JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION.
PUBLISHED BY ELSEVIER. ALL RIGHTS RESERVED.
EDITORIAL COMMENT
Adding CABG to the
Dual Antiplatelet Salad*
Glenn N. Levine, MD,a Faisal G. Bakaeen, MDb
B enefits and risks of dual antiplatelet therapy
(DAPT) in patients with acute coronary syn-
drome (ACS) treated with medical therapy
with or without coronary stent implantation (CSI)
have been the subject of large randomized trials and
hundreds of manuscripts. Less attention has been
given to intermediate- and long-term DAPT in pa-
tients with ACS treated with coronary artery bypass
grafting (CABG).
Conceptually, there are 4 reasons to treat ACS pa-
tients who undergo CABG with DAPT: 1) pacification of
the culprit unstable plaque; 2) prevention of sponta-
neous myocardial infarction resulting from nonculprit
plaque rupture/fissure; 3) increased saphenous vein
graft patency; and 4) prevention of stent thrombosis in
patients treated with CSI before CABG.
The most relevant data on antiplatelet mono-
therapy versus DAPT in patients with ACS undergoing
CABG come from subgroup analysis of the CURE (Clo-
pidogrel in Unstable angina to prevent Recurrent
ischemic Events) trial (1). For those who underwent
CABG during initial hospitalization, the composite
primary endpoint occurred in 14.5% and 16.2% of those
treated with DAPT and aspirin monotherapy, respec-
tively (relative risk: 0.89; 95% confidence interval: 0.71
to 1.11). However, the trial was not powered to detect a
statistically significant benefit for this subgroup anal-
ysis. Of note, almost all of the reduction in ischemic
events occurred before CABG, with little apparent
*Editorials published in the Journal of the American College of Cardiology
reflect the views of the authors and do not necessarily represent the
views of JACC or the American College of Cardiology.
From the aDepartment of Medicine, Baylor College of Medicine and the
Michael E. DeBakey VA Medical Center, Houston, Texas; and the bHeart
and Vascular Institute, Department of Thoracic and Cardiovascular Sur-
gery, Cleveland Clinic, Cleveland, Ohio. Both authors have reported that
they have no relationships relevant to the contents of this paper to
disclose.
VOL. 69, NO.
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2016.10.040
difference in outcomes after CABG. In the PLATO
(Platelet Inhibition and Patient Outcomes) trial, which
compared ticagrelor with clopidogrel (with all patients
receiving aspirin therapy), 1,899 patients underwent
CABG post-randomization (2). At 12-month follow-up,
ticagrelor resulted in statistically significant re-
ductions over clopidogrel in the primary ischemic
composite endpoint (10.6% vs. 13.1%), cardiovascular
death (4.1% vs. 7.9%), and total mortality (4.7% vs.
9.7%). Unfortunately, patients with ACS who under-
went CABG were not included in the PEGASUS-TIMI
54 (Prevention of Cardiovascular Events in Patients
with Prior Heart Attack Using Ticagrelor Compared
to Placebo on a Background of Aspirin) trial (3).
Recent American College of Cardiology/American
Heart Association (ACC/AHA) guidelines on non-ST
elevation myocardial infarction (4), ST-elevation
myocardial infarction (5), and CABG (6) do not
contain specific recommendations on DAPT after
CABG in patients with ACS. The 2016 ACC/AHA
Guideline Focused Update on Duration of Dual
Antiplatelet Therapy in Patients With Coronary
Artery Disease makes a Class I recommendation for
at least 12 months of DAPT in patients with ACS
treated with CABG (7). Although a 2014 European
Society of Cardiology expert position paper stated
that, for patients who undergo CABG within 1 year
of ACS, resumption of P2Y 12 inhibitor should be
considered (Class IIa) (8), the 2015 European Society
of Cardiology Guidelines for management of ACS in
patients presenting without persistent ST-segment
elevation (9) recommend P2Y12 inhibitor therapy in
addition to aspirin for 12 months irrespective of the
revascularization strategy (9).
The impact of DAPT on saphenous vein graft
patency 1 to 12 months post-CABG has been evaluated
in a limited number of studies, 1 systematic overview,
and 2 meta-analyses. Results have been inconsistent,
with some showing no benefit and a few suggesting
JACC VOL. 69, NO. 2, 2017
JANUARY 17, 2017:128–30
increased patency (10,11). A 2015 AHA Scientific
Statement, and the ACC/AHA 2016 DAPT focused
update give “soft” Class IIb recommendations for
DAPT for 1 year post-CABG to improve vein graft
patency (10,11).
There are minimal data regarding DAPT after CABG
in patients with recent prior CSI. Although in many
cases the stented artery may be treated with a bypass
graft, stent thrombosis and subsequent thrombus
propagation in the bypassed coronary artery could
lead to side branch occlusion, distal thrombus
embolization, and bypass conduit compromise.
Although short- and long-term outcome is worse in
those with a history of prior PCI who undergo CABG
(12), the contribution of stent thrombosis to this
observation is not well defined. The 2016 ACC/AHA
DAPT focused update recommends that patients
treated with DAPT after CSI who subsequently
undergo CABG should have P2Y12 inhibitor resumed
postoperatively so that DAPT continues until the
recommended duration of therapy is completed.
This recommendation is, however, admittedly based
on expert opinion (11).
SEE PAGE 119
In this issue of the Journal, van Diepen et al. (13)
report a post hoc secondary analysis of the
FREEDOM (Future Revascularization Evaluation in
Patients with Diabetes Mellitus: Optimal Management
of Multivessel Disease) trial comparing adjudicated
outcomes between aspirin monotherapy and DAPT in
post-CABG patients with diabetes (13). Evaluating
DAPT in post-CABG patients with diabetes is impor-
tant because patients with diabetes are known to be
at higher risk of cardiovascular events (14). This
analysis found no significant differences in either the
primary composite outcome of all-cause death, MI, or
stroke, or bleeding outcomes between aspirin- and
DAPT-treated patients, including a subgroup of pa-
tients with pre-CABG ACS. Several important caveats
are necessary. The primary endpoint was 5-year
all-cause mortality, nonfatal myocardial infarction, or
stroke, yet median duration of DAPT treatment was
only 1 year. DAPT therapy was not randomized, and
there were significant differences in baseline charac-
teristics between those who were and were not
treated with DAPT. Data regarding the precise timing
of DAPT initiation, treatment compliance, or treat-
ment crossover between the 2 groups after 30 days
was not captured, potentially confounding the re-
sults. The study was neither designed nor powered to
assess differences in outcome based upon mode of
Levine and Bakaeen 129
Adding CABG to the Dual Antiplatelet Salad
antiplatelet therapy. The lack of increased bleeding in
those who were believed to be taking DAPT raises
questions about how long and how consistently pa-
tients were taking DAPT because virtually every other
study of comparing DAPT versus aspirin mono-
therapy has reported an increased rate of bleeding
(11,15–19).
Some, though not all, subgroup analysis of diabetic
patients enrolled in studies of DAPT (with clopidog-
rel) versus aspirin monotherapy have found no
greater (or even lesser) benefit with DAPT in those
with diabetes compared with those without
(3,14,20,21). The CABG subgroup analysis from
neither CURE nor PLATO reports outcomes in those
with diabetes versus those without (1,2). More
recently, a subgroup analysis from PEGASUS found
similar relative risk reduction with ticagrelor plus
aspirin therapy, with greater absolute risk reduction,
and reduction in cardiovascular death when
compared with clopidogrel plus aspirin. Whether
DAPT with ticagrelor would be of greater benefit than
DAPT with clopidogrel in patients with diabetes un-
dergoing CABG is a topic that warrants further
investigation.
In the FREEDOM trial, 68% of patients who un-
derwent CABG were treated with DAPT. The study
authors note that this rate of DAPT use is higher than
the 22% to 54% rates reported in retrospective ob-
servations studies (13). In a recent survey of Canadian
cardiac surgeons, fewer than one-half of respon-
dents reported routinely using DAPT post-CABG in
the setting of ACS (22). In the FREEDOM trial, those
treated with DAPT were younger, had a lower
median EuroSCORE (European System for Cardiac
Operative Risk Evaluation) had a higher mean num-
ber of bypass grafts, and less frequently underwent
transmyocardial revascularization or right internal
mammary artery grafting. Those enrolled in North
America, South America, India, and Israel were more
frequently treated with DAPT, whereas those enrolled
in Europe were more commonly treated with aspirin
monotherapy. Indications (stable angina or ACS) for
initial coronary angiography did not appear to
significantly influence choice of antiplatelet mono-
therapy or DAPT. These observations suggest that
surgical philosophy, preference, and local practice
patterns significantly influence the post-CABG
antithrombotic regimens.
In summary, there is modest but not definitive data
on potential benefits of DAPT post-CABG, including in
patients with ACS and patients with diabetes. Addi-
tion, intensification, or prolongation of antiplatelet
therapy, although decreasing ischemic events,
130 Levine and Bakaeen
Adding CABG to the Dual Antiplatelet Salad
increases bleeding complications (11). It is thus not
surprising that many surgeons are not prescribing
such therapy. Whether findings from this current
study lead to modifications of future guideline rec-
ommendations or impact practice patterns remains to
be determined.
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REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Glenn N. Levine, Section of Cardiology, Michael E.
DeBakey VA Medical Center, 2002 Holcombe Boule-
vard, Houston, Texas 77584. E-mail: glevine@bcm.
tmc.edu.
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KEY WORDS antiplatelet therapy, aspirin,
clopidogrel, coronary artery bypass grafting