Clinical Therapeutics/Volume 35, Number 8, 2013
Review Article
Management of Acute Coronary Syndromes in Patients
with Diabetes: Implications of the FREEDOM Trial
Sonya N. Burgess, MBChB, BSc; Christian J. Mussap, PhD, MBBS; and
John K. French, PhD, MBChB
Department of Cardiology, Liverpool Hospital, Southwestern Clinical School, University of New South
Wales, Elizabeth St, Sydney, New South Wales, Australia
ABSTRACT
Background: Diabetes mellitus (DM) is a powerful
independent risk factor for multivessel, diffuse coronary
artery disease (CAD). The optimal coronary revascula-
rization strategy in DM is not clearly dened, but past
trials have suggested an advantage for coronary artery
bypass grafting (CABG). Recently, the Future Revascu-
larization Evaluation in Patients with Diabetes Mellitus:
Optimal Management of Multivessel Disease (FREE-
DOM) trial found patients randomized to CABG had
lower rates of death and myocardial infarction (MI)
compared with those randomized to percutaneous
coronary intervention (PCI).
Objective: This article reviews the contemporary
management of patients with DM presenting with
acute coronary syndromes, particularly ST-elevation
MI, in the post-FREEDOM era.
Methods: We undertook a comprehensive review of
published literature addressing trials in this eld
performed to address current knowledge both in the
pre- and post-FREEDOM era.
Results: The implications of FREEDOM for patients
with acute coronary syndrome are that CABG provides
a signicant benet, compared with PCI with drug-
eluting stents, to patients with DM and multivessel
coronary artery disease; and that patients similar to
those enrolled in FREEDOM should receive CABG in
preference to PCI. The relevance of FREEDOMs nd-
ings to the large proportion of patients who would not
meet inclusion criteriaincluding patients with an acute
coronary syndrome undergoing an early or emergent
invasive strategy, remains uncertain.
Discussion: FREEDOMs outcomes have generated
uncertainty regarding best practice once thrombolysis in
myocardial infarction grade 3 ow is re-established in
patients with DM and multivessel disease. Current
August 2013
interventional guidelines recommend optimally treating
the culprit artery; however, decisions made at the time
of revascularization inuence future revascularization
strategies, particularly stent choice and resultant P2Y12
receptor antagonist therapy. The preferred method for
future revascularization may be questioned if the
patient's residual coronary stenoses do not, post-PCI,
meet the FREEDOM inclusion criteria, or where the left
anterior descending artery is the infarct-related artery,
and after left anterior descending artery PCI the patient
would not receive an internal mammary graft. The
management of residual disease and the preferred
(further) revascularization strategy needs to be tested
in an appropriately powered randomized trial.
Conclusions: The optimal revascularization strat-
egy in patients with acute coronary syndrome, dia-
betes, and multivessel disease, in particular those with
ST elevation, is unclear, and not guided by level A (or
B) evidence. Currently CABG is favored over PCI, and
an individually tailored, collaborative approach,
guided by a multidisciplinary heart team, should be
employed. (Clin Ther. 2013;35:10691075) & 2013
Elsevier HS Journals, Inc. All rights reserved.
Key words: acute coronary syndrome, coronary
artery bypass graft surgery, diabetes, multivessel dis-
ease, percutaneous coronary intervention.
INTRODUCTION
Diabetes mellitus (DM) is a key constituent of the
metabolic syndrome, which is increasingly prevalent in
Accepted for publication July 24, 2013.
http://dx.doi.org/10.1016/j.clinthera.2013.07.427
0149-2918/$ - see front matter
& 2013 Elsevier HS Journals, Inc. All rights reserved.
1069
 Clinical Therapeutics
Western society, and DM is a powerful independent
risk factor for coronary heart disease. It is therefore not
surprising that DM is found in approximately one-
quarter of patients presenting for angiography follow-
ing an acute coronary syndrome (ACS).13 The angio-
graphic pattern of coronary artery disease in patients
with DM is typically complex, characterized by multi-
vessel diffuse plaque, extending into mid and distal
arterial branches. These features make myocardial
revascularization particularly challenging for both in-
terventional cardiologists and cardiothoracic surgeons.
The management of ACS in patients with DM
involves combination pharmacotherapy, including
antiplatelet and thrombin inhibitors, statins, angio-
tensin converting enzyme inhibitors (or similar
agents), and blockers. Early revascularization has
been shown to improve clinical outcomes in patients
with non-ST elevation acute coronary syndromes. In
patients with ST elevation myocardial infarction
(STEMI), emergency reperfusion improves mortality
rates compared with those not receiving reperfusion,
and primary percutaneous coronary intervention
(PCI) is preferred if it can reliably be performed within
90 to 120 minutes of rst medical contact. Rescue PCI
is indicated in patients not achieving timely reperfu-
sion following brinolytic therapy.4
Macrovascular Pathophysiology of DM
Coronary artery plaques from individuals with DM
(type 2) have larger necrotic cores on postmortem
histology, compared with age-, race-, and sex-matched
patients without diabetes, and greater total and distal
plaque loads.5 Coronary angioscopy shows higher
rates of thrombosis in patients with unstable DM,6
and adaptive vascular remodelling is decreased.7
There is up regulation of both receptors and binding
proteins of advanced glycosylation end-products
associated with microangiopathic diasease in the
coronary arteries of DM patients. Moreover, there is
an association with smooth muscle cell apoptosis and
macrophage inltration.6 Decreased levels of nitric
oxide are seen in patients with DM, mediated by
hyperglycemia. This allows a subsequent increase
activity of the proinammatory transcription factor,
nuclear factor B. Increased activity of this factor
results in increased expression of leukocyte adhesion
molecules, cytokines, and chemokines, which promote
monocyte and vascular smooth muscle cell migration
to the intima. Ultimately this cascade results in the
1070
formation of foam cells and the generation of
atherosclerotic plaques.8
The endothelial dysfunction seen in patients with
DM is also characterized by the increased synthesis of
vasoconstrictor prostanoids and endothelin. Endothelin
promotes inammation and causes vascular smooth
muscle cell contraction and growth. In patients with
DM there is increased migration of smooth muscle cells
into new atherosclerotic lesions; these cells replicate and
produce extracellular matrix facilitating atherosclerotic
maturation. Subsequent smooth muscle cell apoptosis is
also increased, destabilizing atherosclerotic plaques and
promoting plaque rupture. The predisposition to plaque
instability and rupture is perpetuated by decreased
collagen synthesis in smooth muscle cells of patients
with DM, along with increased synthesis of matrix
metalloproteinases.8
Patients with DM also have abnormal platelet
function. There is increased expression of glycoprotein
Ib and IIb/IIIa receptors, which augments platelet von
Willebrand factor, and platelet-brin interaction.9
Increased superoxide formation and protein kinase C
activity (further decreasing nitric oxide production) is
also reported and there is decreased platelet-derived
nitric oxide. Further contributing to thrombotic milieu
is enhanced factor VII, thrombin, and tissue factor
concentrations, and decrease in thrombomodulin and
protein C.6 Pathophysiologic changes at the cellular
level predispose to unstable atherosclerotic plaque
prone to rupture, and therefore patients with DM
are especially vulnerable to ACS.
Background to the FREEDOM Trial
The hypothesis behind FREEDOM10 arose from data
from the Bypass Angioplasty Revascularization Investi-
gation (BARI)11 trial (and registry), one of 6 trials
comparing revascularization strategies of coronary
artery bypass grafting (CABG) and PCI in era of plain
old balloon angioplasty. BARI randomized 1829
patients with multivessel disease to CABG or PCI, and
followed another 2535 nonrandomized registry subjects.
Subgroup analysis of patients with DM was performed
in response to a request from the safety and data moni-
toring board in 1992. In the 357 randomized patients
with medically treated DM a signicant difference was
evident in 5-year survival rates with 65.5% survival in
the PCI group and 80.6% survival in the CABG
group. In the remaining 81% of the randomized BARI
population 5-year survival was described as essentially
Volume 35 Number 8

equal (91.1% in the PCI group and 91.4% in the
CABG group). Importantly, in BARI, stents were
considered new interventional devices and were not
used in the initial revascularization procedures. Inter-
ventional success was dened as reduction in stenosis
420% and a residual stenosis of o50%, and normal
thrombolysis in myocardial infarction grade-3 ow.
An average of 1.9 out of 3.5 clinically important
lesions were successfully dilated (54%), whereas
randomization to CABG was associated with a mean
use of 2.8 bypass grafts; 82% of patients received at
least 1 internal-thoracic-artery graft.11
The Bypass Angioplasty Revascularization Investiga-
tion 2 Diabetes (BARI 2D)12 trial randomized 2368
patients with type 2 diabetes and coronary artery
disease, and used a 2
2 randomized factorial trial
design. Patients were selected either for CABG or PCI,
and followed for 5 years. Within each group patients
were randomized to revascularization or medical therapy,
and to insulin provision or insulin sensitization. The
primary end points of death and a composite of death,
myocardial infarction, or stroke did not differ
signicantly in the PCI stratum between the revascular-
ization group and the medical therapy group. In the
CABG stratum, the rate of major cardiovascular
events was signicantly lower in the revascular-
ization group (22.4%) compared with the medical
therapy group (30.5%; P o 0.01; P 0.002 for
interaction between stratum and study group). The
statistically signicant P value for interaction indicated
that the benet associated with prompt coronary
revascularization, compared with medical therapy, was
signicantly greater for patients selected for CABG than
for patients selected for PCI. The BARI 2D trial did not
randomize the method of revascularization, which was
at the discretion of the treating cardiologist, and as a
result the CABG stratum had higher rates of 3-vessel
disease, proximal left anterior descending artery lesions,
more total occlusions, and higher myocardial jeopardy
scores. It should also be noted that 42% of those
originally intended for medical therapy later underwent
revascularization. A mean (SD) of 1.5 (0.8) lesions were
attempted, but only 34.7% of patients who underwent
PCI received a drug-eluting stent, 56.0% received a
bare-metal stent, and 9.3% of PCI patients did not
receive any stent. Within the CABG stratum group
94.2% of patients received an internal mammary artery
graft, and a mean (SD) of 3.0 (1.0) distal anastomoses
were performed.12
August 2013
S.N. Burgess et al.
Considered together, the BARI diabetic subgroup
and BARI 2D trial data suggested that the preferred
revascularization strategy for multivessel disease in
DM was internal mammary artery bypass grafting of
the left anterior descending coronary artery. This was
associated with reduced mortality and possibly less
nonfatal myocardial infarction. There is signicantly
increased durability of internal mammary grafts, with
90% patency rates reported at 20 years13 where
bilateral mammary arteries are used, compared with
saphenous vein grafts. A 2001 meta-analysis from
Taggart et al14 reported outcomes where bilateral
internal mammary arteries (BIMA) are used versus
single internal mammary artery (SIMA) graft use,
included studies had an incidence of diabetes in their
cohorts of between 4% and 21%. They reported an
improved hazard ratio for death with BIMA versus
SIMA grafts of 0.81%, but noted none of the included
studies were randomized. Bypass surgery employing
BIMA is used of only 5% of cases in the United States
and 10% in Europe.15 Taggart et al16 are further
investigating this issue with the Arterial Revascular-
ization Trial, a randomized control trial comparing
SIMA versus BIMA with an intended 10-year follow-
up. Outcome data at 1 year have relevance for
patients with DM, in particular showing 1.9% of
BIMA and 0.6% of SIMA patients having wound
dehiscence. The Arterial Revascularization Trial pop-
ulation includes 734 patients with DM (24%); how-
ever, 50% of those who required sternal recon-
struction had DM, and the authors suggest avoiding
BIMA grafts in obese patients with DM.
The Synergy Between Percutaneous Coronary Inter-
vention with Taxus and Cardiac Surgery (SYNTAX)17
and Coronary Artery Revascularization in Diabetes
(CARDia)18 trials each randomized about 600
patients with DM. The CARDia trial found that the
composite of death, myocardial infarction, stroke, or
revascularization was signicantly higher in patients
with DM with multivessel disease randomized to PCI.
The SYNTAX trial included patients with signicant
left main coronary artery disease, and there had to be
agreement between the interventional cardiologist and
cardiac surgeon that either PCI or CABG was feasible.
In patients with more complex angiographic disease,
such as most patients with DM, there was a higher
rate of major adverse cardiovascular events
randomized to PCI with a drug-eluting stent rather
than CABG. Although it was concluded that CABG
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 Clinical Therapeutics

was the preferred revascularization strategy in this

Table. Key 5-year outcomes of the Future
patient group, the overall rate of clinical events (ie, Revascularization Evaluation in Patients
death, nonfatal myocardial infarction, and stroke) was with Diabetes Mellitus: Optimal
no lower at 3 years in the patients treated with CABG Management of multivessel disease
than in those patients undergoing PCI.19 (FREEDOM) trial.

FREEDOM TRIAL PCI CABG

10
The FREEDOM Trial randomly assigned patients
with DM and multivessel coronary artery disease to
PCI with drug-eluting stents or CABG. The choice of
drug-eluting stent (rst or second generation) and
surgical procedure was left to the discretion of the
investigators. Patients were also prescribed currently
recommended medical therapies to control LDL cho-
lesterol, systolic blood pressure, and glycosylated
hemoglobin and treated to achieve predened targets.
The primary end point was a composite of death from
any cause, nonfatal myocardial infarction, or nonfatal
stroke. Approximately 30% of patients in FREEDOM
were categorized as presenting with a recent ACS.
However, trial exclusion criteria included an ST-
elevation myocardial infarction o72 hours or eleva-
tions of creatine kinase and/or creatine kinase muscle
and brain subunits at randomization,20 so those
randomized ACS patients were stable and medically
treated before inclusion, representing a more stable
subpopulation of patients with ACS.
Only about 3% of screened patients ultimately
participated in the trial. Of 32,966 who were
screened, 3309 met the eligibility criteria and 1900
were enrolled.10 The low recruitment rate may have
partly reected the rigorous exclusion criteria. For
example at Liverpool Hospital we conducted a
detailed screening registry of patients with DM
undergoing coronary angiography between June
2006 and March 2010. Even among patients with 2-
vessel disease with 470% stenoses, only 40% were
eligible for the trial. Reasons for ineligibility included
a relatively high number with prior bypass surgery
( 35%), nonqualifying chronic total occlusions
(10%), left main stenosis (7%), and recent myocardial
infarction (5%). At Liverpool hospital  6% of the
patients with multidisease were randomized in the
FREEDOM trial.10
Outcomes
Key 5-year outcome data from FREEDOM10 are
listed in the Table. Notably, CABG was superior to
PCI in terms of the primary composite end point, and
Outcome % % P
Primary composite* 26.6 18.7 0.005
Death from any 16.3 10.9 0.049
cause
Myocardial infarction 13.9 6.0 o0.001
Stroke 2.4 5.2 0.03
Cardiovascular death 10.9 6.8 0.12
CABG coronary artery bypass surgery; PCI
percutaneous coronary intervention.
*Death, myocardial infarction, or stroke.
the individual outcomes of all-cause mortality and
myocardial infarction. However the incidence of
stroke was greater in the CABG-treated patients.
There was a trend toward a lower rate of cardiovas-
cular death in patients assigned to CABG. Actuarial
analysis suggested an early hazard from CABG, in
terms of the primary outcome, but a signicant and
growing benet over PCI became apparent from about
2 years after the procedure.
The extent of coronary disease in FREEDOM partic-
ipants was quantied using the angiographic SYNTAX17
score. Somewhat contrary to expectations, there was no
interaction between the SYNTAX score and the effect of
the 2 treatment strategies. This may reect insufcient
power in the study to analyze the interaction or a lack of
validity of the score in this patient population. Yet the
observation suggests a likely long-term benet of surgery
with LIMA to left anterior descending artery graft in
patients with DM, regardless of the burden of coronary
disease (total SYNTAX score). A separate cost-
effectiveness analysis of FREEDOM concluded that,
despite higher initial costs, CABG was a highly cost-
effective revascularization strategy compared with PCI
for patients with DM and multivessel coronary artery
disease.21
The implications of FREEDOM are that CABG
provides a signicant benet compared with PCI with
drug-eluting stents in patients with DM and multi-
vessel coronary artery disease. Thus, patients similar

1072 Volume 35 Number 8


to those enrolled in FREEDOM should receive CABG
in preference to PCI. The relevance of FREEDOMs
ndings to the large proportion of patients who would
not meet inclusion criteria, including patients present-
ing with an ACS-driven multivessel disease, remains
questionable. This has real-world practical implica-
tions because, for example, in many cardiac catheter-
ization laboratories in Australia up to 70% of patients
have ACS as the indication for PCI,22,23 although only
30% of patients randomized in the FREEDOM trial
presented with ACS.10 Patients were excluded from
FREEDOM if they experienced STEMI 72 hours before
randomization, or elevations of creatine kinase and/or
creatine kinase muscle and brain subunits at
randomization. The design of the FREEDOM trial
does not provide denitive evidence for a preferred
revascularization strategy in patients with DM and
ACS. Trial data is needed to guide therapy in ACS
where urgent revascularization is preferred.
Although FREEDOM was a landmark trial con-
rming the benet of CABG over multivessel PCI in
patients with DM, results from the BARI,11 BARI
2D,12 and SYNTAX17 trials had already helped to
shape guidelines before the eagerly awaited
FREEDOM results. The 2010 European Association
for Cardiothoracic Surgery guidelines24 on myocardial
revascularization state that CABG should be considered
over PCI when the extent of coronary disease justies a
surgical approach (Class IIa, level of evidence B). The
2011 American College of Cardiology/American Heart
Association/Society for Cardiovascular Angiography
and Interventions guidelines5 also suggest CABG over
PCI in patients with multivessel disease who also have
DM. The FREEDOM trials randomized control design,
drug-eluting stent use, appropriate dual antiplatelet
therapy duration, and goal of complete revasculariza-
tion leave little question that those who would have met
the inclusion criteria for FREEDOM should be treated
as FREEDOM dictates, with surgery. We should be
cautious in applying FREEDOM results to patients
otherwise ineligible for the FREEDOM dataset. In
particular this includes STEMI or non-STEMI patients
undergoing emergent or urgent angiography (see
above), those receiving hemodialysis, and those with
multivessel disease in whom the most severe stenoses
were in more distal coronary artery segments than were
required for FREEDOM trial entry.
Perhaps the most challenging question in the post-
FREEDOM era is the emergent management of STEMI
August 2013
S.N. Burgess et al.
in patients with DM with 3-vessel disease. Emergency
reperfusion is required in the infarct-related artery in the
85% to 90% of STEMI patients who do not have
thrombolysis in myocardial infarction grade-3 ow.
But having established thyrombolysis in myocardial
infarction grade-3 ow uncertainty arises regarding
subsequent treatment strategies. Are responsible inter-
ventionalists obliged to alter their normal practice of
stent deployment, either drug-eluting stents or bare-
metal stents, to ensure the patient remains eligible for
timely surgical revascularization of their nonculprit
disease? Should this include the use of a small molecule
glycoprotein IIb/IIIa inhibitor, which is not commonly
used if bivalirudin is the thrombin inhibitor, thus
avoiding the need for thienopyridine therapy with their
long pharmacodynamic effects, cangrelor excepted?
Having treated the culprit lesion, should we be reset-
ting the clock in STEMI patients with DM and multi-
vessel disease and discounting the infarct-related artery
(assuming it has no other ow-limiting lesions) in
assessing need for further revascularization? An argu-
ment against this view is the lack of interaction with
SYNTAX score and clinical outcome in the FREEDOM
trial suggesting the benet of CABG relates not to the
burden of disease but to the benet of (arterial) grafting.
Current interventional guidelines recommend treating
the infarct-related artery to achieve the best result for its
myocardial territory. This includes aspiration thrombec-
tomy, P2Y12 receptor antagonist therapy with ticagrelor
or prasugrel in those without contraindications, and the
use of bare metal or drug. If the residual disease still
meets FREEDOM criteria, CABG should be the
preferred revascularization strategy. However early
surgical revascularization for the residual disease
exposes patients to the increased risk of peri-infarct
surgery, potential thrombotic complications of early
P2Y12 receptor antagonist therapy cessation also need
to be considered, particularly where stents have been
used to treat the culprit lesion. If POBA and early
surgery are performed, there is a risk of pre-surgery re-
infarction, which needs to be balanced against the likely
long-term survival advantage of a surgical approach.
Culprit vessel PCI with DES and staged PCI should
also be considered a valid approach. If there is a good
short-term outcome after culprit artery PCI and there
is no longer ow-limiting LAD disease, can the clock
be reset with respect to the other arteries? If a LIMA
conduit to the LAD would not be utilized the long-
term benet of surgery may be more questionable.
1073
 Clinical Therapeutics
Many trials suggest much of the benet of CABG over
PCI is due to the durability of internal mammary
grafting.10,14,16 Subgroup analysis from FREEDOM
shows where the left anterior descending artery was
not involved, 95% CI intervals for hazard ratios are
broad and more closely approach 1.0.10
CONCLUSIONS
The optimal revascularization strategies in patients with
DM and ACS with multivessel disease, in particular
those with ST elevation, is not currently guided by level
A (or B) evidence. FREEDOM is the culmination of
several important revascularization trials in patients with
DM with multivessel coronary disease. The concept of
resetting the clock following successful primary PCI
of the infarct-related artery, is hypothesis generating and
needs to be tested in an appropriately powered random-
ized trial. The evidence generally favors CABG over PCI,
yet this dictum needs careful application in the treatment
of FREEDOM-ineligible patients. We suggest an indivi-
dually tailored, collaborative approach under the aus-
pices of a multidisciplinary heart team.
ACKNOWLEDGMENTS
The rst draft of this article was prepared by Drs. Burgess
and French. Further revisions were made by Drs. Burgess,
Mussap and French. Secretarial support was provided by
Philomena Kaarma and Melisa Gallardo.
CONFLICTS OF INTEREST
The authors have indicated that they have no conicts
of interest regarding the content of this article.
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Address correspondence to: John K. French, PhD, MBChB, FRACP,
Southwestern Sydney Clinical School, University of New South Wales,
Elizabeth St Sydney, New South Wales 2052, Australia. E-mail: j.french@-
unsw.edu.au

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