Research

JAMA | Original Investigation

Association of Dual Antiplatelet Therapy With Ticagrelor

With Vein Graft Failure After Coronary Artery Bypass Graft Surgery
A Systematic Review and Meta-analysis
Sigrid Sandner, MD; Björn Redfors, MD, PhD; Dominick J. Angiolillo, MD; Katia Audisio, MD;
Stephen E. Fremes, MD; Paul W.A. Janssen, MD; Alexander Kulik, MD; Roxana Mehran, MD; Joyce Peper, MD;
Marc Ruel, MD; Jacqueline Saw, MD; Giovanni Jr Soletti, MD; Andrew Starovoytov, MD; Jurrien M. ten Berg, MD;
Laura M. Willemsen, MD; Qiang Zhao, MD, PhD; Yunpeng Zhu, MD; Mario Gaudino, MD, PhD

Editorial page 532

IMPORTANCE The role of ticagrelor with or without aspirin after coronary artery bypass graft Supplemental content
surgery remains unclear.

OBJECTIVE To compare the risks of vein graft failure and bleeding associated with ticagrelor
dual antiplatelet therapy (DAPT) or ticagrelor monotherapy vs aspirin among patients
undergoing coronary artery bypass graft surgery.

DATA SOURCES MEDLINE, Embase, and Cochrane Library databases from inception to June 1,
2022, without language restriction.

STUDY SELECTION Randomized clinical trials (RCTs) comparing the effects of ticagrelor DAPT
or ticagrelor monotherapy vs aspirin on saphenous vein graft failure.

DATA EXTRACTION AND SYNTHESIS Individual patient data provided by each trial were
synthesized into a combined data set for independent analysis. Multilevel logistic regression
models were used.

MAIN OUTCOMES AND MEASURES The primary analysis assessed the incidence of saphenous
vein graft failure per graft (primary outcome) in RCTs comparing ticagrelor DAPT with aspirin.
Secondary outcomes were saphenous vein graft failure per patient and Bleeding Academic
Research Consortium (BARC) type 2, 3, or 5 bleeding events. A supplementary analysis
included RCTs comparing ticagrelor monotherapy with aspirin.

RESULTS A total of 4 RCTs were included in the meta-analysis, involving 1316 patients and
1668 saphenous vein grafts. Of the 871 patients in the primary analysis, 435 received
ticagrelor DAPT (median age, 67 years [IQR, 60-72 years]; 65 women [14.9%]; 370 men
[85.1%]) and 436 received aspirin (median age, 66 years [IQR, 61-73 years]; 63 women
[14.5%]; 373 men [85.5%]). Ticagrelor DAPT was associated with a significantly lower
incidence of saphenous vein graft failure (11.2%) per graft than was aspirin (20%; difference,
−8.7% [95% CI, −13.5% to −3.9%]; OR, 0.51 [95% CI, 0.35 to 0.74]; P < .001) and was
associated with a significantly lower incidence of saphenous vein graft failure per patient
(13.2% vs 23.0%, difference, −9.7% [95% CI, −14.9% to −4.4%]; OR, 0.51 [95% CI, 0.35 to
0.74]; P < .001). Ticagrelor DAPT (22.1%) was associated with a significantly higher incidence
of BARC type 2, 3, or 5 bleeding events than was aspirin (8.7%; difference, 13.3% [95% CI,
8.6% to 18.0%]; OR, 2.98 [95% CI, 1.99 to 4.47]; P < .001), but not BARC type 3 or 5 bleeding
events (1.8% vs 1.8%, difference, 0% [95% CI, −1.8% to 1.8%]; OR, 1.00 [95% CI, 0.37 to
2.69]; P = .99). Compared with aspirin, ticagrelor monotherapy was not significantly
associated with saphenous vein graft failure (19.3% vs 21.7%, difference, −2.6% [95% CI,
−9.1% to 3.9%]; OR, 0.86 [95% CI, 0.58 to 1.27]; P = .44) or BARC type 2, 3, or 5 bleeding
events (8.9% vs 7.3%, difference, 1.7% [95% CI, −2.8% to 6.1%]; OR, 1.25 [95% CI, 0.69 to
2.29]; P = .46).
Author Affiliations: Author
CONCLUSIONS AND RELEVANCE Among patients undergoing coronary artery bypass graft affiliations are listed at the end of this
article.
surgery, adding ticagrelor to aspirin was associated with a significantly decreased risk of vein
Corresponding Author: Mario
graft failure. However, this was accompanied by a significantly increased risk of clinically
Gaudino, MD, PhD, Department of
important bleeding. Cardiothoracic Surgery, Weill Cornell
Medicine, New York Presbyterian
Hospital, 525 E 68th St, New York,
NY 10065 (mfg9004@med.cornell.
JAMA. 2022;328(6):554-562. doi:10.1001/jama.2022.11966 edu).

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 Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Bypass Surgery
S
aphenous vein grafts are the most frequently used
conduits in coronary artery bypass graft (CABG) sur-
gery, yet as many as 10% to 25% occlude within the
first year after surgery.1,2 Early saphenous vein graft failure
is mainly due to thrombosis subsequent to endothelial dam-
age or endothelial activation leading to a prothrombotic
phenotype.2,3 Inhibition of platelet aggregation with aspirin
after CABG surgery has been shown to reduce early saphe-
nous vein graft failure and is endorsed in current practice
guidelines.4-6 Dual antiplatelet therapy (DAPT), consisting of
aspirin and an oral platelet P2Y12 receptor inhibitor, is associ-
ated with enhanced platelet inhibitory effects.7 Although
DAPT is the guideline-recommended treatment after percu-
taneous coronary revascularization,7 considerable contro-
versy exists as to the benefit of DAPT for patients after CABG
surgery. Studies comparing ticagrelor DAPT with aspirin have
yielded conflicting results,8-10 and the few studies comparing
ticagrelor monotherapy with aspirin9,11 failed to demonstrate
an effect of ticagrelor monotherapy on saphenous vein graft
failure; however, they were individually underpowered.
A systematic review and individual patient data meta-
analysis of all randomized clinical trials (RCTs) comparing the
effects of ticagrelor DAPT or ticagrelor monotherapy with as-
pirin on saphenous vein graft failure among patients under-
going CABG surgery was performed.
Methods
This study design was published a priori on the International
Prospective Register of Systematic Reviews (CRD42021291997).
The statistical analysis protocol was prespecified to reduce
post hoc bias. The analysis was performed in accordance
with the Individual Patient Data-Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (IPD-PRISMA).12
The PRISMA checklist was followed. Ethics approval and
patient consent were obtained locally by each trial team.
The Weill Cornell Medicine Institutional Review Board
waived the need for ethics approval for the pooled analysis
(protocol 22-03024559).
Search Strategy and Selection Criteria
A medical librarian searched Ovid MEDLINE, Ovid Embase, and
the Cochrane Central (Wiley) databases to identify RCTs pub-
lished between database inception and June 1, 2022, compar-
ing ticagrelor DAPT and/or ticagrelor monotherapy with aspi-
rin in patients undergoing CABG surgery who had follow-up
for graft imaging. No language restrictions were imposed. The
full search strategy is provided in the Supplement (eMethods
1 in the Supplement). Identification of studies meeting the
search criteria was performed by 2 authors (S.S. and K.A.). Con-
flicts over inclusion were resolved by consultation with a third
author (M.G.).
Data Extraction and Quality Assessment
The principal investigators of the eligible trials were con-
tacted and all agreed to share individual patient data. Speci-
fications of core minimum deidentified data requirements were
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Original Investigation Research
Key Points
Question Is ticagrelor dual antiplatelet therapy (DAPT) for
patients undergoing coronary artery bypass graft surgery
associated with differences in vein graft failure and bleeding
events compared with aspirin?
Findings In this individual patient data meta-analysis that
included 4 randomized clinical trials, 1316 patients and 1668
vein grafts, ticagrelor DAPT compared with aspirin was associated
with a significantly lower incidence of vein graft failure (11.2% vs
20.0%) and a significantly higher incidence of Bleeding Academic
Research Consortium type 2, 3, or 5 bleeding events (22.1% vs
8.7%).
Meaning In patients undergoing coronary artery bypass graft
surgery, adding ticagrelor to aspirin was associated with
a significantly decreased risk of vein graft failure, as well
as a significantly increased risk of clinically important bleeding.
provided to each trial (eMethods 2 in the Supplement). Data
received from the individual trial teams by the analysis unit
at Weill Cornell Medicine were checked for completeness and
consistency with previous publications. Discrepancies were re-
solved directly with the trial investigators. For harmoniza-
tion of graft failure definition across trials, occlusion and/or
percent stenosis per graft or anastomosis (for sequential grafts)
were provided by each trial team. Events were readjudicated
centrally. For harmonization of bleeding outcomes, bleeding
events were readjudicated by each trial team according to
Bleeding Academic Research Consortium (BARC) criteria.13 All
analyses were performed independently on the combined data
set of individual patient data provided for each trial. The risk
of bias was assessed using the Cochrane risk-of-bias tool 214
(eFigure 1 in the Supplement).
Outcomes
The primary outcome was the incidence of saphenous vein graft
failure, defined as saphenous vein graft occlusion or stenosis
greater than 50% per graft as assessed by either invasive angi-
ography or computed tomographic angiography at the indi-
vidual trial protocol–defined follow-up. Secondary outcomes
were the incidence of saphenous vein graft failure per patient
(defined as patients with ≥1 failed saphenous vein graft); the in-
cidence of BARC type 2, 3, or 5 bleeding events; the composite
of saphenous vein graft failure or cardiovascular death; and ma-
jor adverse cardiac and cerebrovascular events (MACCE, de-
fined as the composite of all-cause death, myocardial infarc-
tion, stroke, or revascularization). Definitions of events in the
individual trials are provided in eTable 1 in the Supplement.
Post hoc outcomes were the incidence of saphenous vein
graft occlusion per graft; any graft failure (arterial or saphe-
nous vein grafts); BARC type 2 through 5, 3 through 5, and 3
or 5 bleeding events; the individual components of MACCE;
major adverse cardiovascular events (MACE, defined as the
composite of cardiovascular death, myocardial infarction, or
stroke); and net adverse events (defined as graft failure [arte-
rial or saphenous vein grafts] or BARC type ≥3 bleeding event),
net adverse major clinical events (defined as all-cause death,
myocardial infarction, stroke, or BARC type ≥3 bleeding event),
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 Research Original Investigation Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Bypass Surgery

Table 1. Trial Characteristics

Experimental group Control group Time

Total No. of No. of Treatment Type to graft
Dates of No. of No. of No. of patients No. of patients No. of duration, of graft imaging,
Sourcea enrollment patients graftsb SVGs Treatment with SVGs SVGs Treatment with SVGs SVGs mo imaging mo
TAP-CABG,8 2011- 70 167 76 Ticagrelor 19 34 Placebo 23 42 3 CT angiography 3
2016 2014 90 mg 2/d + aspirin
+ aspirin 81 mg 1/d
81 mg 1/d
DACAB,9 2014- 500 1146 712 Group 1: 167 239 Aspirin 166 242 12 CT or coronary 12
2018 2015 ticagrelor 100 mg 1/d angiography
90 mg 2/d
+ aspirin
100 mg 1/d
Group 2: 166 231
ticagrelor
90 mg 2/d
TARGET,11 2014- 250 688 373 Ticagrelor 127 187 Aspirin 123 186 12 CT angiography 12
2022 2019 90 mg 2/d 81 mg 2/d
POPular 2015- 496 1078 507 Ticagrelor 249 254 Placebo 247 253 12 CT angiography 12
CABG,10 2019 90 mg 2/d + aspirin
2020 + aspirin 80 mg or
80 mg or 100 mg 1/d
100 mg 1/d
b
Abbreviations: CT, computed tomography; SVG, saphenous vein graft. Includes SVGs and arterial grafts (left and/or right internal thoracic artery, and
a
See the Methods section for the full names of the studies. radial artery).

and overall net adverse events (defined as graft failure, MACCE,
or BARC type ≥2 bleeding events).
Data Analysis
Baseline categorical variables are reported as counts and per-
centages. Continuous variables are reported as medians and
IQRs. The primary analysis was performed according to ran-
domization group and compared ticagrelor DAPT with aspi-
rin. The primary analysis set was patients with saphenous vein
grafts who were randomized to ticagrelor DAPT or aspirin and
for whom protocol-defined imaging was available. The pri-
mary outcome was evaluated using a multilevel logistic re-
gression model using the GLIMMIX procedure 15 that ac-
counted for clustering of patients within trials and clustering
of grafts within patients. Treatment associations are reported
as odds ratios (ORs) and 95% CIs.
Secondary outcomes were evaluated using a multilevel
logistic regression model with the trial as a random effect
(reported as OR and 95% CI) or a Cox proportional hazards
frailty model with trial as a random effect (reported as hazard
ratio [HR] and 95% CI). Event rates were calculated using the
Kaplan-Meier method. The proportional hazards assumption
was confirmed for each end point by using Schoenfeld residu-
als and visual inspection of the Schoenfeld residuals, Kaplan-
Meier plots, and log-log plots.
Sensitivity analyses for the primary outcome assessed the
incidence of saphenous vein graft failure per anastomosis and
in patients who had 1-year imaging. Sensitivity models for the
primary outcome were performed in the as-treated popula-
tion (according to treatment received) and per-protocol popu-
lation (according to whether treatment was received in com-
pliance with the trial protocol), and after imputation of missing
data by multiple imputation (assuming a joint multivariate nor-
mal distribution for all variables and imputing 20 data sets).
These sensitivity models were adjusted for baseline and
procedure-related confounders that included age, sex, clini-
cal presentation, smoking, diabetes, hypertension, hyperlip-
idemia, prior myocardial infarction, chronic kidney disease,
use of cardiopulmonary bypass, endoscopic saphenous vein
graft harvesting, and sequential saphenous vein grafting.
Prespecified subgroup analyses for the primary outcome
were age, sex, diabetes, smoking, acute coronary syndrome, use
of cardiopulmonary bypass, endoscopic saphenous vein graft
harvesting, target vessel territory, use of sequential saphe-
nous vein grafts, and treatment duration. For subgroup analy-
ses, an interaction-term between the treatment and the sub-
group of interest was included in the logistic regression model.
A supplementary analysis for the primary outcome com-
pared ticagrelor monotherapy with aspirin.
Details on post hoc analyses are provided in eMethods 3
in the Supplement. A post hoc random-effects network meta-
analysis was performed to compare the associations of ticagre-
lor DAPT, ticagrelor monotherapy, and aspirin with saphe-
nous vein graft failure.
A 2-sided P value of <.05 was considered significant for all
tests. There was no adjustment for multiplicity. Because of the
potential for type I error due to multiple comparisons, find-
ings for analyses of secondary end points should be inter-
preted as exploratory. All analyses were performed using SAS
version 9.4 (SAS Institute Inc) except for the network meta-
analysis, which was performed using R version 4.1.0.16
Results
Study Selection
The literature search yielded 776 results, of which 557 were
screened for eligibility. Four trials meeting the inclusion cri-
teria were included in the analysis: Ticagrelor and Aspirin for
the Prevention of Cardiovascular Events after Coronary Artery

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 Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Bypass Surgery Original Investigation Research

Table 2. Baseline Patient and Graft Characteristics Among Patients in the Primary Analysis

No. (%)
Ticagrelor DAPT (n = 435) Aspirin (n = 436)
Patientsa
Age, median (IQR), y 67 (60-72) 66 (61-73)
>65 y 249 (57.2) 241 (55.3)
Sex Abbreviations: ACS, acute coronary
Women 65 (14.9) 63 (14.5) syndrome; DAPT, dual antiplatelet
Men 370 (85.1) 373 (85.5) therapy; LAD, left anterior
descending artery; LVEF, left
Medical history ventricular ejection fraction;
Hypertensionb 294 (67.6) 294 (67.4) PCI, percutaneous coronary
Dyslipidemiac 275 (63.2) 266 (61.0) intervention.
a
Includes patients from the
ACS at presentationd 195 (44.8) 189 (43.3)
TAP-CABG,8 DACAB,9 and POPular
Diabetes 143 (32.9) 143 (32.8) CABG10 trials. See the Methods
Smokinge 114 (26.2) 112 (25.7) section for the full names of the
studies. Definitions and time points
Previous myocardial infarction 92 (21.2) 91 (20.9)
of measurement varied by trial.
Previous PCI 50 (11.5) 65 (14.9) b
History of hypertension or systolic
Chronic kidney diseasef 28 (6.4) 24 (5.5) blood pressure of at least 140 mm
LVEF, median (IQR), %g 58 (51-64) 60 (51-65) Hg and diastolic blood pressure of at
least 90 mm Hg.
Use of cardiopulmonary bypass 297 (68.3) 301 (69.0)
c
Baseline low-density lipoprotein
Endoscopic saphenous vein graft harvestingh 19/415 (4.6) 25/410 (6.1)
cholesterol of at least 69.5 mg/dL
Sequential saphenous vein grafts 320 (73.6) 327 (75.0) (ⱖ1.8 mmol/L).
Grafts d
ST-elevated myocardial infarction,
No. 981 996 non–ST-segment elevation ACS, or
unstable angina.
Graft type e
Current and former smoking and
Saphenous vein grafts 527 (53.7) 537(53.9) includes vaping and use of other
Arterial grafts 454 (46.3) 459 (46.1) tobacco products.
f
Graft target Glomerular filtration rate less than
LAD 407 (41.5) 403 (40.5) 60 mL/min/m2 calculated by the
Chronic Kidney Disease
Saphenous vein grafts 15 (3.7) 16 (4.0) Epidemiology Collaboration
Arterial grafts 392 (96.3) 387 (96.0) formula.
g
Non-LAD 574 (58.5) 593 (59.5) The most recent measurement
before surgery and varied by trial.
Saphenous vein grafts 512 (89.2) 521 (87.9)
h
Changes in denominators indicate
Arterial grafts 62 (10.8) 72 (12.1)
missing data.

Bypass Graft Surgery (TAP-CABG),8 Different Antiplatelet
Therapy Strategy after Coronary Artery Bypass Graft Surgery
(DACAB),9 Effect of Ticagrelor on Saphenous Vein Graft Pat-
ency in Patients undergoing Coronary Artery Bypass Grafting
Surgery (Popular CABG),10 and Ticagrelor Antiplatelet Therapy
to Reduce Graft Events and Thrombosis (TARGET).11 The
PRISMA IPD flow diagram is provided in eFigure 2 in the
Supplement.
An overview of the included trials is provided in Table 1.
Two trials8,10 compared ticagrelor DAPT with aspirin, 1 trial11
compared ticagrelor monotherapy with aspirin, and 1 trial9
compared ticagrelor DAPT and ticagrelor monotherapy with
aspirin. All trials used a 90-mg twice-daily regimen of
ticagrelor. A total of 3079 grafts (1668 saphenous vein grafts
and 1411 arterial grafts) in 1316 patients were included in the
meta-analysis.
Primary Analysis
The primary analysis included 871 patients from the
TAP-CABG,8 DACAB,9 and POPular CABG10 trials. A total of 435
patients (49.9%; 527 saphenous vein grafts) were random-
ized to ticagrelor DAPT, and 436 patients (50.1%; 537 saphe-
nous vein grafts) were randomized to aspirin (Table 2). The me-
dian treatment duration was 365 days (IQR, 307-365 days) for
patients in the ticagrelor DAPT group and 364 days (IQR, 315-
365 days) for patients in the aspirin group. A total of 394 pa-
tients (90.6%) in the ticagrelor DAPT group and 400 patients
(91.7%) in the aspirin group underwent protocol-defined
imaging (eTables 2-4 in the Supplement). Protocol-defined
imaging was performed by computed tomographic angiogra-
phy in 789 patients and coronary angiography in 5 patients.
The median time from CABG surgery to imaging was 369 days
(IQR, 364-375 days) in the ticagrelor DAPT group and 370 days
(IQR, 364-376 days) in the aspirin group.
Primary Outcome
The primary outcome of saphenous vein graft failure oc-
curred in 11.2% (54 of 481) of saphenous vein grafts in the ti-
cagrelor DAPT group and in 20.0% (99 of 494) of saphenous
vein grafts in the aspirin group (difference, −8.7% [95% CI,
−13.5% to −3.9%], OR, 0.51 [95% CI, 0.35 to 0.74]; P < .001;
Figure 1A).

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 Research Original Investigation Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Bypass Surgery

Figure 1. Individual and Pooled Estimates for Saphenous Vein Graft Failure

A Primary outcome: SVG failure per graft

No. of failed SVG/total

No. of SVG (%) Difference, Favors Favors
Source Ticagrelor DAPT Aspirin (95% CI), %a Odds ratio (95% CI)a ticagrelor DAPT aspirin P value
TAP-CABG,8 2016 4/34 (11.7) 15/42 (35.7) –24.0 (–43.7 to –4.2) 0.24 (0.07 to 0.85) .03
DACAB,9 2018 21/226 (9.3) 50/223 (22.4) –14.5 (–22.2 to –6.8) 0.35 (0.19 to 0.63) <.001
POPular CABG,10 2020 29/221 (13.1) 34/229 (14.8) –1.8 (–9.4 to 5.8) 0.87 (0.46 to 1.64) .62
Overall 54/481 (11.2) 99/494 (20.0) –8.7 (–13.5 to –3.9) 0.51 (0.35 to 0.74) <.001

0.1 1 5
Odds ratio (95% CI)

B Secondary outcome: SVG failure per patient

No. of patients with ≥1 failed SVG/
total No. of patients with SVG (%) Difference, Favors Favors
Source Ticagrelor DAPT Aspirin (95% CI), %a Odds ratio (95% CI)a ticagrelor DAPT aspirin P value
TAP-CABG,8 2016 4/19 (21.1) 14/23 (60.9) –40.0 (–66.9 to –12.7) 0.17 (0.04 to 0.72) .02
DACAB,9 2018 20/157 (12.7) 45/153 (29.4) –16.7 (–25.6 to –7.8) 0.35 (0.20 to 0.63) <.001
POPular CABG,10 2020 28/218 (12.8) 33/224 (14.7) –1.9 (–8.3 to 4.5) 0.85 (0.50 to 1.47) .57
Overall 52/394 (13.2) 92/400 (23.0) –9.7 (–14.9 to –4.4) 0.51 (0.35 to 0.74) <.001

0.1 1 5
Odds ratio (95% CI)

a
Adjusted by trial.
DAPT indicates dual antiplatelet therapy; SVG, saphenous vein graft.

Secondary Outcomes
When assessed per patient, saphenous vein graft failure oc-
curred in 13.2% (52 of 394) of patients in the ticagrelor DAPT
group and 23.0% (92 of 400) of patients in the aspirin group
(difference, −9.7% [95% CI, −14.9% to −4.4%]; OR, 0.51 [95%
CI, 0.35 to 0.74]; P < .001; Figure 1B).
Ticagrelor DAPT was associated with a significantly higher
risk of BARC type 2, 3, or 5 bleeding events compared with as-
pirin (22.1% vs 8.7%, difference; 13.3% [95% CI, 8.6% to 18.0%];
OR, 2.98 [95% CI, 1.99 to 4.47]; P < .001) (Figure 2A; eFig-
ure 3 in the Supplement). Ticagrelor DAPT was associated with
a significantly lower risk of the composite of saphenous vein
graft failure or cardiovascular death compared with aspirin
(13.9% vs 23.4%: difference, −9.4% [95% CI, −14.7% to −4.1%];
OR, 0.52 [95% CI, 0.36 to 0.76]; P < .001) but was not signifi-
cantly associated with lower risk of MACCE (6.7% vs 5.5%; dif-
ference, 1.2% [95% CI, −2.0% to 4.3%]; HR, 1.21 [95% CI, 0.70
to 2.08]; P = .50; Figure 2B).
Prespecified Sensitivity and Subgroup Analyses
The results for the primary outcome were confirmed in the sen-
sitivity analysis for saphenous vein graft failure per anasto-
mosis (ticagrelor DAPT vs aspirin, 8.6% vs 14.6%; difference,
−6.1% [95% CI, −9.9% to −2.4%]; OR, 0.54 [95% CI, 0.37 to
0.80]; P < .001; eFigure 4 in the Supplement) and in the sen-
sitivity analysis that included only patients with protocol-
defined imaging at 1 year (eFigure 5 in the Supplement). Sen-
sitivity analyses for the primary outcome in the as-treated and
per-protocol populations and after imputation of missing data
were also consistent with the main analysis (eTable 5 in the
Supplement).
The association of ticagrelor DAPT with the risk of saphe-
nous vein graft failure was consistent across all prespecified
subgroups (Figure 3).
Post Hoc Outcomes
Ticagrelor DAPT was associated with a significantly lower
risk of saphenous vein graft occlusion than was aspirin (9.6%
vs 16.2%; difference, −6.6% [95% CI, −11.0% to −2.2%]; OR,
0.55 [95% CI, 0.37 to 0.82]; P = .003) (eFigure 6 in the
Supplement).
The results of the post hoc analyses for any graft failure
were consistent with the main analysis (eTable 6 in the Supple-
ment). The association of ticagrelor DAPT with any graft fail-
ure remained consistent when stratified by graft type and tar-
get vessel territory (eFigure 7 in the Supplement).
The association of ticagrelor DAPT with bleeding events
is shown in Figure 2 and eFigure 3 in the Supplement. There
were no instances of BARC type 5 bleeding events. The asso-
ciation of ticagrelor DAPT with the risk of BARC type 2, 3, or 5
bleeding events was consistent across important clinical sub-
groups (eFigure 8 in the Supplement). Ticagrelor DAPT was not
associated with significant differences in the individual com-
ponents of MACCE or MACE (Figure 2).
Ticagrelor DAPT was associated with a significantly lower
risk of net adverse events than was aspirin (17.0% vs 27.8%;
difference, −10.6% [95% CI, −16.3% to −4.9%]; OR, 0.53 [95%
CI, 0.38 to 0.75]; P < .001) but was not associated with signifi-
cant differences in net adverse major clinical events or over-
all net adverse events (eTable 7 in the Supplement).
In the network meta-analysis with aspirin as the refer-
ence group, ticagrelor DAPT was associated with a significantly

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 Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Bypass Surgery Original Investigation Research

Figure 2. Pooled Estimates for Bleeding Events and Cardiovascular Events

A Bleeding events

Bleeding Academic No. of patients with event/ Favors

Research Consortium total No. of patients (%) Difference, ticagrelor Favors
typea Ticagrelor DAPT Aspirin (95% CI), %b Odds ratio (95% CI)b DAPT aspirin P value
2-5c 97/435 (22.3) 38/436 (8.7) 13.5 (8.8 to 18.2) OR 3.02 (2.02 to 4.54) <.001
2, 3, or 5d 96/452 (22.1) 38/436 (8.7) 13.3 (8.6 to 18.0) OR 2.98 (1.99 to 4.47) <.001
3-5c 10/435 (2.3) 8/436 (1.8) 0.5 (–1.4 to 2.3) OR 1.25 (0.49 to 3.22) .64
3 or 5c 8/435 (1.8) 8/436 (1.8) 0.0 (–1.8 to 1.8) OR 1.00 (0.37 to 2.69) .99

0.1 1 10 60
Odds ratio (95% CI)

B Cardiovascular events

No. of patients with event/ Favors

total No. of patients (%) Difference, Odds or hazard ticagrelor Favors
Outcome Ticagrelor DAPT Aspirin (95% CI), %b ratio (95% CI)b DAPT aspirin P value
SVG failure or CV deathd 55/397 (13.9) 94/402 (23.4) –9.4 (–14.7 to –4.1) OR 0.52 (0.36 to 0.76) <.001
MACCEd,e 29/435 (6.7) 24/436 (5.5) 1.2 (–2.0 to 4.3) HR 1.21 (0.70 to 2.08) .50
All-cause deathc 9/435 (2.1) 4/436 (0.9) 1.2 (–0.5 to 2.8) HR 2.26 (0.70 to 7.35) .17
CVf 3/435 (0.7) 3/436 (0.7) 0.0 (–1.1 to –1.1) HR 1.01 (0.20 to 4.99) .99
Non-CVf 6/435 (1.4) 1/436 (0.2) 1.2 (0.0 to 2.3) HR 6.03 (0.73 to 50.05) .10
Myocardial infarctionc 8/435 (1.8) 6/436 (1.4) 0.5 (–1.2 to 2.1) HR 1.35 (0.47 to 3.88) .60
Strokec 6/435 (1.4) 11/436 (2.5) –1.2 (-3.0 to 0.7) HR 0.55 (0.20 to 1.47) .22
Revascularizationc 12/435 (2.8) 7/436 (1.6) 1.0 (–7.9 to 3.1) HR 1.74 (0.69 to 4.43) .26
MACEc,g 16/435 (3.7) 20/436 (4.6) –0.9 (–3.6 to 1.7) HR 0.80 (0.42 to 1.55) .48

0.1 1 10 60
Odds or hazard ratio (95% CI)

a b
Type 0 indicates no bleeding; type 1, bleeding that is not actionable and does Adjusted by trial.
not cause the patient to seek unscheduled performance of studies, c
Post hoc outcomes.
hospitalization, or treatment; type 2, any overt, actionable sign of hemorrhage d
Secondary outcome.
(eg, bleeding that does not fit type 3, 4, or 5 criteria but meets at least 1 of the
e
following: [1] requires nonsurgical medical intervention, [2] leads to Defined as the composite of all-cause death, myocardial infarction, stroke, or
hospitalization or increased level of care, or [3] prompts evaluation); type 3a, revascularization.
overt bleeding plus hemoglobin drop of 3 to 5 g/dL (provided hemoglobin f
Additional outcomes.
drop is related to the bleeding event) or any transfusion with overt bleeding; g
Defined as the composite of cardiovascular death, myocardial infarction, or
3b, overt bleeding plus hemoglobin drop of 5 g/dL (provided hemoglobin drop
stroke.
is related to the bleeding event), cardiac tamponade, bleeding requiring
surgical intervention for control (excluding dental, nasal, skin, or hemorrhoid), Includes patients from the TAP-CABG,8 DACAB,9 and POPular CABG10 trials.
and bleeding requiring intravenous vasoactive agents; 3c, intracranial See the Methods section for the full names of the studies.
hemorrhage (does not include microbleeds or hemorrhagic transformation, CV indicates cardiovascular; DAPT, dual antiplatelet therapy; HR, hazard ratio;
does include intraspinal), subcategories confirmed by autopsy or imaging or MACCE, major adverse cardiac and cerebrovascular event; MACE, major
lumbar puncture, intraocular bleed compromising vision; type 4, coronary adverse cardiovascular event; OR, odds ratio; SVG, saphenous vein graft.
artery bypass graft surgery–related bleeding; and type 5, fatal bleeding.

lower risk of saphenous vein graft failure per graft (OR, 0.49
[95% CI, 0.27 to 0.87]) whereas ticagrelor monotherapy was
not (OR, 0.94 [95% CI, 0.51 to 1.74]; I2 = 55.4%; eFigure 9 in
the Supplement).
Supplementary Analysis
Ticagrelor monotherapy was not associated with a signifi-
cant difference in saphenous vein graft failure compared with
aspirin per graft (19.3% vs 21.7%; difference, −2.6% [95% CI,
−9.1% to 3.9%]; OR, 0.86 [95% CI, 0.58 to 1.27]; P = .44) or per
patient (25.2% vs 29.3%; difference, −4.1% [95% CI, −11.9% to
3.7%]; OR, 0.81 [95% CI, 0.55 to 1.20]; P = .30; eTable 8 in the
Supplement). There was no significant difference between ti-
cagrelor monotherapy and aspirin in the association with BARC
type 2, 3, or 5 bleeding events (8.9% vs 7.3%; difference, 1.7%;
[95% CI, −2.8% to 6.1%]; OR, 1.25 [95% CI, 0.69 to 2.29]; P = .46;
eTable 9 in the Supplement).
Discussion
In this individual patient data meta-analysis of 4 RCTs includ-
ing 1316 patients and 1668 saphenous vein grafts, ticagrelor
DAPT was associated with a significantly lower risk of saphe-
nous vein graft failure and a significantly higher risk of clini-
cally important bleeding events than was aspirin.
CABG surgery is the treatment of choice for patients
with high-complexity coronary artery disease and those with
reduced left ventricular ejection fraction.6 In the US alone
approximately 300 000 patients undergo CABG surgery
annually.17 The saphenous vein is used in more than 90% of
CABG procedures.18
RCTs investigating the effect of ticagrelor DAPT vs aspi-
rin on saphenous vein graft failure have reported conflicting
results. In the DACAB trial,9 ticagrelor DAPT significantly

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 Research Original Investigation Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Bypass Surgery

Figure 3. Saphenous Vein Graft Failure in Subgroups

No. of failed SVG/

total No. of SVG (%) Difference, Odds ratio Favors Favors
Ticagrelor DAPT Aspirin (95% CI), %a (95% CI)a ticagrelor DAPT aspirin P value
Age, y
>65 28/253 (11.1) 61/270 (22.6) –11.0 (–17.7 to –4.2) 0.43 (0.26 to 0.72)
.37
≤65 26/228 (11.4) 38/224 (17.0) –6.1 (–12.9 to 0.07) 0.62 (0.35 to 1.09)
Sex
Women 10/71 (14.1) 10/70 (14.3) 1.4 (–12.0 to 14.8) 1.03 (0.35 to 3.08)
.15
Men 44/410 (10.7) 89/424 (21.0) –10.2 (–15.4 to –5.1) 0.46 (0.30 to 0.68)
Diabetesb
Yes 19/168 (11.3) 43/164 (26.2) –14.7 (–23.5 to –5.8) 0.36 (0.19 to 0.68)
.16
No 35/313 (11.1) 56/330 (17.0) –5.8 (–11.5 to –0.1) 0.62 (0.39 to 0.99)
Smoking
Yes 13/137 (9.5) 26/132 (19.7) –10.4 (–19.1 to –1.6) 0.43 (0.20 to 0.89)
.58
No 41/344 (11.9) 73/362 (20.2) –8.0 (–13.7 to –2.3) 0.54 (0.35 to 0.84)
ACSc
Yes 25/238 (10.5) 44/227 (19.4) –9.2 (–16.1 to –2.2) 0.48 (0.27 to 0.84)
.83
No 29/243 (11.9) 55/267 (20.6) –8.5 (–15.2 to –1.8) 0.53 (0.32 to 0.88)
Use of CPB
Yes 33/331 (10.0) 55/357 (15.4) –4.8 (–10.1 to 0.5) 0.62 (0.38 to 1.02)
.15
No 21/150 (14.0) 44/137 (32.1) –18.1 (–28.0 to –8.3) 0.34 (0.19 to 0.63)
Sequential SVGd
Yes 41/287 (14.3) 70/304 (23.0) –8.6 (–16.1 to –1.0) 0.56 (0.33 to 0.93)
.41
No 13/194 (6.7) 29/190 (15.3) –8.7 (–15.5 to –1.9) 0.40 (0.19 to 0.84)

0.1 1 5
Odds ratio (95% CI)

Subgroup analyses for harvesting technique and target vessel territory could
not be performed due to the limited number of events in the endoscopic-
harvesting group and left anterior descending coronary artery territory group.
Treatment duration varied in 1 trial only.
a
Adjusted by trial.
b ACS indicates acute coronary syndrome; CPB, cardiopulmonary bypass;
Self-reported diagnosis, elevated hemoglobin A1c levels, or active therapy.
Definitions varied by trial.
c
Includes ST-segment elevation myocardial infarction, non–ST-segment
elevation ACS, or unstable angina. Definitions varied by trial.
d
Defined as saphenous vein grafts with more than 1 anastomosis.
Includes patients from the TAP-CABG,8 DACAB,9 and POPular CABG10 trials.
See the Methods section for the full names of the studies.
DAPT, dual antiplatelet therapy; SVG, saphenous vein graft.

increased saphenous vein graft patency 1 year after CABG.
In contrast, in the POPular CABG trial,10 ticagrelor DAPT did
not significantly reduce saphenous vein graft occlusion 1 year
after CABG surgery. The TAP-CABG trial8 also did not find a
significant difference in the absolute risk of saphenous vein
graft occlusion between ticagrelor DAPT and aspirin 3 months
after CABG.
In addition, the published RCTs were all individually un-
derpowered to detect even moderate differences in bleeding
outcomes. Although they did not individually report an in-
crease in major bleeding events with ticagrelor DAPT,8-10 a solid
estimate of the risk to benefit ratio of ticagrelor DAPT after
CABG surgery was not possible.
An aggregate network meta-analysis of 20 RCTs that as-
sessed the effects of oral antithrombotic drugs and included
2 RCTs (203 patients) comparing ticagrelor DAPT with aspirin
did not show a significant difference in major bleeding events
between the groups (OR, 1.93 [95% CI, 0.30-12.4]).19 In an-
other meta-analysis of 5 RCTs and 3996 patients, there was no
significant difference in the risk of bleeding between ticagrelor–
based antiplatelet therapy vs aspirin and/or clopidogrel (rela-
tive risk, 1.04 [95% CI, 0.95-1.14]; P = .41).20 However, indi-
vidual studies used different bleeding definitions and this
greatly limits the clinical relevance of the results from trial-
level meta-analyses.
In the present work, graft failure and bleeding events were
readjudicated using a common definition before pooling, al-
lowing generation of homogeneous pooled estimates of the as-
sociation of ticagrelor DAPT with saphenous vein graft fail-
ure and bleeding events.
This comprehensive synthesis of all RCTs with angio-
graphic follow-up provides solid evidence that ticagrelor DAPT
is associated with a significantly lower risk of saphenous vein
graft failure 1 year after CABG surgery. The association of ti-
cagrelor DAPT with the risk of saphenous vein graft failure was
consistent across subgroups. However, compared with aspi-
rin, ticagrelor DAPT was also associated with a significantly
higher risk of BARC type 2 or higher bleeding events. There was
also an absolute increase in the risk of all-cause death in the
ticagrelor DAPT group, although not statistically significant.
Taken together, the present analysis suggests that a patient’s
individual risk of graft failure, ischemic events, and bleeding
needs to be weighed carefully when deciding whether to add
ticagrelor to aspirin after CABG surgery. Longer-term follow-up
is required to fully evaluate a potential benefit of ticagrelor
DAPT on clinical events.21

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 Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Bypass Surgery Original Investigation Research

Individual RCTs investigating the effect of ticagrelor mono-
therapy vs aspirin after CABG surgery have not shown an effect
on saphenous vein graft failure but have all been limited by the
small sample size.9,11 In this meta-analysis, ticagrelor mono-
therapy was not associated with a significant difference in the
risk of saphenous vein graft failure compared with aspirin, but
the pooled estimate was compatible with a potential benefit of
ticagrelor monotherapy. Because ticagrelor monotherapy was
not associated with a significant difference in the risk of bleed-
ing events compared with aspirin, its role as a treatment option
after CABG surgery requires further investigation.
agement across the included RCTs. Third, the duration of ti-
cagrelor DAPT and timing of follow-up ranged from 3 to 12
months across the included RCTs. Fourth, the analysis was not
designed to evaluate differences in clinical outcomes be-
tween groups. Lastly, protocol-directed imaging was missing
in 9.1% of patients. However, patient characteristics were bal-
anced across randomization groups for patients who under-
went imaging, and the results for the primary outcome were
consistent after multiple imputation of missing data.

Limitations
This study has several limitations. First, the pooled analysis
is subject to the limitations of the original RCTs, including the
open-label treatment allocation in 1 of them, although out-
come adjudication was blinded in all RCTs. Second, there was
heterogeneity in surgical technique and postoperative man-
Conclusions
In patients undergoing coronary artery bypass graft surgery,
adding ticagrelor to aspirin was associated with a signifi-
cantly decreased risk of vein graft failure. However, this was
accompanied by a significantly increased risk of clinically im-
portant bleeding.

ARTICLE INFORMATION
Accepted for Publication: June 23,2022.
Author Affiliations: Department of Cardiac
Surgery, Medical University of Vienna, Vienna,
Austria (Sandner); Weill Cornell Medicine, New
York, New York (Sandner); Department of
Cardiology, Sahlgrenska University Hospital,
Gothenburg, Sweden (Redfors); Division of
Cardiology, University of Florida College of
Medicine, Jacksonville (Angiolillo); Department of
Cardiothoracic Surgery, Weill Cornell Medicine,
New York, New York (Audisio, Soletti, Gaudino);
Schulich Heart Centre, Sunnybrook Health Sciences
Centre, University of Toronto, Toronto, Ontario,
Canada (Fremes); Institute of Health Policy
Management and Evaluation, University of Toronto,
Toronto, Ontario, Canada (Fremes); Department of
Cardiology, St Antonius Hospital, Nieuwegein, the
Netherlands (Janssen, Peper, ten Berg, Willemsen);
Division of Cardiac Surgery, Boca Raton Regional
Hospital and Florida Atlantic Hospital, Boca Raton
(Kulik); Zena and Michael A. Wiener Cardiovascular
Institute, Icahn School of Medicine at Mount Sinai,
New York, New York (Mehran); Division of Cardiac
Surgery, University of Ottawa Heart Institute,
Ottawa, Ontario, Canada (Ruel); Division of
Cardiology, Vancouver General Hospital, British
Columbia, Canada (Saw, Starovoytov); Division of
Cardiology St Paul’s Hospital, University of British
Columbia, Vancouver, Canada (Saw); Ruijin Hospital
Shanghai Jiao Tong University School of Medicine,
Shanghai, China (Zhao, Zhu).
Author Contributions: Drs Sandner and Redfors
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis. Drs Sandner and
Redfors contributed equally.
Concept and design: Sandner, Fremes, Mehran,
Peper, Ruel, Zhao, Zhu, Gaudino.
Acquisition, analysis, or interpretation of data:
Sandner, Redfors, Angiolillo, Audisio, Fremes,
Janssen, Kulik, Peper, Ruel, Saw, Soletti,
Starovoytov, ten Berg, Willemsen, Gaudino.
Drafting of the manuscript: Sandner, Redfors, Kulik,
Gaudino.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Redfors, Kulik, Gaudino.
Obtained funding: Janssen, Ruel.
Administrative, technical, or material support:
Janssen, Ruel, Saw, Soletti, Starovoytov.
Supervision: Angiolillo, Janssen, Soletti,
Starovoytov, ten Berg, Willemsen, Gaudino.
Other - protocol review: Willemsen.
Conflict of Interest Disclosures: Dr Sandner
reported receiving institutional research grants
from Vascular Grafts Solutions outside the
submitted work. Dr Angiolillo reported receiving
consulting fees or honoraria from Abbott, Amgen,
AstraZeneca, Bayer, Biosensors, Boehringer
Ingelheim, Bristol Myers Squibb, Chiesi,
Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen,
Merck, PhaseBio, PLx Pharma, Pfizer, and Sanofi;
and research grants to his institution from Amgen,
AstraZeneca, Bayer, Biosensors, CeloNova, CSL
Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead,
Janssen, Matsutani Chemical Industry Co, Merck,
Novartis, Osprey Medical, Renal Guard Solutions,
and the Scott R. MacKenzie Foundation. Dr Janssen
reported receiving grants from AstraZeneca
funding for the POPular CABG trial during the
conduct of the study. Dr Kulik reported receiving
grants from AstraZeneca during the conduct of the
study. Dr Mehran reported receiving research
grants from Abbott, Abiomed, Alleviant Medical,
AM-Pharma, Applied Therapeutics, Arena,
AstraZeneca, Bayer, Beth Israel Deaconess,
Biosensors, Biotronik, Bristol Myers Squibb, Boston
Scientific Research, CardiaWave Research,
CellAegis, CeloNova, CERC, Chiesi, Concept
Medical, CSL Behring, Daiichi Sankyo Inc, Duke
University, Humacyte, Idorsa Pharmaceuticals, Insel
Gruppe AG, Janssen, Medtronic, Novartis,
OrbusNeich, Philips, Vivasure, and Zoll, all to her
institution; serving as a consultant to the California
Institute for Regenerative Medicine; serving on the
scientific advisory board of the American Medical
Association; serving on the advisory boards of
CERC (Biosnsors), Abbott, Arena, Biotronik,
CardiaWave, Chiesi, Concept Medical, Humacyte,
Magenta, Novartis, and Philips, all to her institution;
serving on the board of the American College of
Cardiology, and as a committee member of the
Women in Innovations of the Society for
Cardiovascular Angiography, all to her institution;
serving as an unpaid faculty of the Cardiovascular
Research Foundation; receiving personal fees from
Cine-Med, Janssen, and WebMD; receiving less
than 1% of equity in Applied Therapeutics Equity,
Elixir Medical, Stel, and ControlRad Equity (spouse)
outside the submitted work; and having other
financial or nonfinancial interests in Boston
Scientific Corp and divested final stock options of
less than 1% in Claret Medical. Dr Saw reported
receiving grants from AstraZeneca outside the
submitted work and serving as the principal
investigator for the TAP-CABG study. Dr ten Berg
reported receiving speaker fees from AstraZeneca,
Bayer, Boehringer Ingelheim, and Celecor and
institutional research grants from AstraZeneca and
ZonMw. Dr Willemsen reported receiving grants
from AstraZeneca funding of the POPular CABG
trial during the conduct of the study. Dr Zhao
reported receiving grants from AstraZeneca during
the conduct of the study and from Chugai Pharma
China outside the submitted work. Dr Zhu reported
receiving personal fees from Chugai Pharma China
outside the submitted work. No other disclosures
were reported.
Funding/Support: This study was supported using
internal funds from the Department of
Cardiothoracic Surgery at Weill Cornell Medicine,
New York.
Role of the Funder/Sponsor: The funder had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
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