Dual Antiplatelet Therapy Versus Aspirin Monotherapy in Diabetics With Multivessel Disease Undergoing CABG

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 69, NO. 2, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2016.10.043

ORIGINAL INVESTIGATIONS

Dual Antiplatelet Therapy Versus Aspirin Monotherapy in Diabetics With Multivessel Disease Undergoing CABG FREEDOM Insights Sean van Diepen, MD, MSC,a,b Valentin Fuster, MD, PHD,c Subodh Verma, MD, PHD,d Taye H. Hamza, PHD,e F. Sandra Siami, MPH,e Shaun G. Goodman, MD, MSC,b,f Michael E. Farkouh, MD, MSCg

ABSTRACT BACKGROUND Clinical practice guidelines recommend post-operative dual antiplatelet therapy (DAPT) in patients who undergo coronary artery bypass grafting (CABG) following acute coronary syndromes (ACS). OBJECTIVES The authors have evaluated DAPT utilization rates and associated outcomes among post-CABG patients with diabetes. METHODS In a post hoc, nonrandomized analysis from the FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial, we compared patients receiving DAPT (aspirin plus thienopyridine) and aspirin monotherapy at 30 days post-operatively. The primary outcome was the risk adjusted 5-year FREEDOM composite of all-cause mortality, nonfatal myocardial infarction, or stroke. Safety outcomes included major bleeding, blood transfusion, and hospitalization for bleeding. RESULTS At 30 days post-CABG, 544 (68.4%) patients received DAPT and 251 (31.6%) patients received aspirin alone. The median (25th, 75th percentile) duration of clopidogrel therapy was 0.98 (0.23 to 1.91) years. There was no significant difference in the 5-year primary composite outcome between DAPT- and aspirin-treated patients (12.6% vs. 16.0%; adjusted hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.54 to 1.27; p ¼ 0.39). The 5-year primary composite outcomes were similar for patients receiving DAPT versus aspirin monotherapy respectively, in subgroups with pre-CABG ACSs (15.2% vs. 16.5%; HR: 1.06; 95% CI: 0.53 to 2.10; p ¼ 0.88) and those with stable angina (11.6% vs. 15.8%; HR: 0.82; 95% CI: 0.50 to 1.343; p ¼ 0.42). The composite outcomes of both treatment groups were also similar by SYNTAX score, duration of DAPT therapy, completeness of revascularization, and in off-pump CABG. No treatment-related differences in major bleeding (5.6% vs. 5.7%; HR: 1.00; 95% CI: 0.50 to 1.99; p ¼ 0.99), blood transfusions (4.8% vs. 4.5%; HR: 1.09; 95% CI: 0.51 to 2.34; p ¼ 0.82), or hospitalization for bleeding (2.6% vs. 3.3%; HR: 0.85; 95% CI: 0.34 to 2.17; p ¼ 0.74) were observed between aspirin- and DAPT-treated patients, respectively. CONCLUSIONS The use of DAPT in patients with diabetes post-CABG in our cohort was high. Compared with aspirin monotherapy, no associated differences were observed in cardiovascular or bleeding outcomes, suggesting that routine use of DAPT may not be clinically warranted. (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease [FREEDOM]; NCT00086450) (J Am Coll Cardiol 2017;69:119–27) Listen to this manuscript’s

© 2017 by the American College of Cardiology Foundation.

audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. From the aDepartment of Critical Care and Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada; bCanadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada; cIcahn School of Medicine at Mount Sinai, New York, New York; dDivision of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; eNew England Research Institutes, Inc., Watertown, Massachusetts; fTerrence Donnelly Heart Centre, Division of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; and the gPeter Munk Cardiac Centre and the Heart and Stroke Richard

120

van Diepen et al.

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:119–27

Dual Antiplatelet Therapy in Diabetics After CABG

C

ABBREVIATIONS AND ACRONYMS CABG = coronary artery bypass

oronary

artery

bypass

surgery

(CABG) reduces long-term morbidity and mortality in patients with

multivessel disease with or without diabetes

surgery

(1–3). Aspirin alone has been reported to

CI = confidence interval

improve vein graft patency and mortality

DAPT = dual antiplatelet

(4,5). Dual antiplatelet therapy (DAPT) with

therapy

aspirin and a thienopyridine is a theoretically

HR = hazard ratio

attractive secondary prevention therapy,

MI = myocardial infarction

given that bypass graft thrombosis and sys-

NSAID = nonsteroidal anti-

temic hypercoagulability are potential causes

inflammatory drug

of saphenous vein graft failure (6). In addi-

PPI = proton pump inhibitor

tion, native coronary artery atherothrombotic risk for plaque rupture, ulceration, or erosion remains post-CABG (7,8). Clinical practice guidelines currently recommend DAPT in patients who undergo CABG for

drug-eluting stents. All study participants provided written consent. STUDY POPULATION AND DEFINITIONS. This anal-

ysis included all patients who underwent primary revascularization with CABG (per-protocol analysis) and were taking aspirin 30 days post-operatively. Patients undergoing DAPT were defined as all patients who were receiving aspirin and a thienopyridine (clopidogrel or ticlopidine) at 30 days post-operatively. The aspirin cohort was defined as those receiving aspirin monotherapy at 30 days. Patients receiving warfarin at 30 days were excluded. The primary analysis compared 5-year outcomes in patients treated with DAPT versus aspirin alone at 30-days post-CABG. The secondary analysis examined 1-year outcomes.

an acute coronary syndrome; however, the efficacy

OUTCOMES. The primary outcome was the FREEDOM

of DAPT reported in observational studies, subgroup

trial primary endpoint of 5-year all-cause mortality,

analyses, and small randomized trials that underpin

nonfatal myocardial infarction (MI), or stroke. Second-

these recommendations is uncertain, and DAPT may

ary outcomes included the individual components of

be associated with a higher risk of bleeding (9–16).

the composite outcomes: vascular death, MI, and cardiovascular

SEE PAGE 128

Diabetes

is

independently

hospitalization

(defined

as

unstable

angina, MI, heart failure, chest pain, arrhythmia, with

peripheral vascular disease, or stroke or transient

increased perioperative and long-term mortality in

associated

ischemic attack). Safety outcomes were major bleeding,

CABG patients, and may be a clinical risk factor for

blood transfusions, and bleeding hospitalization. All

vein graft failure (17–20). Hence, diabetics may be a

events were adjudicated by a clinical events committee.

unique high-risk subgroup that may benefit from

In a priori analysis, we also explored the primary

DAPT secondary prevention therapy, but little evi-

outcome and major bleeding in the following sub-

dence is available to support this hypothesis. The

groups: 1) patients revascularized following an acute

purpose of this analysis is to compare the long-term

coronary syndrome event versus stable angina; 2)

clinical and bleeding outcomes associated with

SYNTAX score (<22, 22 to 32, $32); 3) complete versus

DAPT versus aspirin monotherapy in post-bypass di-

incomplete revascularization; 4) patients with an

abetics with multivessel coronary artery disease from

endarterectomy or vein graft patching; 5) on- and off-

the FREEDOM (Future REvascularization Evaluation

pump CABG; 6) patients who maintained DAPT for a

in patients with Diabetes mellitus: Optimal manage-

minimum of 1 year; and 7) post-operative glomerular

ment of Multivessel disease) trial (1).

filtration rate.

METHODS

STATISTICAL METHODS. Categorical baseline char-

acteristics were summarized as number of subjects DATA SOURCE. The methods and results of the

and percentages. The difference between the 2 treat-

FREEDOM trial have been published (1,21). Briefly,

ment groups was tested using Fisher exact test.

this

enrolled

Continuous baseline characteristics were summarized

patients $ 18 years of age with diabetes mellitus (DM)

as median and quartiles. The differences between the 2

and with $70% stenosis of 2 or more major epi-

treatment groups were tested using Kruskal-Wallis

cardial vessels. Patients were randomized to either

test statistics. The times to primary, secondary, and

CABG or percutaneous coronary intervention with

safety outcomes were analyzed using Cox proportional

international

multicenter

study

Lewar Centre, University of Toronto, Toronto, Ontario, Canada. Dr. van Diepen has received honoraria and/or grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Pfizer, Merck, Novartis, Amgen, Sorin, Abbott, and Janssen. Dr. Goodman has received research grant support and speaker/consulting honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, and Sanofi. All other authors have reported that they have no relationships relevant to the contents for this paper to disclose. Faisal Bakaeen, MD, served as Guest Editor for this paper. Manuscript received September 29, 2016; accepted October 12, 2016.

van Diepen et al.

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:119–27

121

Dual Antiplatelet Therapy in Diabetics After CABG

hazard regression. Cumulative event rate curves were compared using log-rank test statistics. Whenever

T A B L E 1 Baseline Characteristics By Treatment Groups

DAPT (n ¼ 544)

Aspirin Monotherapy (n ¼ 251)

p Value

61.2 (54.8, 68.5)

63.7 (59.4, 71.2)

<0.001

392 (72.1)

176 (70.1)

possible, the Cox models were adjusted for EuroSCORE (European System for Cardiac Operative Risk Evaluation), region of enrollment (North America, Europe,

Age, yrs

South America, and others), number of grafts, right

Male

internal thoracic artery graft use, endarterectomy,

Race

endoscopic vein harvesting, and beta-blocker, non-

White

388 (71.3)

228 (90.8)

steroidal anti-inflammatory drugs (NSAID), and proton

Black or African American

38 (7.0)

8 (3.2)

Asian

57 (10.5)

7 (2.8)

Other

61 (11.2)

8 (3.2)

80.9 (69.0, 95.0)

82.0 (73.0, 93.5)

pump inhibitor (PPI) medication use at the 1 month post-CABG visit whenever possible. All analyses were

Body weight, kg

0.61 <0.001

0.32

performed using SAS (Statistical Analysis Systems,

Medical history

Cary, North Carolina) version 9.4 and R (RStudio,

Hypertension

458 (84.2)

213 (84.9)

0.83

Boston, Massachusetts) version 3.1.1.

Dyslipidemia

455 (83.6)

217 (86.5)

0.34

Type 1

20 (3.7)

16 (6.4)

Type 2

524 (96.3)

235 (93.6)

Diabetes mellitus

RESULTS

0.10

Seven hundred and ninety-five patients (83.9%) of

Current tobacco use

98 (18.0)

35 (13.9)

947 patients from the FREEDOM trial who were

MI

149 (27.4)

56 (22.3)

0.14

randomized to CABG were included in this analysis.

PCI or PTCA in previous 12 months

5 (0.9)

4 (1.6)

0.47

History of arrhythmia

18 (3.3)

7 (2.8)

0.83

Stroke or transient ischemic attack

12 (2.2)

9 (3.6)

0.34

Peripheral vascular disease

49 (9.0)

31 (12.4)

0.16

COPD

23 (4.2)

16 (6.4)

0.22

no revascularization (n ¼ 36), deceased within in the

Chronic kidney disease

22 (4.0)

19 (7.6)

0.06

first 30 days from the date of procedure (n ¼ 15), no

Indication for coronary angiography 0.13

Patients were excluded for the following reasons: randomized to CABG but underwent percutaneous coronary intervention revascularization (n ¼ 18),

aspirin therapy at 30 days (n ¼ 52), and warfarin ther-

Stable angina

398 (73.2)

170 (67.7)

apy at 30 days (n ¼ 31). At 30-days post-CABG,

Acute coronary syndrome

146 (26.8)

81 (32.3)

544 (68.4%) patients received DAPT and 251 (31.6%) patients received aspirin. The median (25th, 75th percentile) duration of thienopyridine therapy was

Physical examination and laboratory variables Heart rate, beats/min Systolic blood pressure, mm Hg LVEF, %

0.98 (0.23 to 1.91) years. Baseline differences between

Hemoglobin, g/l

aspirin- and DAPT-treated patients are provided in

Creatinine, mmol/l

Table 1. Participants who received DAPT were more

Hemoglobin A1c, %

frequently younger, non-Caucasian, and had surgery

Region of enrollment

performed in North America, South America, India, or Israel. Surgical variables, in-hospital complications, length of stay, and pharmacotherapy at 30 days stratified by

0.18

72.0 (64.0, 79.0)

70.0 (62.0, 77.0)

0.02

130.0 (120.0, 140.0)

130.0 (120.0, 145.0)

0.12 0.26

60.0 (53.0, 66.0)

60.0 (50.0, 65.0)

139.0 (128.5, 148.0)

137.0 (126.0, 147.0)

0.13

88.4 (74.0, 106.1)

88.4 (74.5, 106.1)

0.94

7.4 (6.6, 8.7)

7.2 (6.5, 8.1)

North America

0.94 <0.001

233 (42.8)

86 (34.3)

Europe

74 (13.6)

113 (45.0)

South America

167 (30.7)

36 (14.3)

Australia/New Zealand

32 (5.9)

15 (6.0)

India/Israel

38 (7.0)

1 (0.4)

treatment cohort are presented in Table 2. Patients who received DAPT had lower median EuroSCORE,

Values are median (25th, 75th percentile) or n (%).

less frequently underwent right internal mammary

COPD ¼ chronic obstructive pulmonary disease; DAPT ¼ dual antiplatelet therapy; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; PTCA ¼ percutaneous transluminal coronary angioplasty or atherectomy.

artery grafting and transmyocardial revascularization, had a higher mean number of bypass grafts, and more frequently underwent endoscopic vein harvesting. No differences in in-hospital complications or lengths of stay were observed. NSAID use was less frequent in the DAPT cohort.

the secondary outcomes of all-cause mortality, vascular mortality, MI, stroke, or cardiovascular hospitalizations between DAPT- and aspirin-treated patients. There were no differences in the 5-year

CLINICAL OUTCOMES. The primary and secondary

safety outcomes of major bleeding (5.6% vs. 5.7%;

outcomes are described in Table 3 and shown in

HR: 1.00; 95% CI: 0.50 to 1.99; p ¼ 0.99), blood

the

differ-

transfusions (4.8% vs. 4.5%; HR: 1.09; 95% CI: 0.51 to

ences were observed in the 5-year primary composite

2.34; p ¼ 0.82), and bleeding hospitalizations (2.6%

Central

Illustration.

No

significant

outcome of all-cause death, MI, or stroke (12.5% vs.

vs. 3.3%; HR: 0.80; 95% CI: 0.31 to 2.04; p ¼ 0.64)

16.0%; adjusted hazard ratio [HR]: 0.83; 95% confi-

between DAPT- and aspirin-treated patients. Point

dence interval [CI]: 0.54 to 1.27; p ¼ 0.39) (Figure 1) or

estimates were similar at 1 year.

van Diepen et al.

122

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:119–27

Dual Antiplatelet Therapy in Diabetics After CABG

SUBGROUP ANALYSES. The primary FREEDOM trial

T A B L E 2 Surgical Variables and Discharge Medications By Treatment Group

outcome and major bleeding in subgroups of interest

DAPT (n ¼ 544)

Aspirin Monotherapy (n ¼ 251)

p Value

differences in the incidence of the composite of

1.7 (1.2, 3.0)

2.1 (1.4, 3.7)

<0.001

all-cause death, MI, or stroke were observed by

26.0 (19.0, 31.5)

26.0 (19.3, 32.0)

0.35

surgical indication (stable angina or acute coronary

Number of lesions $70%

543 (99.8)

251 (100.0)

>0.99

syndrome), SYNTAX score, complete or incomplete

3-vessel disease

451 (82.9)

216 (86.1)

0.25

revascularization, duration of DAPT, or by on- or

85.0 (66.0, 108.0)

88.0 (64.5, 109.0)

0.88

59.0 (41.0, 77.0)

60.0 (42.0, 80.0)

0.99

108 (19.9)

43 (17.1)

EuroSCORE SYNTAX score

are presented in Table 4. No treatment-related

Surgical variables Cardiopulmonary bypass time, min

off-pump bypass at 5 years. The primary outcome was

Cross-clamp time, min Off-pump bypass Number of grafts

lower among DAPT-treated patients who had a

0.38

reduced glomerular filtration rate. No differences in

0.02

5-year major bleeding were observed across the

1

8 (1.5)

2 (0.8)

subgroups of interest. In a post hoc sensitivity anal-

2

135 (24.8)

88 (35.1)

ysis restricted to events occurring 30 days after sur-

3

278 (51.1)

123 (49.0)

gery, no differences in outcomes were observed

4

106 (19.5)

34 (13.5)

(Online Tables 1 and 2). In a post hoc analysis, the

17 (3.1)

4 (1.6)

Left internal thoracic artery graft

512 (94.1)

239 (95.2)

0.62

Right internal thoracic artery graft

54 (9.9)

51 (20.3)

<0.001

Radial artery graft

56 (10.3)

23 (9.2)

0.70

Endarterectomy

34 (6.3)

9 (3.6)

0.13

$5

Transmyocardial revascularization

were age, country, race, transmyocardial revascularization, and right internal thoracic artery graft use (Online Table 3).

4 (0.7)

10 (4.0)

96 (17.6)

30 (12.0)

0.05

Graft patching

9 (1.7)

7 (2.8)

0.29

Intra-aortic balloon pump use

3 (0.6)

1 (0.4)

>0.99

Antifibrinolytics given

296 (54.4)

150 (59.8)

0.17

Aspirin post-operative day 0/1

461 (84.7)

202 (80.5)

0.15

Thienopyridine post-operative day 0/1

159 (29.2)

9 (3.6)

<0.001

Any

105 (19.3)

59 (23.5)

0.19

received DAPT for a median duration of 1 year post-

MI

29 (5.3)

9 (3.6)

0.37

CABG. Second, no significant differences in either the

Stroke

18 (3.3)

10 (4.0)

0.68

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

Atrial fibrillation

26 (4.8)

18 (7.2)

0.46

stroke) or bleeding outcomes were observed between

Repeat sternotomy for bleeding

13 (2.4)

7 (2.8)

>0.99

aspirin- and DAPT-treated patients. Third, results

Gastrointestinal bleeding

4 (0.7)

0 (0.0)

0.30

were similar across clinically important subgroups in

Renal failure

12 (2.2)

10 (4.0)

0.35

10.0 (7.0, 16.0)

11.0 (7.0, 18.0)

0.46

2.0 (1.0, 4.0)

2.0 (1.0, 4.0)

0.86

tion of DAPT.

Beta-blockers

462 (84.9)

205 (81.7)

0.08

DAPT prescription rates range from 22.0% to 53.8%

Statins

486 (89.3)

218 (86.9)

0.44

(14,22–24). The reasons underpinning this wide range

19 (3.5)

10 (4.0)

0.69

are unclear, but they may reflect differences in case

283 (52.0)

128 (51.0)

0.41

Aldosterone antagonists

77 (14.2)

41 (16.3)

0.45

mix, regional practices patterns, or variations in

Antiarrhythmics

45 (8.3)

22 (8.8)

0.89

Thiazide diuretics

49 (9.0)

26 (10.4)

0.69

DAPT post-CABG (9,10,15). In this analysis, approxi-

Endoscopic vein harvesting

0.002

variables identified associated with DAPT therapy

Perioperative medications

Length of stay Intensive care days

ACE or ARB

pared aspirin monotherapy with DAPT post-CABG in patients with diabetes. We observed 3 important findings. First, approximately two-thirds of patients

including pre-operative acute coronary syndrome, SYNTAX score, complete revascularization, and duraIn retrospective observational studies, post-CABG

Medications at 30 days

Ezetimibe

This post hoc secondary analysis of the FREEDOM trial with centrally adjudicated clinical outcomes com-

Post-operative complications

Hospital days

DISCUSSION

practice guideline recommendation weighting of

108 (19.9)

65 (25.9)

0.09

mately two-thirds of all trial participants were pre-

6 (1.1)

1 (0.4)

0.44

scribed thienopyridines in addition to aspirin. We

107 (19.7)

44 (17.5)

0.49

hypothesize that the higher rates of DAPT prescrip-

PPIs

23 (4.2)

17 (6.8)

0.08

tion observed in this analysis may have been influ-

NSAIDs

17 (3.1)

16 (6.4)

0.05

enced by the FREEDOM study protocol, which

Loop diuretics Digoxin Calcium-channel blockers

Values are median (25th, 75th percentile) or n (%). ACE ¼ angiotensin-converting enzyme inhibitors; ARB ¼ angiotensin receptor blockers; DAPT ¼ dual antiplatelet therapy; EuroSCORE ¼ European System for Cardiac Operative Risk Evaluation; NSAIDs ¼ nonsteroidal anti-inflammatory drugs; PPIs ¼ proton pump inhibitors.

provided participants with up to 1 year of thienopyridine drug coverage at the discretion of their treating physician regardless of study randomization. This may also reflect the perceived benefit of DAPT after

van Diepen et al.

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:119–27

123

Dual Antiplatelet Therapy in Diabetics After CABG

T A B L E 3 Outcomes in Patients on DAPT and Aspirin Monotherapy

1-Yr Outcomes

Outcome*

DAPT

Aspirin Monotherapy

HR (95% CI)

534 (6.7)

244 (6.6)

1.08 (0.56–2.06)

5-Yr Outcomes

DAPT

Aspirin Monotherapy

HR (95% CI)

0.82

534 (12.5)

244 (16.0)

0.83 (0.54–1.27)

0.39

p Value

p Value

Primary FREEDOM outcome All-cause mortality, MI, or stroke Secondary outcomes All-cause mortality

538 (1.9)

244 (3.7)

0.54 (0.20–1.45)

0.22†

538 (5.8)

244 (9.4)

0.62 (0.34–1.13)

0.12

Vascular mortality

538 (1.3)

244 (1.6)

0.80 (0.23–2.83)

0.73‡

538 (3.5)

244 (3.3)

1.17 (0.50–2.72)

0.72§

MI

534 (3.9)

244 (2.0)

1.87 (0.65–5.36)

0.25

534 (5.2)

244 (3.7)

1.42 (0.63–3.21)

0.40

Stroke

538 (1.1)

244 (1.6)

0.89 (0.21–3.69)

0.87k

538 (3.2)

244 (4.1)

0.85 (0.36–1.99)

0.71k

Cardiovascular hospitalizations

533 (9.9)

243 (10.7)

0.99 (0.59–1.65)

0.97

533 (19.5)

243 (18.1)

1.10 (0.75–1.61)

0.62

Major bleeding

538 (4.3)

244 (4.5)

1.05 (0.48–2.30)

0.91

538 (5.6)

244 (5.7)

1.00 (0.50–1.99)

0.99

Blood transfusions

538 (4.3)

244 (3.7)

1.28 (0.55–2.96)

0.57

538 (4.8)

244 (4.5)

1.09 (0.51–2.34)

0.82

Bleeding hospitalization

538 (1.7)

244 (2.5)

0.73 (0.24–2.25)

0.58¶

538 (2.6)

244 (3.3)

0.85 (0.34–2.17)

0.74¶

Primary safety outcomes

Values are n (%) unless otherwise indicated. *All unadjusted outcomes presented as valid n (event %). Because of 0 events in 1 or more covariate categories, some covariates were excluded from specific time to event analysis as follows: †adjusted for EuroSCORE, region of enrollment, number of grafts, right internal thoracic artery graft, endarterectomy, endoscopic vein harvesting, and PPI or beta-blocker use at 1 month; ‡adjusted for EuroSCORE, number of grafts, right internal thoracic artery graft, endarterectomy, endoscopic vein harvesting, and PPI or beta-blocker use at 1-month visit; §adjusted for EuroSCORE, number of grafts, right internal thoracic artery graft, endarterectomy, endoscopic vein harvesting, and PPI, NSAID, or beta-blocker use at 1-month visit; kadjusted for EuroSCORE, region of enrollment, number of grafts, right internal thoracic artery graft, endarterectomy, endoscopic vein harvesting, and NSAID or beta-blocker use at 1-month visit; ¶adjusted for EuroSCORE, region of enrollment, number of grafts, endoscopic vein harvesting, and PPI or beta-blocker use at 1 month. CI ¼ confidence internal; HR ¼ hazard ratio; other abbreviations as in Tables 1 and 2.

C ENTR AL I LL U STRA T I O N Dual Antiplatelet Therapy in Diabetics After CABG: Adjusted Hazard Ratio Plot of Clinical and Safety Outcomes

van Diepen, S. et al. J Am Coll Cardiol. 2017;69(2):119–27.

No differences were observed in the 5-year incidence the primary FREEDOM outcome (all-cause death, myocardial infarction, or stroke), secondary outcomes, or primary safety outcomes in diabetic patients with multivessel coronary artery disease who underwent CABG treated with dual antiplatelet therapy or aspirin monotherapy. CABG ¼ coronary artery bypass surgery; CI ¼ confidence interval; DAPT ¼ dual antiplatelet therapy; FREEDOM ¼ Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease; MI ¼ myocardial infarction.

van Diepen et al.

124

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:119–27

Dual Antiplatelet Therapy in Diabetics After CABG

includes those with antecedent acute coronary syn-

F I G U R E 1 Kaplan-Meier Plot of the 5-Year Primary FREEDOM Outcome

dromes and incomplete revascularization and high SYNTAX

40

log-rank P = 0.377 DAPT

35

(31,32).

Although

our

scientific

post-CABG population is incomplete, observational

Aspirin alone Cumulative Event Rate, %

scores

understanding of the effectiveness of DAPT in the studies suggest a reduced efficacy of DAPT among

30

diabetic patients. A recent DAPT trial secondary 25

analysis reported that patients with diabetes mellitus had a higher long-term risk of cardiovascular events

20

but a significantly attenuated benefit of prolonged

15

DAPT after percutaneous coronary intervention (33). The authors suggested the potential for other ischemic

10

pathophysiological process including greater plaque

5

burden, inflammation, and/or a reduced response to antiplatelet therapies.

0 1

0

2

3

4

5

Time to FREEDOM Outcome , Years

The lack of an observed difference in major bleeding by treatment assignment in this analysis was an un-

DAPT (Yes/No) / Number of patients at risk Yes

540

492

449

349

233

111

No

251

231

207

166

107

43

expected finding. Prior meta-analyses have reported point estimates for bleeding were nonsignificantly higher in DAPT CABG patients (28). We hypothesize this finding may be due to inadequate power because

No differences were observed in the incidence of all-cause mortality, myocardial

of a small number of events or differential treatment

infarction, or stroke in diabetic coronary artery bypass patients treated with dual antiplatelet therapy or aspirin monotherapy. DAPT ¼ dual antiplatelet therapy;

strategies. Prior studies have primarily evaluated

FREEDOM ¼ Future REvascularization Evaluation in patients with Diabetes mellitus:

bleeding outcomes among CABG patients initiated on

Optimal management of Multivessel disease.

early post-operative DAPT, a period when the antithrombotic-related treatment bleeding is potentially highest. In the present study, only 29% of

CABG among cardiovascular physicians when finan-

DAPT-treated patients were initiated on therapy on

cial barriers to drug prescription are removed.

post-operative day 0 or 1 and the DAPT cohort was

Guideline recommendations for DAPT in patients

defined according to DAPT therapy at 30 days.

who underwent a CABG for an acute coronary syn-

The results of this large international cohort anal-

drome are only supported by observational cohorts

ysis add to the limited body of research of DAPT in

and

trials

diabetic post-CABG patients. The observational design

(13–16,25,26). Importantly, all randomized studies of

precludes causal inferences and we recognize the

DAPT after on-pump CABG have failed to demonstrate

modest sample size; however, no benefit was observed

clinical benefits compared to aspirin monotherapy.

with the routine use of DAPT in diabetic patients post-

Select meta-analyses that reported lower mortality in

CABG. These results can potentially be incorporated

DAPT-treated patients have been driven primarily by

into

the inclusion of observational analysis and/or off-

studies evaluating the efficacy of DAPT in post-CABG

pump CABG (15,27–29). The lack of observed differ-

patients; however, future randomized controlled tri-

ences in the primary composite outcome between

als powered for both mortality and graft patency are

subgroup

analyses

of

controlled

meta-analyses

of

primarily

nonrandomized

aspirin- and DAPT-treated patients in the overall

required to evaluate the efficacy and safety of DAPT

cohort is in line with previous randomized studies.

versus aspirin monotherapy. The results of the

However, a subgroup analysis of patients with acute

ongoing TiCAB (Ticagrelor in CABG) trial may also help

coronary syndrome undergoing CABG <7 days from

improve our knowledge of the optimal post-CABG

the PLATO (Platelet Inhibition and Patient Outcomes)

antiplatelet treatment strategy (34).

trial demonstrated benefits of ticagrelor over clopidogrel in aspirin-treated patients that were consistent

STUDY LIMITATIONS. Our findings should be inter-

with the overall trial results, including a statistically

preted in the context of its limitations. First, out-

significant mortality reduction (30). The current

comes were derived from prescription rates at 30 days

analysis builds on prior research by extending these

post-CABG; thus, clinical and bleeding outcomes

findings into a higher risk diabetic population and into

associated with early post-operative use cannot be

clinically important subgroups with a higher long-

inferred from this analysis. Second, this study was

term risk of post-CABG cardiovascular events; this

conducted before the approval of

novel P2Y12

van Diepen et al.

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:119–27

Dual Antiplatelet Therapy in Diabetics After CABG

T A B L E 4 Outcomes in Clinically Important Subgroups

1-Yr Outcomes

DAPT

Aspirin Monotherapy

Stable angina

389 (6.4)

165 (7.9)

Acute coronary syndrome

145 (7.6)

79 (3.8)

Outcome*

5-Yr Outcomes

p Value

DAPT

Aspirin Monotherapy

0.89 (0.45–1.76)

0.74

389 (11.6)

165 (15.8)

0.82 (0.50–1.34)

0.42

2.28 (0.62–8.39)

0.21†

145 (15.2)

79 (16.5)

1.06 (0.53–2.10)

0.88†

HR (95% CI)

HR (95% CI)

p Value

FREEDOM endpoint Surgical indication

SYNTAX score <22

174 (5.2)

72 (6.9)

0.91 (0.30–2.81)

0.87*

174 (11.5)

72 (18.1)

0.69 (0.34–1.40)

0.30

22-32

228 (7.9)

106 (6.6)

1.20 (0.50–2.89)

0.68

228 (12.7)

106 (17.0)

0.77 (0.43–1.38)

0.38

$32

129 (7.0)

63 (6.3)

1.19 (0.36–3.91)

0.77‡

129 (14.0)

63 (12.7)

1.18 (0.51–2.72)

0.71‡

Revascularization Incomplete Complete

50 (10.0) 484 (6.4)

26 (3.8)

3.24 (0.33–31.97)

218 (6.9)

1.00 (0.54–1.87)

0.31† >0.99

50 (22.0) 484 (11.6)

26 (11.5)

1.92 (0.53–7.00)

0.32†

218 (16.5)

0.75 (0.49–1.15)

0.19

Endarterectomy or vein patching Yes None

41 (17.1)

15 (6.7)

493 (5.9)

229 (6.6)

2.76 (0.34–22.52)

0.34§

0.98 (0.52–1.85)

0.96

493 (11.8)

41 (22.0)

15 (20.0) 229 (15.7)

1.30 (0.35–4.85) 0.80 (0.53–1.22)

0.69§ 0.31

DAPT $1 yr Yes

403 (4.2)

-

-

-

403 (10.4)

-

-

No

135 (14.1)

244 (6.6)

2.45 (1.24–4.83)

0.01

135 (19.3)

244 (16.0)

1.60 (0.96–2.66)

-

On pump

428 (7.2)

203 (5.9)

1.27 (0.65–2.48)

0.49

428 (13.1)

203 (16.3)

0.84 (0.55–1.30)

0.44

Off pump

106 (4.7)

41 (9.8)

0.75 (0.18–3.16)

0.70†

106 (10.4)

41 (14.6)

0.89 (0.30–2.58)

0.83

150 (5.3)

76 (9.2)

0.72 (0.25–2.10)

0.54

150 (10.7)

76 (23.7)

0.47 (0.24–0.95)

0.04

Stable angina

393 (4.3)

165 (4.8)

0.93 (0.40–2.18)

0.87‡

393 (5.6)

165 (6.7)

0.85 (0.41–1.76)

0.66‡

Acute coronary syndrome

145 (4.1)

79 (3.8)

1.02 (0.25–4.11)

0.95†

145 (5.5)

79 (3.8)

1.43 (0.38–5.40)

0.60† 0.69†

0.07

Cardiopulmonary bypass

Renal function GFR <60, per 10 ml/min/1.73 m2 Bleeding outcomes Surgical indication

SYNTAX score <22

175 (6.3)

72 (4.2)

1.59 (0.44–5.79)

0.48†

175 (8.6)

72 (6.9)

1.23 (0.44–3.41)

22-32

229 (3.1)

106 (5.7)

0.55 (0.19–1.66)

0.29‡

229 (3.5)

106 (5.7)

0.63 (0.22–1.83)

0.40‡

131 (3.1)

63 (3.2)

1.05 (0.19–5.88)

0.96§

131 (4.6)

63 (4.8)

1.12 (0.28–4.54)

0.87§

$32 Revascularization Incomplete Complete

50 (0.0)

26 (0.0)

-

-

488 (4.7)

218 (5.0)

0.93 (0.45–1.92)

0.84

50 (4.0)

26 (0.0)

-

-

488 (5.7)

218 (6.4)

0.87 (0.46–1.67)

0.68

Endarterectomy or vein patching Yes None

41 (2.4)

15 (0.0)

497 (4.4)

229 (4.8)

-

-

0.91 (0.44–1.89)

0.80

497 (5.8)

41 (2.4)

15 (0.0)

-

407 (5.7)

0.74§

135 (5.2)

244 (5.7)

229 (6.1)

0.93 (0.49–1.78)

0.83

DAPT $1 yr Yes

407 (3.9)

-

No

135 (5.2)

244 (4.5)

1.17 (0.45–3.04)

-

-

-

0.96 (0.39–2.40)

0.94§

On pump

430 (4.2)

203 (4.4)

0.93 (0.42–2.09)

0.87

430 (5.3)

203 (5.4)

0.98 (0.48–2.03)

0.96

Off pump

108 (4.6)

41 (4.9)

1.06 (0.20–5.55)

0.95§

108 (6.5)

41 (7.3)

0.90 (0.23–3.52)

0.88§

152 (5.9)

76 (5.3)

1.07 (0.32–3.59)

0.91†

152 (7.9)

76 (7.9)

0.92 (0.34–2.52)

0.88†

Cardiopulmonary bypass

Renal function GFR <60, per 10 ml/min/1.73 m2

Values are n (%) unless otherwise indicated. *All unadjusted outcomes presented as valid n (event %). Because of 0 events in 1 or more covariate categories, some covariates were excluded from specific time to event analysis as follows: †adjusted only for EuroSCORE and known PPI at 1-month visit; ‡adjusted only for EuroSCORE and NSAIDs at 1-month visit; §adjusted only for EuroSCORE. GFR ¼ glomerular filtration rate; other abbreviations as in Tables 1 to 3.

inhibitors (ticagrelor and prasugrel); thus, results

dosing was available in the case report form. Finally,

cannot be extrapolated to these agents. Third, a mi-

the analysis was nonrandomized and may not have

nority of patients in this analysis underwent off-

been adequately powered to detect a clinically sig-

pump CABG in whom DAPT post-CABG is recom-

nificant difference; thus, the results should be

mended (15,28). Fourth, no information of DAPT

considered hypothesis-generating.

125

126

van Diepen et al.

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:119–27

Dual Antiplatelet Therapy in Diabetics After CABG

CONCLUSIONS

PERSPECTIVES

In a secondary analysis of the FREEDOM trial, we observed that use of DAPT in patients with diabetes post-CABG was high, and, compared with aspirin monotherapy,

no

significant

associations

were

observed with all-cause mortality, MI, or stroke. Additionally,

no

differences

in

outcomes

were

observed in bleeding, clinical indication for revascularization, complexity of coronary artery disease, completeness

of

revascularization,

or

treatment

duration. Collectively, our findings suggest that the routine use of DAPT in post-CABG diabetic patients warrants an adequately powered, prospective randomized clinical outcome trial. REPRINT REQUESTS AND CORRESPONDENCE: Dr.

Sean van Diepen, Department of Critical Care and Division of Cardiology, 2C2 Cardiology Walter MacKenzie Center, University of Alberta Hospital, 8440-11 Street, Edmonton, Alberta T6G 2B7, Canada. E-mail:

COMPETENCY IN MEDICAL KNOWLEDGE: In a nonrandomized, post hoc analysis of patients with diabetes and multivessel coronary artery disease undergoing CABG surgery in the FREEDOM trial, there were no differences in rates of recurrent ischemia or bleeding with DAPT compared with aspirin monotherapy. Results were similar when results were stratified by pre-operative coronary syndrome acuity, SYNTAX score, completeness of revascularization, or use of off-pump bypass. Outcomes were lower among DAPT-treated patients with impaired renal function. TRANSLATIONAL OUTLOOK: Adequately powered randomized trials are needed to more accurately compare the efficacy and safety of DAPT versus aspirin monotherapy in patients with diabetes undergoing CABG surgery.

[email protected].

REFERENCES 1. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367: 2375–84. 2. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629–38. 3. Verma S, Farkouh ME, Yanagawa B, et al. Comparison of coronary artery bypass surgery and percutaneous coronary intervention in patients with diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2013;1:317–28. 4. Collaborative overview of randomised trials of antiplatelet therapy-II: Maintenance of vascular graft or arterial patency by antiplatelet therapy. Antiplatelet Trialists’ Collaboration. BMJ 1994; 308:159–68. 5. Mangano DT. Aspirin and mortality from coronary bypass surgery. N Engl J Med 2002;347: 1309–17. 6. Donaldson MC, Mannick JA, Whittemore AD. Causes of primary graft failure after in situ saphenous vein bypass grafting. J Vasc Surg 1992; 15:113–20. 7. Harskamp RE, Lopes RD, Baisden CE, Winter RJ, Alexander JH. Saphenous vein graft failure after coronary artery bypass surgery: pathophysiology, management, and future directions. Ann Surg 2013;257:824–33. 8. Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation 1998;97:916–31.

9. Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:776S–814S. 10. Dunning J, Versteegh M, Fabbri A, et al. Guideline on antiplatelet and anticoagulation management in cardiac surgery. Eur J Cardiothorac Surg 2008;34:73–92. 11. Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non–ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial. Circulation 2004;110:1202–8. 12. Kulik A, Le May MR, Voisine P, et al. Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) trial. Circulation 2010;122:2680–7. 13. Saw J, Topol EJ, Steinhubl SR, et al. Comparison of long-term usefulness of clopidogrel therapy after the first percutaneous coronary intervention or coronary artery bypass grafting versus that after the second or repeat intervention. Am J Cardiol 2004;94:623–5. 14. Sørensen R, Abildstrøm SZ, Hansen PR, et al. Efficacy of post-operative clopidogrel treatment in patients revascularized with coronary artery bypass grafting after myocardial infarction. J Am Coll Cardiol 2011;57:1202–9. 15. Kulik A, Ruel M, Jneid H, et al. Secondary prevention after coronary artery bypass graft surgery: a scientific statement from the American Heart Association. Circulation 2015;131:927–64.

16. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/ AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082–115. 17. Campeau L, Enjalbert M, Lespérance J, et al. The relation of risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the native circulation. A study 10 years after aortocoronary bypass surgery. N Engl J Med 1984;311:1329–32. 18. Neitzel GF, Barboriak JJ, Pintar K, Qureshi I. Atherosclerosis in aortocoronary bypass grafts. Morphologic study and risk factor analysis 6 to 12 years after surgery. Arteriosclerosis 1986;6:594–600. 19. Morris JJ, Smith LR, Jones RH, et al. Influence of diabetes and mammary artery grafting on survival after coronary bypass. Circulation 1991;84 Suppl: III275–84. 20. Nashef SAM, Roques F, Sharples LD, et al. EuroSCORE II. Eur J Cardiothorac Surg 2012;41:734–44. 21. Farkouh ME, Dangas G, Leon MB, et al. Design of the Future REvascularization Evaluation in patients with Diabetes mellitus: optimal management of Multivessel disease (FREEDOM) Trial. Am Heart J 2008;155:215–23. 22. Chan V, Kulik A, Bourke ME, Ressler L, Mesana TG, Ruel M. Clopidogrel is safe early after on- and off-pump coronary artery bypass surgery. J Card Surg 2007;22:493–7. 23. Ebrahimi R, Bakaeen FG, Uberoi A, et al. Effect of clopidogrel use post coronary artery bypass surgery on graft patency. Ann Thorac Surg 2014;97:15–21.

van Diepen et al.

JACC VOL. 69, NO. 2, 2017 JANUARY 17, 2017:119–27

24. Kim DH, Daskalakis C, Silvestry SC, et al. Aspirin and clopidogrel use in the early postoperative period following on-pump and off-pump coronary artery bypass grafting. J Thorac Cardiovasc Surg 2009;138:1377–84. 25. Gao G, Zheng Z, Pi Y, Lu B, Lu J, Hu S. Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial. J Am Coll Cardiol 2010;56:1639–43. 26. Sun JC, Teoh KH, Lamy A, et al. Randomized trial of aspirin and clopidogrel versus aspirin alone for the prevention of coronary artery bypass graft occlusion: the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting study. Am Heart J 2010;160:1178–84. 27. de Leon N, Jackevicius CA. Use of aspirin and clopidogrel after coronary artery bypass graft surgery. Ann Pharmacother 2012;46:678–87. 28. Deo SV, Dunlay SM, Shah IK, et al. Dual antiplatelet therapy after coronary artery bypass

Dual Antiplatelet Therapy in Diabetics After CABG

grafting: is there any benefit? A systematic review and meta-analysis. J Card Surg 2013;28:109–16.

observational studies. J Am Coll Cardiol 2013;62: 1421–31.

29. Verma S, Goodman SG, Mehta SR, et al. Should dual antiplatelet therapy be used in patients following coronary artery bypass surgery? A meta-analysis of randomized controlled trials. BMC Surg 2015;15:112.

33. Meredith IT, Tanguay J-F, Kereiakes DJ, et al. Diabetes mellitus and prevention of late myocardial infarction after coronary stenting in the Randomized Dual Antiplatelet Therapy study.

30. Held C, Åsenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011;57:672–84. 31. Cho Y, Shimura S, Aki A, Furuya H, Okada K, Ueda T. The SYNTAX score is correlated with longterm outcomes of coronary artery bypass grafting for complex coronary artery lesions. Interact Cardiovasc Thorac Surg 2016;23:125–32. 32. Garcia S, Sandoval Y, Roukoz H, et al. Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and

Circulation 2016;133:1772–82. 34. de Waha A, Sandner S, von Scheidt M, et al. A Randomized, parallel group, double-blind study of ticagrelor compared with aspirin for prevention of vascular events in patients undergoing coronary artery bypass graft operation: rationale and design of the ticagrelor in CABG (TiCAB) trial. An investigator-initiated trial. Am Heart J 2016;179: 69–76.

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

A PP END IX For supplemental tables, please see the online version of this article.

127