Adding CABG to the Dual Antiplatelet Salad∗

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 69, NO. 2, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION.

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER. ALL RIGHTS RESERVED.

http://dx.doi.org/10.1016/j.jacc.2016.10.040

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

difference in outcomes after CABG. In the PLATO

(DAPT) in patients with acute coronary syn-

(Platelet Inhibition and Patient Outcomes) trial, which

drome (ACS) treated with medical therapy

compared ticagrelor with clopidogrel (with all patients

with or without coronary stent implantation (CSI)

receiving aspirin therapy), 1,899 patients underwent

have been the subject of large randomized trials and

CABG post-randomization (2). At 12-month follow-up,

hundreds of manuscripts. Less attention has been

ticagrelor resulted in statistically significant re-

given to intermediate- and long-term DAPT in pa-

ductions over clopidogrel in the primary ischemic

tients with ACS treated with coronary artery bypass

composite endpoint (10.6% vs. 13.1%), cardiovascular

grafting (CABG).

death (4.1% vs. 7.9%), and total mortality (4.7% vs.

Conceptually, there are 4 reasons to treat ACS pa-

9.7%). Unfortunately, patients with ACS who under-

tients who undergo CABG with DAPT: 1) pacification of

went CABG were not included in the PEGASUS-TIMI

the culprit unstable plaque; 2) prevention of sponta-

54 (Prevention of Cardiovascular Events in Patients

neous myocardial infarction resulting from nonculprit

with Prior Heart Attack Using Ticagrelor Compared

plaque rupture/fissure; 3) increased saphenous vein

to Placebo on a Background of Aspirin) trial (3).

graft patency; and 4) prevention of stent thrombosis in patients treated with CSI before CABG.

Recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines on non-ST

The most relevant data on antiplatelet mono-

elevation myocardial infarction (4), ST-elevation

therapy versus DAPT in patients with ACS undergoing

myocardial infarction (5), and CABG (6) do not

CABG come from subgroup analysis of the CURE (Clo-

contain specific recommendations on DAPT after

pidogrel in Unstable angina to prevent Recurrent

CABG in patients with ACS. The 2016 ACC/AHA

ischemic Events) trial (1). For those who underwent

Guideline Focused Update on Duration of Dual

CABG during initial hospitalization, the composite

Antiplatelet Therapy in Patients With Coronary

primary endpoint occurred in 14.5% and 16.2% of those

Artery Disease makes a Class I recommendation for

treated with DAPT and aspirin monotherapy, respec-

at least 12 months of DAPT in patients with ACS

tively (relative risk: 0.89; 95% confidence interval: 0.71

treated with CABG (7). Although a 2014 European

to 1.11). However, the trial was not powered to detect a

Society of Cardiology expert position paper stated

statistically significant benefit for this subgroup anal-

that, for patients who undergo CABG within 1 year

ysis. Of note, almost all of the reduction in ischemic

of ACS, resumption of P2Y 12 inhibitor should be

events occurred before CABG, with little apparent

considered (Class IIa) (8), the 2015 European Society of Cardiology Guidelines for management of ACS in patients presenting without persistent ST-segment

*Editorials published in the Journal of the American College of Cardiology

elevation (9) recommend P2Y12 inhibitor therapy in

reflect the views of the authors and do not necessarily represent the

addition to aspirin for 12 months irrespective of the

views of JACC or the American College of Cardiology.

revascularization strategy (9).

From the aDepartment of Medicine, Baylor College of Medicine and the

The impact of DAPT on saphenous vein graft

Michael E. DeBakey VA Medical Center, Houston, Texas; and the bHeart

patency 1 to 12 months post-CABG has been evaluated

and Vascular Institute, Department of Thoracic and Cardiovascular Sur-

in a limited number of studies, 1 systematic overview,

gery, Cleveland Clinic, Cleveland, Ohio. Both authors have reported that they have no relationships relevant to the contents of this paper to

and 2 meta-analyses. Results have been inconsistent,

disclose.

with some showing no benefit and a few suggesting

Levine and Bakaeen

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:128–30

Adding CABG to the Dual Antiplatelet Salad

increased patency (10,11). A 2015 AHA Scientific

antiplatelet therapy. The lack of increased bleeding in

Statement, and the ACC/AHA 2016 DAPT focused

those who were believed to be taking DAPT raises

update give “soft” Class IIb recommendations for

questions about how long and how consistently pa-

DAPT for 1 year post-CABG to improve vein graft

tients were taking DAPT because virtually every other

patency (10,11).

study of comparing DAPT versus aspirin mono-

There are minimal data regarding DAPT after CABG in patients with recent prior CSI. Although in many

therapy has reported an increased rate of bleeding (11,15–19).

cases the stented artery may be treated with a bypass

Some, though not all, subgroup analysis of diabetic

graft, stent thrombosis and subsequent thrombus

patients enrolled in studies of DAPT (with clopidog-

propagation in the bypassed coronary artery could

rel) versus aspirin monotherapy have found no

lead to side branch occlusion, distal thrombus

greater (or even lesser) benefit with DAPT in those

embolization,

with

and

bypass

conduit

compromise.

diabetes The

compared

those

those with a history of prior PCI who undergo CABG

neither CURE nor PLATO reports outcomes in those

(12), the contribution of stent thrombosis to this

with diabetes versus those without (1,2). More

observation is not well defined. The 2016 ACC/AHA

recently, a subgroup analysis from PEGASUS found

DAPT focused update recommends that patients

similar relative risk reduction with ticagrelor plus

treated with DAPT after CSI who subsequently

aspirin therapy, with greater absolute risk reduction,

undergo CABG should have P2Y12 inhibitor resumed

and

postoperatively so that DAPT continues until the

compared with clopidogrel plus aspirin. Whether

in

subgroup

without

(3,14,20,21).

reduction

CABG

with

Although short- and long-term outcome is worse in

analysis

cardiovascular

death

from

when

recommended duration of therapy is completed.

DAPT with ticagrelor would be of greater benefit than

This recommendation is, however, admittedly based

DAPT with clopidogrel in patients with diabetes un-

on expert opinion (11).

dergoing CABG is a topic that warrants further investigation.

SEE PAGE 119

In the FREEDOM trial, 68% of patients who underwent CABG were treated with DAPT. The study

In this issue of the Journal, van Diepen et al. (13)

authors note that this rate of DAPT use is higher than

the

the 22% to 54% rates reported in retrospective ob-

FREEDOM (Future Revascularization Evaluation in

servations studies (13). In a recent survey of Canadian

Patients with Diabetes Mellitus: Optimal Management

cardiac surgeons, fewer than one-half of respon-

of Multivessel Disease) trial comparing adjudicated

dents reported routinely using DAPT post-CABG in

outcomes between aspirin monotherapy and DAPT in

the setting of ACS (22). In the FREEDOM trial, those

post-CABG patients with diabetes (13). Evaluating

treated with DAPT were younger, had a lower

DAPT in post-CABG patients with diabetes is impor-

median EuroSCORE (European System for Cardiac

tant because patients with diabetes are known to be

Operative Risk Evaluation) had a higher mean num-

at higher risk of cardiovascular events (14). This

ber of bypass grafts, and less frequently underwent

analysis found no significant differences in either the

transmyocardial revascularization or right internal

primary composite outcome of all-cause death, MI, or

mammary artery grafting. Those enrolled in North

stroke, or bleeding outcomes between aspirin- and

America, South America, India, and Israel were more

DAPT-treated patients, including a subgroup of pa-

frequently treated with DAPT, whereas those enrolled

tients with pre-CABG ACS. Several important caveats

in Europe were more commonly treated with aspirin

are necessary. The primary endpoint was 5-year

monotherapy. Indications (stable angina or ACS) for

all-cause mortality, nonfatal myocardial infarction, or

initial coronary angiography did not appear to

stroke, yet median duration of DAPT treatment was

significantly influence choice of antiplatelet mono-

only 1 year. DAPT therapy was not randomized, and

therapy or DAPT. These observations suggest that

there were significant differences in baseline charac-

surgical philosophy, preference, and local practice

report

a

post

hoc

secondary

analysis

of

teristics between those who were and were not

patterns

treated with DAPT. Data regarding the precise timing

antithrombotic regimens.

significantly

influence

the

post-CABG

of DAPT initiation, treatment compliance, or treat-

In summary, there is modest but not definitive data

ment crossover between the 2 groups after 30 days

on potential benefits of DAPT post-CABG, including in

was not captured, potentially confounding the re-

patients with ACS and patients with diabetes. Addi-

sults. The study was neither designed nor powered to

tion, intensification, or prolongation of antiplatelet

assess differences in outcome based upon mode of

therapy,

although

decreasing

ischemic

events,

129

130

Levine and Bakaeen

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:128–30

Adding CABG to the Dual Antiplatelet Salad

increases bleeding complications (11). It is thus not surprising that many surgeons are not prescribing

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

such therapy. Whether findings from this current

Glenn N. Levine, Section of Cardiology, Michael E.

study lead to modifications of future guideline rec-

DeBakey VA Medical Center, 2002 Holcombe Boule-

ommendations or impact practice patterns remains to

vard, Houston, Texas 77584. E-mail: glevine@bcm.

be determined.

tmc.edu.

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KEY WORDS antiplatelet therapy, aspirin, clopidogrel, coronary artery bypass grafting