; ASA:
ASA: -/2.00 ASA: 82.3 1.62); riva v ASA: 0.91
ASA: 100 mg OD 66±8.5
(0.63 to 1.33)
Values are presented as mean±standard deviation or No (%) unless stated otherwise. ASA=aspirin; BID=twice a day; C=control; CABG=coronary artery bypass graft; clopi=clopidogrel;
INR=international normalised ratio; MSCT=multislice computed tomography angiography; NR=not reported; OAC=oral anticoagulation; OD=once a day; OR=odds ratio; riva= rivarox-
aban; SVG=saphenous vein graft; SVGF=saphenous vein graft failure; tica=ticagrelor; TID=three times a day; VKA=vitamin K antagonist.
*Data that were not reported in the original studies were calculated from total number of grafts/number of patients enrolled.
†Calculated from Hage24 reporting long term data.

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according to prespecified inclusion criteria. The Risk of bias and certainty assessment
full text reports of potentially relevant studies were We assessed the risk of bias in included studies by
retrieved, and data on study and patient characteristics, using the Cochrane Collaboration tool for randomised
treatment strategies, and results of all included studies trials 2.044 for each outcome. We graded the certainty
were then independently extracted (KS and AAH/ of direct and network evidence by using the Grade of
TC) using a data extraction form. Any discrepancies Recommendations Assessment, Development, and
were resolved by consensus after consulting a third Evaluation (GRADE) for network meta-analysis.45
investigator (RB).
Statistical analyses
Outcome measures We performed a frequentist network meta-analysis
The primary efficacy outcome was the incidence of of aggregate data to obtain network estimates for
saphenous vein graft failure, defined as participants the aforementioned outcomes of interest. The model
with at least one occluded saphenous vein graft as framework used random effects to allow for apparent
assessed by either invasive angiogram or computed heterogeneity among studies in treatment comparison
tomography (table 1 and supplementary table 1). effects. We conducted a pairwise meta-analysis to
We prespecified a sequence in the protocol23 in case generate direct estimates for outcomes by using a
the overall preferred definition of total occlusion random effects model. Transitivity assumption, the
was not used. Because not all the included studies distribution of patient and study characteristics that
expressed saphenous vein graft failure on a per modify treatment effects (effect modifiers) across
patient basis, we also included studies that reported treatment comparisons, was explored to assess
per graft data in our base case analysis to increase whether these characteristics were sufficiently similar
the totality of evidence. We made the decision about between comparisons. Additionally, we evaluated
combining per patient and per graft data after we incoherence assumption (the statistical disagreement
compared the results from per patient14-16 25-37 and per between direct and indirect evidence in a closed loop)
graft14-17 24-36 38-40 (accounting for clustering effects) locally using a loop specific approach, and globally
meta-analyses. The results for magnitude and direc- using a design by treatment interaction model.46 We
tion of effect estimates were consistent and there used surface under the cumulative ranking (SUCRA)47
were large overlapping 95% confidence intervals of to rank the intervention’s hierarchy in the network
effect sizes in most comparisons. Because a sensitivity meta-analysis and then we estimated mean ranks. We
analysis showed the per graft network meta-analysis used the comparison adjusted funnel plot to explore
and the base case network meta-analysis did not differ the potential for publication bias.47
substantially, the inference for our base case analysis We performed sensitivity analyses to assess the
was made on per patient basis. This approach is robustness of the model for the primary outcomes.
clinically preferable given that treatments are applied We visually compared the results of the base case
to patients (and not grafts). analysis with those of the per graft and in-trial data
We calculated and used effective sample size instead (to exclude the legacy effect of drug interventions)
of originally reported outcome data to account for analyses, and excluding trials with off pump coronary
clustering effects for per graft data.41-43 The effective artery bypass graft only. We performed an “all missing
sample size was estimated by using a design effect failure” analysis to explore the impact of missing data;
that includes an intra cluster correlation coefficient.43 this analysis assumed that all missing patients had a
We obtained the intra cluster correlation coefficient negative event.48 All outcomes of interest were binary
needed to calculate the effective sample size from and the relative treatment effects were reported as odds
an external source.42 The size of the intra cluster ratios with 95% confidence intervals. All analyses were
correlation coefficient and the number of observations done in Stata version 14 using the network command.
sampled within each cluster influence the power
of the study.43 We used an intra cluster correlation Patient and public involvement
coefficient of 0.177 for this review.42 Additionally, if There was no patient or public involvement around
studies reported the incidence of saphenous vein graft the research question or conception and design of the
failure at multiple time points, we included the longest study. Because of the nature of the study, there was no
available follow-up period in our base case analysis. patient or public involvement in any recruitment or
The primary safety outcome was the incidence of conduction of the study. There was no patient or public
major bleeding. Secondary outcomes were all cause involvement in measuring the outcomes, in providing
mortality and myocardial infarction. These outcomes interpretations of the findings, or writing of the results.
were binary and defined according to the definitions
of the study authors (table 1 and supplementary table Results
1). We collected data on major adverse cardiac and Data selection
cerebrovascular events, heart failure, minor bleeding, Our systematic search identified 3266 citations
red blood cell transfusion, and admission to hospital published between 1979 and 2019. Of these, we
owing to a cardiovascular cause; however, because included 21 articles14-17 24-40 that related to 20
these data were sparse, we did not report them in our unique parallel group randomised controlled trials
study. in the network meta-analysis. These trials comprised

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4803 participants and investigated nine different for different interventions compared with aspirin
interventions (eight active and one placebo) (fig 1); monotherapy. Network meta-analysis showed that dual
three trials had three eligible arms and the remaining antiplatelet therapy with either aspirin plus ticagrelor
trials had two eligible arms.16 17 26 (odds ratio 0.50, 95% confidence interval 0.31 to 0.79,
The study sample size ranged from 20 to 1448 number needed to treat 10) or aspirin plus clopidogrel
patients, patient age ranged from 44 to 83 years, (0.60, 0.42 to 0.86, 19) was more efficacious than
83% were male, and 83% underwent elective (stable aspirin monotherapy to prevent saphenous vein graft
coronary artery disease) surgery. The number of failure. Pooled effect sizes also suggested that all active
saphenous vein grafts ranged from 1.14 to 3.60 per interventions reduced saphenous vein graft failure
patient, and drug interventions were started from compared with placebo. However, the evidence does
seven days before coronary artery bypass graft surgery not support the efficacy of clopidogrel monotherapy in
to 14 days after the procedure. The duration of follow- reducing saphenous vein graft failure compared with
up ranged from one month to eight years. Assessment placebo (fig 3, top panel). According to SUCRA values,
of saphenous vein graft failure was performed by the top two ranked interventions for the reduction of
either invasive angiography or computed tomography saphenous vein graft failure were dual antiplatelet
(table 114-17 24-40 and supplementary table 1). therapy with aspirin plus ticagrelor (94.4) and aspirin
Across comparisons, the distribution of baseline plus clopidogrel (85.3; table 3).
characteristics by treatment was generally balanced, In our sensitivity analyses we used per graft data,
except for the type of coronary artery bypass graft excluded off pump only trials,35 36 and accounted
technique (on pump versus off pump coronary artery for missing outcome data. The study effect estimates
bypass graft), and the timing of drug initiation (table (supplementary table 2) and SUCRA values
2). Information on antifibrinolytic use was not reported (supplementary table 3) did not substantially
because of limited data. change. One of the included studies in our network
meta-analysis reported post-trial24 (used in the base
Mixed treatment meta-analyses case analysis) and in-trial37 data. We performed a
Primary efficacy outcome sensitivity analysis to explore the legacy effect of drug
The network of treatment comparisons for saphenous interventions by using in-trial data. Effect estimates
vein graft failure included nine individual nodes (fig and SUCRA values did not substantially change
2, top panel). Each of the nodes represents placebo or compared with the base case analysis (supplementary
different drug interventions; aspirin was the most well tables 2 and 3, respectively).
connected intervention with all other interventions
directly linked to it, except for clopidogrel monotherapy. Primary safety outcome
Figure 3 (top panel) shows network estimates of Eleven randomised controlled trials15-17 24 26 31 33 34 35 39 40
treatment effect on saphenous vein graft failure comprising 3745 patients reported the incidence
Table 2 | Summary of baseline and procedural characteristics of patients across different treatment comparisons
Treatment comparison (No of RCTs)
ASA v VKA v Riva v ASA+riva ASA+riva ASA+clopi ASA+clopi ASA+tica ASA+clopi
Characteristics placebo control VKA v ASA Tica v ASA ASA v aspirin v riva v ASA v clopi v ASA v ASA+tica ASA+tica v
(No of RCTs*) (n=7) (n=2) (n=2) (n=1) (n=1) (n=1) (n=1) (n=6) (n=1) (n=2) (n=1) tica (n=1)
Age (n=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 1212/1278 129/148 632/722 275/332 773/946 774/965 785/985 599/736 163/197 336/404 105/140 183/217
(n=16) (95) (87) (88) (83) (82) (80) (80) (81) (83) (83) (75) (84)
Diabetes 45/560 18/111 74/722 142/332 412/946 413/965 393/985 168/756 108/197 163/404 94/140 124/217
(n=14) (8) (16) (10) (43) (44) (43) (40) (22) (55) (40) (67) (57)
Hypertension 528/1218 20/111 250/722 242/332 417/756 125/197 301/404 92/140 176/217
NR NR NR
(n=15) (43) (18) (35) (73) (55) (64) (75) (66) (81)
Dyslipidaemia 27/116 271/616 243/332 426/736 41/197 299/404 245/292
NR NR NR NR NR
(n=9) (23) (44) (73) (58) (21) (74) (84)
Prior MI 703/1076 74/111 401/722 103/332 351/946 350/965 355/985 253/623 105/197 108/404 53/140 102/217
(n=13) (65) (67) (56) (31) (37) (36) (36) (41) (53) (27) (38) (47)
Prior PCI 77/524 24/197 8/70 18/140
NR NR NR NR NR NR NR NR
(n=5) (15) (12) (11) (13)
Prior CVA 35/332 29/946 36/965 37/985 16/436 48/334 75/217
NR NR NR NR NR
(n=3) (11) (3.1) (4.0) (3.8) (3.7) (14) (35)
OPCABG 862/862 37/37 616/616 82/332 235/946 228/965 245/985 321/776 124/197 85/334 26/140 88/217
(n=16) (100) (100) (100) (25) (25) (24) (25) (41) (63) (25) (19) (41)
Elective surgery 932/1006 73/145 695/755 332/332 582/946 599/965 601/985 776/776 186/197 381/404 140/140 217/217
(n=16) (93) (50) (92) (100) (61) (62) (61) (100) (94) (94) (100) (100)
Time of drug 14 preop 3-4 12 preop Within 24 4-14 4-14 4-14 Immediately Within 24- Within 24
initiation to 5 postop postop hours to 4 postop postop postop postop postop to 48 1 day 59 postop NR postop
(range) (n=20) days days postop days hours days days days hours hours hours
Values presented as mean±standard deviation or No (%) unless stated otherwise. ASA=aspirin; clopi=clopidogrel; CVA=cerebrovascular accident; MI=myocardial infarction; NR=not reported;
OPCABG=off pump coronary artery bypass graft; PCI=percutaneous coronary intervention; RCT=randomised controlled trial; riva=rivaroxaban; tica=ticagrelor; VKA=vitamin K antagonist.
*Number of RCTs reporting data.

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of major bleeding. The network diagram of eligible substantial statistical evidence (fig 3, bottom panel).
treatment comparisons included eight individual nodes According to SUCRA values, after placebo (84.4), the
(fig 2, bottom panel). Each of the nodes represents top ranked intervention associated with fewer major
different active interventions or placebo, in which aspirin bleeding events was dual antiplatelet therapy with
monotherapy was the most well connected intervention aspirin plus clopidogrel (66.5; table 3).
with all other interventions directly linked to it. Figure Sensitivity analyses that excluded one off pump
3 (bottom panel) shows network estimates of treatment only trial,35 accounted for missing outcome data, and
effect on major bleeding for different interventions used in-trial data did not show substantial changes
compared with aspirin monotherapy. Network meta- in study effect estimates (supplementary table 4) and
analyses showed no evidence of differences among all SUCRA values (supplementary table 5). When we used
possible treatment comparisons. Pooled effect sizes in-trial data for analysis, aspirin monotherapy and its
also suggested that all active interventions increased combination with rivaroxaban obtained a higher rank
bleeding compared with placebo, although without (supplementary table 5).
Saphenous vein gra failure

Aspirin and ticagrelor
Vit K A
1 trial Aspirin and
2 trials clopidogrel
Clopidogrel 2 trials 6 trials

1 trial
Aspirin
1 trial
2 trials
7 trials
Placebo 1 trial 1 trial 1 trial
Rivaroxaban
Aspirin and rivaroxaban 1 trial

Ticagrelor
Major bleeding
1 trial Aspirin and

Vit K A clopidogrel
2 trials
2 trials
4 trials
1 trial
1 trial Aspirin
2 trials
Placebo
1 trial 1 trial
1 trial
Aspirin and 1 trial Rivaroxaban

rivaroxaban
Ticagrelor
Fig 2 | Network of treatment comparisons for saphenous vein graft failure (primary efficacy outcome) and major
bleeding (primary safety outcome). Each node represents different active interventions or placebo. Size of nodes
is proportional to number of studies comparing respective nodes. Increasing thickness of lines between nodes
is proportional to number of randomly assigned patients contributing to direct comparisons. Vit K A=vitamin K
antagonist

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Secondary outcomes Risk of bias and certainty of evidence

Ten randomised controlled trials14 15 25 26 29 30 31 33 37 39 We judged two randomised controlled trials27 39 to
comprising 1921 patients reported all cause mortality, have a high risk of bias arising from the randomisation
and 12 randomised controlled trials14-17 24 26 31 33 34 35 39 40 process and five randomised controlled trials24-26 30 40
comprising 3994 patients reported myocardial infarction. to have a high risk of bias because of missing outcome
Figure 4 shows networks of treatment comparisons for data (supplementary table 7). Five of the trials26 29 36 38 39
secondary outcomes. Figure 5 summarises results had some concerns about measurement of the outcome
for secondary outcomes. Network meta-analyses and three randomised controlled trials27 36 38 had
showed no evidence of differences among all possible some concerns about bias from selective reporting of
comparisons for secondary outcomes (all cause outcomes. We judged only five unique trials15 16 35 37 40
mortality and myocardial infarction). Supplementary to have a low risk of bias due to deviation from
table 6 presents SUCRA values. The included intended interventions. Overall, we judged eight trials
randomised controlled trials sparsely reported (40%)24-28 30 39 40 to have a high risk of bias, primarily
other prespecified secondary outcomes; therefore, owing to failure to blind and missing outcome data.
network meta-analyses were not conducted for these Of trials reporting incomplete outcome data, 10
outcomes. trials14-17 27 33-35 37 39 performed intention to treat
Saphenous vein gra failure

0.64 0.56 0.56 0.45 0.48 0.28 0.60 0.34
Placebo
(0.19 to 2.16) (0.42 to 0.76) (0.37 to 0.86) (0.26 to 0.79) (0.30 to 0.77) (0.16 to 0.48) (0.38 to 0.98) (0.21 to 0.54)
0.88 0.88 0.70 0.75 0.44 0.93 0.52
Clopidogrel
(0.27 to 2.84) (0.26 to 2.98) (0.20 to 2.47) (0.22 to 2.55) (0.13 to 1.52) (0.27 to 3.16) (0.17 to 1.60)
1.00 0.80 0.85 0.50 1.06 0.60
Aspirin
(0.71 to 1.41) (0.49 to 1.29) (0.59 to 1.23) (0.31 to 0.79) (0.75 to 1.50) (0.42 to 0.86)
Vitamin K 0.80 0.85 0.50 1.06 0.60
antagonists (0.44 to 1.44) (0.51 to 1.41) (0.28 to 0.88) (0.65 to 1.73) (0.36 to 0.98)
1.07 0.62 1.33 0.75
Ticagrelor
(0.58 to 1.95) (0.37 to 1.05) (0.73 to 2.40) (0.42 to 1.35)
0.58 1.25 0.70
Rivaroxaban
(0.32 to 1.05) (0.87 to 1.78) (0.42 to 1.18)
Aspirin + 2.13 1.20
Ticagrelor (1.20 to 3.85) (0.69 to 2.09)
Aspirin + 0.56
Rivaroxaban (0.34 to 0.93)
Aspirin +
Clopidogrel
Major bleeding
2.98 5.31 4.86 4.45 2.96 5.74 2.53
Placebo
(0.31 to 28.2) (0.56 to 50.2) (0.20 to 119) (0.42 to 47.0) (0.28 to 31.8) (0.31 to 106) (0.21 to 30.0)
1.78 1.63 1.50 0.99 1.93 0.85
Aspirin
(0.95 to 3.34) (0.17 to 15.9) (0.73 to 3.04) (0.46 to 2.14) (0.30 to 12.4) (0.30 to 2.37)
Vitamin K 0.91 0.84 0.56 1.08 0.48
0.92 0.61 1.18 0.52
Ticagrelor
(0.08 to 9.93) (0.06 to 6.71) (0.24 to 5.91) (0.05 to 5.39)
0.66 1.29 0.57
Rivaroxaban
(0.33 to 1.33) (0.18 to 9.42) (0.16 to 1.98)
Aspirin + 1.94 0.86
Rivaroxaban (0.26 to 14.5) (0.24 to 3.08)
Aspirin + 0.44
Ticagrelor (0.07 to 2.97)
Aspirin +
Clopidogrel
Fig 3 | Network meta-analysis and certainty of evidence for saphenous vein graft failure (primary efficacy outcome) and major bleeding (primary
safety outcome). Results are odds ratios (95% confidence intervals) from the network meta-analysis between the column defining intervention
and row defining intervention. Significant results are in bold. Certainty of evidence is also given: green=moderate certainty evidence, yellow=low
certainty evidence, red=very low certainty evidence

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Table 3 | Summary of network meta-analysis estimates of effects, confidence intervals, and certainty of evidence for the comparison of different
antithrombotic drugs in patients undergoing coronary artery bypass graft surgery
Anticipated absolute effect, per 1000 patients†
Relative effect, (95% CI)
Comparator (reference): odds ratio (95% ASA Other NNT/NNH
ASA monotherapy CI)* monotherapy strategies Difference Certainty of evidence* (95% CI) SUCRA‡
SVGF§ (total studies: 20 RCTs; total participants: 4803):
ASA+tica 0.50 (0.31 to 0.79), 100 fewer ⊕⊕⊕○, moderate, NNT: 10
230 130 94.4
(2 RCTs; 420 participants) network estimate (145 to 39 fewer) due to indirectness (7 to 26)
ASA+clopi 0.60 (0.42 to 0.86), 54 fewer ⊕⊕⊕○, moderate, NNT: 19
150 96 85.3
(6 RCTs; 1118 participants) network estimate (81 to 18 fewer) due to indirectness (13 to 55)
Not calculated
ASA+riva 1.06 (0.75 to 1.50), 5 more ⊕⊕○○, low, due to
99 104 (non-statistically 32.9
(1 RCT; 1401 participants) network estimate (23 fewer to 43 more) indirectness and imprecision
significant)
Not calculated
Tica monotherapy 0.80 (0.49 to 1.29), 43 fewer ⊕⊕○○, low, due to
significant)
Not calculated
Riva monotherapy 0.85 (0.59 to 1.23), 14 fewer ⊕⊕○○, low, due to
significant)
⊕○○○, very low, due to Not calculated
VKA 1.00 (0.71 to 1.41), 0 fewer
284 284 risk of bias, indirectness, (non-statistically 39.7
(2 RCTs; 601 participants) network estimate (64 fewer to 75 more)
and imprecision significant)
Clopi monotherapy (no direct 12 more
1.14 (0.35 to 3.69) 100¶ 112 intransitivity, indirectness, (non-statistically 36.2
evidence, indirect evidence only) (63 fewer to 191 more)
Placebo 1.77 (1.31 to 2.39), 122 more ⊕⊕⊕○, moderate, due to
255 377 NNH: 9 (6 to 19) 3.3
(7 RCTs; 831 participants) network estimate (55 to 195 more) indirectness
Major bleeding (total studies: 11 RCTs; total participants: 3745):
Not calculated
Placebo 0.34 (0.04 to 3.23), 5 fewer ⊕⊕○○, low, due to
(2 RCTs; 385 participants) network estimate (7 fewer to 16 more) indirectness and imprecision
significant)
Not calculated
ASA+clopi 0.85 (0.30 to 2.37), 5 fewer ⊕⊕○○, low, due to
(5 RCTs; 518 participants) network estimate (23 fewer to 42 more) indirectness and imprecision
significant)
Not calculated
ASA+riva 0.99 (0.46 to 2.14), 0 fewer ⊕⊕⊕○, moderate, due to
(1 RCT; 965 participants) network estimate (15 fewer to 30 more) imprecision
significant)
Not calculated
Riva 1.50 (0.73 to 3.04), 13 more ⊕⊕⊕○, moderate,
(1 RCT; 946 participants) network estimate (7 fewer to 53 more) due to imprecision
significant)
Not calculated
Tica 1.63 (0.17 to 15.9), 2 more ⊕⊕⊕○, moderate,
(1 RCT; 332 participants) network estimate (2 fewer to 43 more) due to imprecision
significant)
Not calculated
ASA+tica 1.93 (0.30 to 12.4), 11 more ⊕⊕⊕○, moderate,
(2 RCTs; 404 participants) network estimate (9 fewer to 123 more) due to imprecision
significant)
VKA 1.78 (0.95 to 3.34), 31 more
42 74 risk of bias, indirectness (non-statistically 24.4
(2 RCTs; 755 participants) network estimate (2 fewer to 88 more)
ASA=aspirin; clopi=clopidogrel; NNH=number needed to harm; NNT=number needed to treat; RCT=randomised controlled trial; riva=rivaroxaban; SUCRA=surface under the cumulative ranking;
SVGF=saphenous vein graft failure; tica=ticagrelor; VKA=vitamin K antagonist.
*Significant results are in bold.
†Data obtained directly from study sample (studies reporting outcome data), unless stated otherwise.
‡Larger SUCRA values indicate better interventions and higher hierarchy ranks are in bold.
§Saphenous vein graft failure (base case analysis), range of follow-up between one month and eight years.
¶Assumed risk (risk was assumed because of lack of direct evidence).
analysis, and two of these16 27 clearly reported the and network estimates. The network evidence for dual
use of intention to treat analysis with worst case antiplatelet therapy with aspirin plus ticagrelor and
assumptions for imputation of missing data. It was aspirin plus clopidogrel was of moderate certainty
unclear how the remaining trials with incomplete data compared with aspirin monotherapy. The symmetrical
handled missing outcome data. comparison adjusted funnel plot shows neither
Figure 3 (top panel) also provides the certainty of evidence of publication bias for placebo controlled
evidence of network estimates for saphenous vein trials nor small study effects (supplementary figure
graft failure. We downgraded evidence certainty to 1). When we performed a sensitivity analysis that
low or very low for most comparisons, mainly because excluded studies considered at serious risk of bias,
of study limitations owing to incomplete outcome the effect estimates did not change substantially,
data, imprecision, indirectness, and the possibility except for aspirin plus clopidogrel versus vitamin
of intransitivity. Supplementary tables 8 and 9 K antagonist, which became non-significant
summarise certainty of evidence for direct, indirect, (supplementary figure 2).

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All cause mortality

Aspirin and clopidogrel
1 trial
3 trials
Aspirin and
ticagrelor
Aspirin
2 trials
Vit K A
4 trials
2 trials
Placebo
Myocardial infarction
1 trial Aspirin and

Vit K A clopidogrel
2 trials
2 trials
1 trial 5 trials
1 trial
2 trials Aspirin
Placebo
1 trial
1 trial 1 trial
Aspirin and 1 trial Rivaroxaban

rivaroxaban
Ticagrelor
Fig 4 | Network of treatment comparisons for secondary outcomes all cause mortality and myocardial infarction.
Each node represents different active interventions or placebo. Size of nodes is proportional to number of studies
comparing respective nodes. Increasing thickness of lines between nodes is proportional to number of randomly
assigned patients contributing to direct comparisons. Vit K A=vitamin K antagonist
We also downgraded the certainty of evidence to low Network assumptions

or very low for most comparisons of clinical outcomes, The distribution of potential effect modifiers was not
including major bleeding, myocardial infarction, and balanced across comparisons; however, the evidence
mortality (fig 3, bottom panel, fig 5, and supplementary of intransitivity was inconclusive because of missing
tables 8 and 9). However, comparisons with moderate data in several comparisons (table 2). While we could
certainty evidence should be interpreted with caution not rule out the possibility of intransitivity (lack of
mainly because of inconsistency and publication bias. similar characteristics across the studies and treatment
We could not thoroughly assess inconsistency because comparisons), between-trial heterogeneity (τ2) was low
many of the comparisons consisted of a single study. in all included analyses compared with the expected
Additionally, we could not assess publication bias value reported in the literature.49 Supplementary table
for secondary outcomes because this network meta- 9 shows direct and indirect estimates, and τ2. Loop
analysis was designed to exclude studies that did not specific approach (supplementary table 10) and design
evaluate our primary efficacy outcome (saphenous by treatment interaction models (supplementary table
vein graft failure), regardless of reported secondary 11) showed no evidence of incoherence between direct
outcomes (supplementary tables 8 and 9). and indirect comparisons for all analyses.

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All cause mortality

1.77 1.04 1.24 1.24
Placebo
(0.52 to 5.99) (0.23 to 4.72) (0.01 to 114) (0.13 to 11.5)
0.59 0.70 0.70
Aspirin
(0.19 to 1.87) (0.01 to 54.3) (0.11 to 4.50)
Vitamin K 1.19 1.19
antagonists (0.01 to 107) (0.13 to 10.6)
Aspirin + 1.00
Ticagrelor (0.02 to 51.1)
Aspirin +
Clopidogrel
0.49 0.45 0.33 0.47 0.34 0.25 0.34
Placebo
(0.11 to 2.11) (0.10 to 2.00) (0.03 to 3.28) (0.08 to 2.84) (0.04 to 2.84) (0.04 to 1.73) (0.06 to 2.05)
0.92 0.68 0.96 0.70 0.52 0.71
Aspirin
(0.52 to 1.63) (0.12 to 3.97) (0.33 to 2.75) (0.15 to 3.22) (0.15 to 1.80) (0.26 to 1.96)
Vitamin K 0.74 1.04 0.76 0.57 0.77
1.40 1.03 0.77 1.04
Ticagrelor
(0.18 to 10.93) (0.16 to 6.80) (0.09 to 6.58) (0.14 to 7.68)
0.74 0.55 0.74
Rivaroxaban
(0.12 to 4.68) (0.16 to 1.88) (0.17 to 3.20)
Aspirin + 0.74 1.00
Ticagrelor (0.10 to 5.27) (0.18 to 5.74)
Aspirin + 1.35
Rivaroxaban (0.27 to 6.70)
Aspirin +
Clopidogrel
Fig 5 | Network meta-analysis and certainty of evidence for secondary outcomes all cause mortality and myocardial infarction. Results are odds ratios
(95% confidence intervals) from the network meta-analysis between the column defining intervention and the row defining intervention. Certainty of
evidence is also given: green=moderate certainty evidence, yellow=low certainty evidence, red=very low certainty evidence
Discussion clustering effects of data expressed on a per graft basis,

Principal findings and made an inference at the patient level, which
This systematic review included 20 parallel group improved the applicability of the results in light of a
randomised controlled trials of 4803 patients under- newer P2Y12 inhibitor (ticagrelor) and direct factor Xa
going coronary artery bypass graft. The review com- inhibitor (rivaroxaban). Our analysis adds new data
pared eight active antithrombotic interventions in a on the use of dual antiplatelet therapy with aspirin
single framework to assess saphenous vein graft failure. plus ticagrelor and direct oral anticoagulation with
The results of this network meta-analysis suggest that rivaroxaban, thereby providing a better understanding
among active interventions and based on moderate of the role of these drug interventions to prevent
certainty evidence, dual antiplatelet therapies with saphenous vein graft failure after coronary artery
aspirin plus ticagrelor or aspirin plus clopidogrel were bypass graft surgery.
the most efficacious treatment regimens to prevent The certainty of evidence for the saphenous vein
saphenous vein graft failure compared with aspirin graft failure endpoint was considered low or moderate
monotherapy. However, the tradeoff was an increased for making a recommendation for most treatments
risk of major bleeding, although the risk did not differ compared with aspirin. Therefore, additional well
among the drug interventions. designed research might change the findings.
For clinical (secondary) outcomes, the results of our
Strengths and limitations of the study network meta-analysis show no differences in effect
The strength of our analysis is its robust design and estimates among multiple treatment comparisons;
transparency. We prespecified the research question nonetheless, these were not our prespecified primary
and published a peer reviewed protocol23 for this outcomes. Interestingly, the recently published and
systematic review of published randomised controlled prematurely terminated trial that compared ticagrelor
trials of drug interventions to prevent saphenous vein with aspirin after coronary artery bypass graft surgery
graft failure after coronary artery bypass graft surgery. showed no important differences in major adverse
To increase the totality of evidence, we accounted for cardiovascular events or bleeding between the

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monotherapies.50 These findings support the need for differences in treatment effects across doses. Fifth, the
studies that evaluate dual antiplatelet therapy after trials in which most of patients underwent off pump
coronary artery bypass graft surgery. Although our coronary artery bypass graft surgery,16 35 36 the dose of
study might be underpowered to detect differences aspirin (monotherapy or dual antiplatelet therapy) was
in clinical outcomes, further and larger randomised 81-100 mg daily. However, we were unable to compare
controlled trials that compare all the relevant and confirm the potential benefit of higher doses (such
antithrombotic strategies after coronary artery bypass as 160-325 mg) of aspirin in patients undergoing
graft surgery will be difficult to undertake with a mixed off pump procedures because of a lack of off pump
treatment comparison design. Therefore, our study is trials using these doses of aspirin. Nevertheless, when
clinically meaningful and contributes up to date data combined with a P2Y12 inhibitor, the recommended
to guide future directions in preventing saphenous dose of aspirin is less than 100 mg daily.
vein graft failure after coronary artery bypass graft Sixth, our network meta-analysis included trials
surgery. published over a 39 year period, which might not reflect
In this study, we used a frequentist framework the current clinical practice; for example, patient
to perform the analysis as opposed to a Bayesian characteristics, surgical techniques (eg, off pump
approach because the results of Bayesian analysis with coronary artery bypass graft), drug regimens (early
non-informative priors are numerically equivalent trials were more likely to compare against placebo and
to frequentist results. Although informative priors later trials were more likely to be active comparator
would make Bayesian methods more appealing than trials), and secondary prevention strategies18 (sta-
a frequentist framework, especially when dealing tins, angiotensin converting enzyme inhibitors, or
with small studies, such priors were not available. angiotensin receptor blockers and β blockers). There-
Therefore, the risk of using inaccurate informative fore, changes in adjunct medical treatment over time
priors can cause even more damage to the validity of could potentially affect treatment estimates. Post hoc
the results. meta-regression analysis did not show evidence of
Our study has several limitations. First, the quality an association between treatment effect and year of
of our analysis is limited by the inherent limitations publication for some treatments. However, it was not
of individual included trials. In particular, patient possible to estimate the effect of publication year for
level data were not available, which precluded all treatments owing to multicollinearity and missing
adjustment for any differences in clinical setting; linkage (supplementary table 12). We performed a
for example, stable coronary artery disease versus sensitivity analysis stratified by publications before
acute coronary syndromes, elective versus urgent and after the year 2000 (supplementary figure 3), and
surgery, and on pump versus off pump coronary the findings did not change the treatment effect when
artery bypass graft surgery. In this study, more than the results were split by more recent trials. Finally,
80% of the patients underwent elective coronary legacy or post trial persistent treatment effect was
artery bypass graft surgery; moreover, in the acute explored. While the sensitivity analysis did not change
coronary syndrome setting, there is consensus among the effect estimates, this was based on a single study
international guidelines that dual antiplatelet therapy that reported saphenous vein graft failure at one37and
is resumed soon after surgery and continued for one eight24 years.
year (class I).2 51 52 Also, we were unable to perform
competing risk analysis. If we had reported measures Comparison with other studies
of effects that reflect time to event (that is, hazard Aspirin monotherapy is currently recommended
ratio), the results would have been more informative. for patients with stable coronary artery disease
However, the studies that were eligible for this review after coronary artery bypass graft surgery to reduce
did not report these measures. saphenous vein graft failure.18 In patients who present
Second, although we presented full details about the with acute coronary syndromes, dual antiplatelet
risk of bias of all included trials (supplementary table therapy is recommended to be resumed soon after
7), many trials did not report adequate information coronary artery bypass graft surgery.2 51 52 However,
about allocation sequence concealment, proportions of there is a lack of evidence that dual antiplatelet therapy
and reasons for missing outcome data, and how trials is associated with a decrease in thromboembolic
handled missing data. This lack of information could complications or mortality in patients with stable
have led to inaccurate interpretation of the certainty of coronary artery disease undergoing coronary artery
evidence. Third, different trials used different outcome bypass graft surgery.53 Few observational and
definitions and also various imaging follow-up protocols, randomised data suggest that additional drug
which could have threatened the internal validity of our intervention with dual antiplatelet therapy reduces
network meta-analysis. Although our sensitivity analysis the risk of saphenous vein graft failure. This effect
showed no substantial differences in effect estimates appears to be more pronounced in patients undergoing
between per graft and per patient analyses for most off pump coronary artery bypass graft surgery than
comparisons, the credibility of this data driven approach on pump coronary artery bypass graft surgery, or for
remains unclear. Fourth, we combined studies using arterial graft recipients.54 55
different doses of the same drug intervention in the same The 2016 American guidelines51 recommend that
node, and assumed that there would be no systematic in patients with stable coronary artery disease, aspirin

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81 mg (75-100 mg) plus clopidogrel (started early after of myocardial infarction or repeat revascularisation.
surgery) for 12 months after coronary artery bypass However, not all saphenous vein grafts are the same
graft might be reasonable to improve saphenous vein because of individual graft quality or technical (that
graft patency (class IIb, level of evidence B). Conversely, is, anastomoses) matters. Additionally, the grafts
the 2017 European guidelines state that there is depend on which are the target vessels, the severity of
insufficient evidence to generally recommend dual stenosis and ischemia,60 and the territory and amount
antiplatelet therapy to reduce saphenous vein graft of myocardium being supplied by a given graft. Hence,
failure.53 To mitigate the relative hypercoagulable state saphenous vein graft failure will occur because
that off pump patients experience, the 2015 American of physiological or functional causes rather than
Heart Association scientific statement18 recommends saphenous vein graft driven thrombotic mechanisms,
the combination of aspirin and clopidogrel after off yet without apparent clinical consequence.60 61 Lopes
pump coronary artery bypass graft surgery (class I, and colleagues61 showed that saphenous vein graft
level of evidence A). However, the European guidelines failure was associated with an increased risk for the
state that there is weak evidence to support dual composite of death, myocardial infarction, or repeat
antiplatelet therapy in this subset of patients,53 and revascularisation at four years after the angiogram.
the American guidelines51 do not comment on this. However, this association was mainly because of repeat
The clinical benefits of adding a P2Y12 inhibitor revascularisation; there were no differences in terms
to aspirin originate from the Clopidogrel in Unstable of death or the composite of death and myocardial
Angina to Prevent Recurrent Events (CURE) trial. infarction among individuals with and without
Participants with non-ST elevation acute coronary saphenous vein graft failure.61 These findings highlight
syndromes who were allocated to receive aspirin the confounded association between saphenous
plus clopidogrel experienced a major reduction in vein graft failure and major adverse cardiovascular
the composite outcome of death from cardiovascular events. Therefore, when saphenous vein graft failure is
causes, non-fatal myocardial infarction, or stroke, and accompanied by clinical symptoms,61 for example new
a range of related ischaemic events.56 However, there onset angina and progressive symptoms of angina,
was a tradeoff of increased risk of bleeding, and most or hospital admission for acute coronary syndromes
of the major bleeding events were gastrointestinal and leading to revascularisation, this could be more
arterial access site bleeds.56 In our analysis, although relevant for prognosis and patient preferences and
the occurrence of major bleeding with aspirin plus values.
ticagrelor was not statistically significant compared Not all the included trials reported the actual data
with aspirin alone, the network estimates showed an on duration of treatment. Therefore, patients might
odds ratio of 1.93, and wide 95% confidence intervals have received different durations of antithrombotic
(0.30 to 12.4) compared with aspirin plus clopidogrel treatments, which resulted in patient level covariate
(0.85, 0.30 to 2.37). The lack of different doses of effects. Post hoc meta-regression analysis did not
clopidogrel precludes further analysis. Notably, the show evidence of an association between duration of
combination of aspirin plus rivaroxaban 2.5 mg treatment (originally prespecified by the trial authors,
twice daily or rivaroxaban 5 mg twice daily alone did not actual duration) and treatment effect for some
not reduce saphenous vein graft failure compared drug interventions; however, it was not possible
with aspirin alone in the COMPASS (Cardiovascular to estimate the effect of treatment duration for all
OutcoMes for People Using Anticoagulation StrategieS) treatments because of multicollinearity and missing
coronary artery bypass graft trial.17 However, the linkage (supplementary table 13). Moreover, this meta-
combination of aspirin plus rivaroxaban 2.5 mg twice regression probably had low power to detect such an
daily was associated with similar reductions in major association, and its credibility is questionable owing to
adverse cardiovascular events, and this was consistent the lack of patient level data; therefore, it is subject to
with the findings of the main COMPASS trial.57 ecological bias.
Therefore, because major bleeding has been associated Further research is needed to improve strategies to
with increased morbidity and mortality,58 59 the risk optimise saphenous vein graft patency after coronary
of bleeding should be carefully balanced against the artery bypass graft surgery. We need studies of adequate
benefits when planning long term (>12 months) dual duration and sample size that report saphenous vein
antiplatelet therapy in patients undergoing coronary graft failure at different time points to determine the
artery bypass graft surgery. potential legacy effect of dual antiplatelet therapy
during the first year after coronary artery bypass graft
Unanswered questions and future research surgery. Additionally, these studies should report long
We did not have enough power to detect significance for term (that is, five or 10 years) incidence of saphenous
clinical outcomes because we restricted the inclusion vein graft failure, and patient important outcomes
to trials that reported saphenous vein graft failure (our (mortality, ischaemic, or bleeding events).
primary outcome), hence reducing statistical power
in this regard. However, the eligibility criteria were Conclusion and policy implications
purposefully stringent to reduce heterogeneity and risk The results of this network meta-analysis suggest an
of bias. Saphenous vein graft failure is not a clinical important absolute benefit of adding ticagrelor or
outcome in itself; it is considered a surrogate endpoint clopidogrel to aspirin to prevent saphenous vein graft

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failure after coronary artery bypass graft surgery. Dual Sanofi Aventis, The Medicines Company, Roche, Pfizer, Forest
Laboratories/AstraZeneca, Ischemix, Amgen, Lilly, Chiesi, Ironwood,
antiplatelet therapy after surgery should be tailored to Abbott, Regeneron, Idorsia, Synaptic, Afimmune; other from FlowCo,
the patient by balancing the safety and efficacy profile PLx Pharma, Takeda, Medscape Cardiology, Regado Biosciences,
of the drug intervention against important patient Boston VA Research Institute, Clinical Cardiology, VA, St Jude Medical
(now Abbott), Biotronik, Cardax, Boston Scientific, Svelte, Merck,
outcomes. Future guideline updates are needed to
Novo Nordisk, CSL Behring, Fractyl; personal fees from Duke Clinical
optimise antithrombotic management of patients Research Institute, Mayo Clinic, Population Health Research Institute,
undergoing coronary artery bypass graft surgery. Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP
Global, Harvard Clinical Research Institute (now Baim Institute for
Meanwhile, dual antiplatelet therapy with aspirin
Clinical Research), Journal of the American College of Cardiology,
plus ticagrelor or aspirin plus clopidogrel could be Cleveland Clinic, Mount Sinai School of Medicine, TobeSoft, Bayer,
considered for most patients after surgery. Medtelligence/ReachMD, Cereno Scientific, Ferring Pharmaceuticals;
personal fees, non-financial support, and other from American College
of Cardiology; personal fees and non-financial support from Society
AUTHOR AFFILIATIONS of Cardiovascular Patient Care; non-financial support from American
1
Department of Epidemiology and Biostatistics, Schulich School of
Heart Association; grants and other from PhaseBio; personal fees and
Medicine & Dentistry, Western University, London, ON, Canada
2
other from Boehringer Ingelheim, outside the submitted work. The
Cochrane Canada Center, MacGRADE Center and Department remaining authors have nothing to disclose.
of Health Research Methods, Evidence and Impact, McMaster
Ethical approval: Not required.
University, Hamilton, ON, Canada
3 Data sharing: No additional data available.
London Health Sciences Centre, Division of Cardiology, Department
of Medicine, Schulich School of Medicine & Dentistry, Western The lead author (RB) affirms that this manuscript is an honest,
University, London, ON, Canada accurate, and transparent account of the study being reported; that
4 no important aspects of the study have been omitted; and that
Epidemiology Division, Dalla Lana School of Public Health,
any discrepancies from the study as planned in the peer-reviewed
University of Toronto, Toronto, ON, Canada
5
published protocol have been explained.
Department of Medicine, Baylor College of Medicine, Houston, TX,
USA This is an Open Access article distributed in accordance with the
6
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
Lynn Heart and Vascular Institute, Boca Raton Regional Hospital, which permits others to distribute, remix, adapt, build upon this work
and Charles E. Schmidt College of Medicine, Florida Atlantic non-commercially, and license their derivative works on different
University, Boca Raton, FL, USA terms, provided the original work is properly cited and the use is non-
7
Department of Anesthesia & Perioperative Medicine and Centre commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
for Medical Evidence, Decision Integrity & Clinical Impact (MEDICI),
Western University, London, ON, Canada 1 Patel MR, Calhoon JH, Dehmer GJ, et al. ACC/AATS/AHA/ASE/
8 ASNC/SCAI/SCCT/STS 2017 Appropriate Use Criteria for Coronary
Interfaculty Program in Public Health, Western University, London,
Revascularization in Patients With Stable Ischemic Heart Disease:
ON, Canada
A Report of the American College of Cardiology Appropriate Use
9
Schulich Heart Centre, Sunnybrook Health Science, University of Criteria Task Force, American Association for Thoracic Surgery,
Toronto, Toronto, ON, Canada American Heart Association, American Society of Echocardiography,
10
Institute of Health Policy, Management and Evaluation, Dalla Lana American Society of Nuclear Cardiology, Society for Cardiovascular
School of Public Health, University of Toronto, ON, Canada Angiography and Interventions, Society of Cardiovascular Computed
11 Tomography, and Society of Thoracic Surgeons [correction in: J Am
Population Health Research Institute, McMaster University and Coll Cardiol 2018;71:2279-80]. J Am Coll Cardiol 2017;69:2212-41.
Hamilton Health Sciences, Hamilton, ON, Canada doi:10.1016/j.jacc.2017.02.001
12 2 Neumann FJ, Sousa-Uva M, Ahlsson A, et al, ESC Scientific Document
University of Ottawa Heart Institute, Ottawa, ON, Canada
13 Group. 2018 ESC/EACTS Guidelines on myocardial revascularization.
Division of Cardiovascular Medicine, Department of Medicine,
Eur Heart J 2019;40:87-165. doi:10.1093/eurheartj/ehy394
Brigham and Women’s Hospital, Harvard Medical School, Boston, 3 Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton
MA, USA JR. Coronary bypass graft fate and patient outcome: angiographic
14
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Science and Centre for Prognosis Research, Institute of Primary Care 1,388 patients during 25 years. J Am Coll Cardiol 1996;28:616-26.
and Health Sciences, Keele University, Stoke on Trent, UK doi:10.1016/0735-1097(96)00206-9
4 Halabi AR, Alexander JH, Shaw LK, et al. Relation of early
A preliminary version of this work was performed as partial fulfilment
saphenous vein graft failure to outcomes following coronary artery
towards Karla Solo’s Master of Sciences degree, Department of bypass surgery. Am J Cardiol 2005;96:1254-9. doi:10.1016/j.
Epidemiology and Biostatistics, Schulich School of Medicine & amjcard.2005.06.067
Dentistry, Western University, London, Ontario, Canada. 5 Lopes RD, Mehta RH, Hafley GE, et al, Project of Ex Vivo
Contributors: KS and RB conceived and designed the study. KS, Vein Graft Engineering via Transfection IV (PREVENT IV)
AAH, and TC performed a literature search, screened articles for Investigators. Relationship between vein graft failure and
inclusion, and extracted data. KS and RB analysed, interpreted the subsequent clinical outcomes after coronary artery bypass
data, and drafted the first version of the manuscript. All authors have surgery. Circulation 2012;125:749-56. doi:10.1161/
interpreted the data, critically revised the data, provided intellectual CIRCULATIONAHA.111.040311
contributions, and approved the final version of the manuscript. RB is 6 Adelborg K, Horváth-Puhó E, Schmidt M, et al. Thirty-
the guarantor. The corresponding author attests that all listed authors year mortality after coronary artery bypass graft surgery:
a Danish nationwide population-based cohort study. Circ
meet authorship criteria and that no others meeting the criteria have
Cardiovasc Qual Outcomes 2017;10:e002708. doi:10.1161/
been omitted.
CIRCOUTCOMES.116.002708
Funding: This research received no specific grant from any funding 7 Alexander JH. Ticagrelor following coronary artery bypass
agency in the public, commercial or not-for-profit sectors. grafting: for better vein graft patency or better patient outcomes?
Competing interests: All authors have completed the ICMJE uniform JAMA 2018;319:1661-2. doi:10.1001/jama.2018.3793
8 Cooper GJ, Underwood MJ, Deverall PB. Arterial and venous conduits
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No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

Supplementary Figure 1. Comparison-adjusted funnel plot for saphenous vein graft failure
(primary efficacy outcome)
Primary efficacy outcome. 1 versus 6: aspirin monotherapy versus placebo. 4 versus 6: vitamin-
K antagonist versus placebo.
Supplementary Figure 2. Sensitivity analysis excluding studies at serious risk of bias.
Network meta-analysis for saphenous vein graft failure (primary efficacy outcome).
0.58 0.50 0.50 0.39 0.43 0.23 0.53 0.30

Placebo
(0.17-2.03) (0.33-0.76) (0.28-0.89) (0.20-0.75) (0.24-0.75) (0.12-0.47) (0.31-0.92) (0.18-0.53)
0.87 0.86 0.67 0.73 0.40 0.92 0.52

Clopidogrel
(0.26-2.84) (0.24-3.00) (0.19-2.45) (0.21-2.56) (0.11-1.49) (0.26-3.17) (0.17-1.61)
0.99 0.78 0.85 0.47 1.06 0.61

Aspirin
(0.66-1.48) (0.47-1.29) (0.58-1.25) (0.27-0.81) (0.74-1.52) (0.41-0.89)
Vitamin-K 0.79 0.86 0.47 1.07 0.61

inhibitor (0.41-1.49) (0.49-1.49) (0.24-0.93) (0.62-1.83) (0.35-1.06)
1.09 0.60 1.36 0.78

Ticagrelor
(0.58-2.06) (0.34-1.05) (0.73-2.53) (0.41-1.47)
0.55 1.25 0.71

Rivaroxaban
(0.28-1.07) (0.86-1.81) (0.41-1.23)
ASA + 2.27 1.30

Ticagrelor (1.17-4.37) (0.66-2.53)
ASA + 0.57
Rivaroxaban (0.34-0.97)
ASA +
Clopidogrel
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.
Studies considered at serious risk of bias were: Pantely 1979; McEnany 1982; Sharma 1983;
Lorenz 1984; Hockings 1993; Hage 2017; Saw 2016; and Xu 2018.
Supplementary Figure 3. Sensitivity analysis stratified by publications before and after year
2000. Network meta-analysis for saphenous vein graft failure (primary efficacy outcome).
Before 2000
0.56 0.56
Placebo
(0.41-0.77) (0.36-0.88)
1.00
Aspirin
(0.69-1.44)
Vitamin K
Antagonists
After 2000
1.14 0.80 0.85 0.50 1.06 0.60
Aspirin
(0.35-3.69) (0.49-1.29) (0.59-1.23) (0.31-0.79) (0.75-1.50) (0.42-0.86)
0.70 0.75 0.44 0.93 0.52

Clopidogrel
(0.20-2.47) (0.22-2.55) (0.13-1.52) (0.27-3.16) (0.17-1.60)
1.07 0.62 1.33 0.75

Ticagrelor
(0.58-1.95) (0.37-1.05) (0.73-2.40) (0.42-1.35)
0.58 1.25 0.70

Rivaroxaban
(0.32-1.05) (0.87-1.78) (0.42-1.18)
Aspirin + 2.13 1.20

Ticagrelor (1.20-3.79) (0.69-2.09)
Aspirin + 0.56
Rivaroxaban (0.34-0.93)
Aspirin +
Clopidogrel
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.
Supplementary Table 1. Outcomes definitions used in the randomised-controlled trials
included in the present network meta-analysis
Author, year DESCRIPTION OF OUTCOME

SAPHENOUS VEIN GRAFT FAILURE
Measured at six postoperative months using coronary angiography and expressed per
Pantely, 1979 patient. A graft was defined as occluded if the contrast agent failed to flow through it
and into the grafted artery.
Measured at 21.5 postoperative months using coronary angiography and expressed

McEnany, 1982
per graft and per patient, including post-mortem.
Measured at 12 postoperative months. Expressed per patient. Vein grafts were

Sharma, 1983
opacified by selective cannulation or aortic root angiography.
Measured at four postoperative months using coronary angiography and expressed

Lorenz, 1984
per patient. Contrast was selectively injected into each vein graft bypass.
Measured at 12 postoperative months. Expressed per patient. Grafts (distal
Brown, 1985 anastomoses) fully visualized to supply the distal artery during selective injection
were called “patent”; otherwise, they were considered occluded.
Measured at 367 postoperative days. Expressed per patient. A single vein graft was
Goldman, 1989 defined as occluded if the contrast agent failed to flow through it and into the grafted
artery. Each distal anastomotic site is counted as a single graft.
Measured at 363 postoperative days using invasive angiography. Vein graft occlusion
Gavaghan, (or patency) rates were expressed per patient (with one or more distal anastomoses
1991 occluded). A graft was defined as occluded if the contrast agent failed to flow through
it and into the grafted artery.
Measured at 371 postoperative days. Expressed per patient. A graft was defined as
Van der Meer, occluded if the contrast agent failed to flow through the graft, or one or more distal
1993 anastomoses were occluded. A distal anastomosis was defined as occluded if contrast
did not flow from the proximal graft into the grafted native artery.
Measured at 6 postoperative months using invasive angiography. Expressed per
Hockings, 1993
patient.
Mujanovic, Measured at three postoperative months using angiography. FitzGibbon’s*

2009 classification was used. Expressed per graft.
Measured at 12 postoperative months using 64-Multislice Computed Tomography

Gao, 2009
Angiography (MSCTA) and expressed per graft.
Measured at 12 postoperative months using invasive angiography and expressed per

Kulik, 2010
patient.
Measured at eight postoperative years using MSCTA and expressed per graft in
Hage, 2017
surviving patients.
Measured at three postoperative months using MSCTA and expressed per graft. A
Gao, 2010
graft was considered occluded if a conduit did not fill with contrast at all.
Measured at 50 postoperative days using MSCTA and expressed Per patient.
Sun, 2010
“Stenosed grafts without diffuse luminal narrowing were considered to be patent”.
Measured at 12 postoperative months using 64-MSCTA. The quality of the
Mannacio,
anastomosis and conduits was graded according to FitzBibbon’s method of
2012
classification.
Measured at 12 postoperative months using 128- or 320-MSCTA. A graft was defined
Saw, 2016 as occluded if there was lack of contrast flow in the graft segment from the proximal
anastomosis.
Measured at 12 postoperative months using a 128-MSCTA. Failure was defined as
Slim, 2016
stenosis ≥50% and expressed as per graft.
Measured at 12 postoperative months using MSCTA and coronary angiography.
Zhao, 2018 Death was included in the analysis. FitzGibbon’s grade O was used to define graft
occlusion.
Xu, 2018 Measured at 1 postoperative month.
Measured at 1 postoperative year using MSCTA. Graft failure was defined as absence
Lamy, 2019
of blood flow in a graft.
MAJOR BLEEDING
McEnany, 1982 No definition.
Gavaghan,
Gastro-intestinal bleeding.
1991
Van der Meer,
If life threatening or fatal and if blood transfusion or surgery was necessary.
1993
As per Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial
Kulik, 2010
definition.
A follow-up case report form was designed to collect long-term clinical data and was
Hage, 2017
sent to patients via mail.
Intracranial hemorrhage, bleeding causing death, or bleeding requiring transfusion of
Sun, 2010
>1 unit of red blood cells.
Mannacio,
Defined according to CURE trial.
2012
Bleeding events were defined as per Platelet Inhibition and Patient Outcomes
(PLATO) study. Major bleeding was defined as “bleeding that led to clinically
Saw, 2016
significant disability, or bleeding with haemoglobin drop ≥ 3.0 g/dL but <5.0 g/dL or
requiring 2-3 units of transfusion”.
Bleeding events were defined as per Thrombolysis in Myocardial Infarction (TIMI)
Slim, 2016
classification.#
Zhao, 2018 No definition.

Xu, 2018 Type 3a Bleeding Academic Research Consortium (BARC) definitions.‡
Modification of the International Society on Thrombosis and Haemostasis (ISTH) for
major bleeding, which included fatal bleeding, symptomatic bleeding in a critical
Lamy, 2019 organ, bleeding into a surgical site requiring reoperation, and bleeding leading to
hospitalization (including presentation to an acute care facility without overnight
stay).
MORTALITY
Pantely, 1979 All-cause mortality at 6 months.
McEnany, 1982 Mortality at 34 months.
Sharma, 1983 All-cause mortality at 12 months.
Brown, 1985 All-cause mortality at 12 months.
Gavaghan,
All-cause mortality at 12 months.
1991
Van der Meer,
All-cause mortality at 12 months.
1993
Mujanovic,
No definition at 3 months.
2009
Kulik, 2010 All-cause mortality at 12 months.
Gao, 2010 All-cause mortality at 3 months.
Sun, 2010 All-cause mortality at 1 month.
Xu, 2018 All-cause at 30-day mortality.
MYOCARDIAL INFARCTION
McEnany, 1982 Fatal and non-fatal myocardial infarction at 24 months.
Gavaghan,
Peri-operative new Q wave myocardial infarction.
1991
Van der Meer,
Diagnosed according to strict ECG criteria at 12 months.
1993
Kulik, 2010 Assessed at 12 months.
Collected at 8 years. A follow-up case report form was designed to collect long-term
Hage, 2017
clinical data and was sent to patients via mail.
30-day myocardial infarction defined as “creatine kinase-MB >10 times the upper
Sun, 2010 limit of normal or >5 times the upper limit of normal with new Q waves >30 msec in
2 contiguous leads on electrocardiogram of a new wall abnormality.
Mannacio, Assessed at 12 months. According to the Universal Definition of Myocardial
2012 Infarction.§
Assessed at 12 months. In accordance with the Universal definition § where
Saw, 2016 myocardial infarction after CABG was defined as “>5 times normal reference
elevation of troponin-I within 72 h after coronary artery bypass surgery.”
Slim, 2016 Unknown. Assessed at 12 months.
Zhao, 2018 Non-fatal myocardial infarction.
Xu, 2018 30-day perioperative myocardial infarction.
Lamy, 2019 Third Universal Definition of Myocardial Infarction.†
Definitions are presented as per author’s definition statement extracted from their manuscript.
*FitzGibbon GM, Burton JR, Leach AJ. Circulation 1978;57:1070-1074.
#
Chesebro JH, Knatterud G, Roberts R, et al. Circulation. 1987;76:142-154.
‡
Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a
consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-47.
§
Thygesen K, Alpert JS, White HD, et al. Universal Definition of Myocardial Infarction. 2007;116:2634-
2653.
†
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation
2012;126:2020-2035.
Supplementary Table 2. Sensitivity analyses: Effect estimates for saphenous vein graft failure
Network meta-analysis - OR (95% CI)

Pairwise Without
Treatment Comparator Base Case Imputation Per graft In-trial
OR (95% CI) OPCABG only
analysis analysis analysis analysis†
studies*
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)
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.
Supplementary Table 3. Sensitivity analyses: Surface Under the Cumulative Ranking
(SUCRA) values for saphenous vein graft failure
Without
Base case All Missing Per graft In-trial
OPCAB only
Treatment by analysis Failure analysis analysis†
studies*
outcome
SUCRA 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.
Larger SUCRA values indicate better interventions and higher hierarchy ranks are in bold.
Supplementary Table 4. Sensitivity analyses: Effect estimates for major bleeding
Network meta-analysis - Odds Ratio (95% CI)

Pairwise Without
Treatment Comparator Base Case Imputation In-trial
OR (95% CI) OPCABG only
analysis analysis analysis†
studies*
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)
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).
Supplementary Table 5. Sensitivity analyses: Surface Under the Cumulative Ranking
(SUCRA) values for major bleeding
Without
Base case All Missing In-trial
Treatment by OPCABG
analysis Failure analysis†
outcome only studies*
SUCRA 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).
Larger SUCRA values indicate better interventions and higher hierarchy ranks are in bold.
Supplementary Table 6. Surface Under the Cumulative Ranking (SUCRA) secondary
outcomes
Myocardial All-cause
Treatment by outcome Infarction Mortality
SUCRA SUCRA
Aspirin + Rivaroxaban 75.2 NA
Aspirin + Clopidogrel 61.3 50.4
Rivaroxaban 44.0 NA
Ticagrelor 59.5 NA
Vitamin-K Antagonist 46.6 59.3
Aspirin + Ticagrelor 59.1 50.3
Aspirin 39.5 29.0
Placebo 14.9 61.0
No Clopidogrel monotherapy. NA: not available data. Larger SUCRA values indicate better interventions
and higher hierarchy ranks are in bold.
Supplementary Table 7: Study-specific risk of bias
Bias due to Bias due Bias in

Bias arising Bias in Overall
deviation to selection
from the measurement (SVGF/
Study ID from missing of the
randomization of the clinical
intended outcome reported
process outcome outcomes*)
interventions data result
Pantely, some High/Some
Low risk High risk Low risk Low risk
1979 concerns concerns
McEnany, Some High/Some
Some concerns High risk Some concern Low risk
Sharma, Some High/Some
Some concerns High risk Low risk Low risk
Lorenz, Some Some
High risk Low risk Low risk High/High
Some
Brown, Some Some concerns/
Some concerns Low risk Low risk
1985 concerns concerns Some
concerns
Some
Goldman, Some concerns/
Some concerns Low risk Low risk Low risk
1989 concerns Some
concerns
Some
Gavaghan, Some concerns/
1991 concerns Some
concerns
Some
Van der Some concerns/
Low risk Low risk Low risk Low risk
Meer, 1993 concerns Some
concerns
Hockings, Some Some
Some concerns Low risk High risk High/High
Some
Mujanovic, Some Some Some concerns/
Some concerns Low risk
2009 concerns concerns concerns Some
concerns
Some
Gao, Some Some Some concerns/
Some concerns Low risk
2009 concerns concerns concerns Some
concerns
Kulik,
Low risk Low risk Low risk Low risk Low risk Low/Low
2010
Hage,
Low risk Low risk High risk Low risk Low risk High/Low
2017*
Some
Gao, Some concerns/
2010 concerns Some
concerns
Some
Sun, Some
Low risk Low risk Low risk Low risk concerns/
2010 concerns
Low
Some
Mannacio, concerns/
Some concerns Low risk Low risk Low risk Low risk
2012 Some
concerns
Saw, High /
Low risk Low risk High risk Low risk Low risk
2016 Low
Some
Slim, Some concerns/
2016 concerns Some
concerns
Zhao, Low/
Low risk Low risk Low risk Low risk Low risk
2018 Low
Xu, Some Some High risk/
High risk Low risk Low risk
2018 concerns concerns High risk
Some
Lamy, Some concerns/
Low risk Low risk Low risk Low risk
2019 concerns Some
concerns
SVGF: saphenous vein graft failure. *Clinical outcomes include major bleeding, mortality and myocardial
infarction.
Supplementary Table 8. Certainty of direct evidence assessment
No. of Publication Odds Ratio Certainty

Comparison Risk of bias Inconsistency Indirectness
RCTs bias (95% CI) of evidence
Saphenous vein graft failure (Base case analysis)
Aspirin vs
7 Not Serious Not Serious Serious2 Unclear3 0.55 (0.39-0.78) Moderate
Placebo
Vit-K Antag vs
2 Serious4 Not Serious Serious2 Unclear3 0.68 (0.30-1.51) Low
Placebo
Vit-K Antag vs
2 Serious5 Not Serious Serious2 Unclear3 0.94 (0.66-1.35) Low
Aspirin
ASA+Clopi vs
Aspirin
ASA+Clopi vs
1 Not Serious NA6 Serious2 Unclear3 0.52 (0.17-1.60) Moderate
Clopi
ASA+Clopi vs
1 Serious1 NA6 Serious2 Unclear3 0.81 (0.24-2.73) Low
ASA+Tica
ASA+Tica vs
Aspirin
ASA+Riva vs
Aspirin
ASA+Riva vs
Riva
Riva vs Aspirin 1 Not Serious NA6 Serious2 Unclear3 0.85 (0.59-1.23) Moderate
ASA+Tica vs
Ticagrelor
Ticagrelor vs
Aspirin
Major bleeding
Aspirin vs
2 Not Serious NA6 Serious2 NA7 2.62 (0.11-65) Moderate
Placebo
Vit-K Antag vs
1 Serious1 NA6 Not Serious NA7 10.81 (0.57-204) Moderate
Placebo
Vit-K Antag vs
2 Serious1 Not Serious Serious2 NA7 2.26 (0.56-9.12) Low
Aspirin
ASA+Clopi vs
4 Not Serious Not Serious Serious2 NA7 0.76 (0.25-2.31) Moderate
Aspirin
ASA+Clopi vs
1 Serious1 NA6 Not Serious NA7 1.00 (0.06-16.31) Moderate
ASA+Tica
ASA+Tica vs
2 Not Serious NA6 Not Serious NA7 7.04 (0.36-137) High
Aspirin
ASA+Riva vs
1 Not Serious NA6 Not Serious NA7 0.99 (0.46-2.14) High
Aspirin
ASA+Riva vs
Riva
Riva vs Aspirin 1 Not Serious NA6 Not Serious NA7 1.50 (0.73-3.04) High
ASA+Tica vs
Ticagrelor
Ticagrelor vs
1 Not Serious NA6 Not Serious NA7 5.06 (0.24-106) High
Aspirin
Mortality
Aspirin vs
Placebo
Vit-K Antag vs
Placebo
Vit-K Antag vs
Aspirin
ASA+Clopi vs
Aspirin
ASA+Clopi vs
1 Serious1 NA6 Not Serious NA7 Not estimable Moderate
ASA+Tica
Aspirin vs
Placebo
Vit-K Antag vs
Placebo
Vit-K Antag vs
Aspirin
ASA+Clopi vs
Aspirin
ASA+Clopi vs
1 Serious1 NA6 Not Serious NA7 Not estimable Moderate
ASA+Tica
ASA+Tica vs
Aspirin
ASA+Riva vs
Aspirin
ASA+Riva vs
Riva
Riva vs Aspirin 1 Not Serious NA6 Not Serious NA7 0.96 (0.33-2.75) High
ASA+Tica vs
Ticagrelor
Ticagrelor vs
Aspirin
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.
1
All studies failed to blind patients and personnel completely
2
At 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.
3
As per protocol, the funnel plot or Egger’s test was not performed because of insufficient information (<10 studies).
4
No 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.
5
Both 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.
6
Unable to assess because there are <2 studies available with non-zero events in both arms.
7
This 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.
Supplementary Table 9. 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 Evidence
SVGF (Base case analysis)
ASA+Clopi vs Placebo - - 0.34 (0.21-0.54) Moderate1,2,3 0.34 (0.21-0.54) Moderate
ASA+Riva vs Placebo - - 0.60 (0.38-0.98) Low1,4 0.60 (0.38-0.98) Low
ASA+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) Moderate
Ticagrelor 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) Low
Clopidogrel 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) Moderate
ASA+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) Moderate
ASA+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) Moderate
Riva 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 Low
ASA+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 Low
Riva 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 Low
ASA+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
ASA+Clopi vs ASA+Riva - - 0.56 (0.34-0.93) Low1,3 0.56 (0.34-0.93) Low
The estimated common between-study variance (tau2) = (1.03×10-10)2 = 1.06×10-20
Major Bleeding
ASA+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+Tica vs Vit-K Antag - - 1.08 (0.15-7.69) Very Low1,5 1.08 (0.15-7.69) 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
Mortality
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
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 Infarction
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+Tica vs Vit-K Antag - - 0.76 (0.15-3.88) Very Low1,5 0.76 (0.15-3.88) 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.
2
*𝜏𝑁𝑀𝐴 <50% quantiles of the empirical distribution (i.e.- low heterogeneity) and lack of evidence of incoherence.
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.
Supplementary Table 10. Local inconsistency tests assuming a common loop-specific
heterogeneity estimated using the method of moments
Inconsistency factor Loop heterogeneity-

Closed loop of evidence
(IF - 95% CI) 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-Tica 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.
Supplementary Table 11. Global inconsistency using the design-by-treatment interaction
model
Global inconsistency
Outcomes of interest Chi-square
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.

Supplementary Table 12: Meta-regression of treatment effect and year of publication
relative to the reference therapy (Aspirin)
Log odds ratio* 95% CI P-value

Aspirin + Clopidogrel
0.04 -0.09 to 0.169 0.552
year of publication
Aspirin + Ticagrelor
0.07 -0.668 to 0.806 0.854
year of publication
Vitamin K antagonist
0.01 -0.065 to 0.093 0.727
year of publication
Placebo
0.06 -0.026 to 0.143 0.173
year of publication
*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. CI: confidence interval.
Supplementary Table 13: Meta-regression of treatment effect and duration of treatment
relative to the reference therapy (Aspirin)
Log odds ratio* 95% CI P-value

Aspirin + Clopidogrel
0.009 -0.005 to 0.024 0.204
Duration
Aspirin + Ticagrelor
-0.019 -0.122 to 0.851 0.726
Duration
Vitamin K antagonist
-0.182 -0.451 0.086 0.183
Duration
Placebo
-0.080 -0.211 to 0.050 0.228
Duration
*Log odds ratio shows the strength of association between the treatment effect and duration of treatment
relative to the reference therapy (aspirin). Estimates of the effect of duration of treatment on clopidogrel,
aspirin + rivaroxaban, ticagrelor and rivaroxaban, compared to the reference therapy aspirin, could not be
obtained due to collinearity and missing linkage. CI: confidence interval.

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BMJ: first published as 10.1136/bmj.l5476 on 10 October 2019. Downloaded from http://www.bmj.

Antithrombotic treatment after coronary artery bypass graft

the bmj | BMJ 2019;367:l5476 | doi: 10.1136/bmj.l5476 1

2 doi: 10.1136/bmj.l5476 | BMJ 2019;367:l5476 | the bmj

Table 1 | Characteristics of the included randomised controlled trials

the bmj | BMJ 2019;367:l5476 | doi: 10.1136/bmj.l5476 3

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the bmj | BMJ 2019;367:l5476 | doi: 10.1136/bmj.l5476 5

Saphenous vein gra failure

Clopidogrel 2 trials 6 trials

Placebo 1 trial 1 trial 1 trial

Aspirin and rivaroxaban 1 trial

Aspirin and ticagrelor

1 trial Aspirin and

Aspirin and 1 trial Rivaroxaban

6 doi: 10.1136/bmj.l5476 | BMJ 2019;367:l5476 | the bmj

Secondary outcomes Risk of bias and certainty of evidence

Saphenous vein gra failure

the bmj | BMJ 2019;367:l5476 | doi: 10.1136/bmj.l5476 7

8 doi: 10.1136/bmj.l5476 | BMJ 2019;367:l5476 | the bmj

All cause mortality

Aspirin and ticagrelor

1 trial Aspirin and

Aspirin and 1 trial Rivaroxaban

We also downgraded the certainty of evidence to low Network assumptions

the bmj | BMJ 2019;367:l5476 | doi: 10.1136/bmj.l5476 9

All cause mortality

Discussion clustering eﬀects of data expressed on a per graft basis,

10 doi: 10.1136/bmj.l5476 | BMJ 2019;367:l5476 | the bmj

the bmj | BMJ 2019;367:l5476 | doi: 10.1136/bmj.l5476 11

12 doi: 10.1136/bmj.l5476 | BMJ 2019;367:l5476 | the bmj

the bmj | BMJ 2019;367:l5476 | doi: 10.1136/bmj.l5476 13

14 doi: 10.1136/bmj.l5476 | BMJ 2019;367:l5476 | the bmj

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

0.58 0.50 0.50 0.39 0.43 0.23 0.53 0.30

0.87 0.86 0.67 0.73 0.40 0.92 0.52

0.99 0.78 0.85 0.47 1.06 0.61

Vitamin-K 0.79 0.86 0.47 1.07 0.61

1.09 0.60 1.36 0.78

0.55 1.25 0.71

ASA + 2.27 1.30

0.70 0.75 0.44 0.93 0.52

1.07 0.62 1.33 0.75

0.58 1.25 0.70

Aspirin + 2.13 1.20

Author, year DESCRIPTION OF OUTCOME

Measured at 21.5 postoperative months using coronary angiography and expressed

Measured at 12 postoperative months. Expressed per patient. Vein grafts were

Measured at four postoperative months using coronary angiography and expressed

Mujanovic, Measured at three postoperative months using angiography. FitzGibbon’s*

Measured at 12 postoperative months using 64-Multislice Computed Tomography

Measured at 12 postoperative months using invasive angiography and expressed per

Zhao, 2018 No definition.

Network meta-analysis - OR (95% CI)

ASA+Tica 94.4 93.3 95.6 94.4 94.1

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

Bias due to Bias due Bias in

No. of Publication Odds Ratio Certainty

Saphenous vein graft failure (Base case analysis)

Direct Evidence Indirect Evidence Network Meta-Analysis*

Inconsistency factor Loop heterogeneity-

SVGF: saphenous vein graft failure.

Log odds ratio* 95% CI P-value