Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes (FREEDOM)

BACKGROUND:

The study addresses the critically important problem of how to best revascularize diabetic
individuals with multivessel CAD. CAD and diabetes diagnoses are increasing at alarming
rates, and much of the information regarding optimal revascularization comes from the Bypass
Angioplasty Revascularization Investigation (BARI) study. After five years, data from the
BARI study showed 15 excess deaths for every 100 diabetic participants revascularized by
percutaneous coronary intervention (PCI) compared to CABG, and at 7 years there were more
than 20 deaths. These findings provide compelling evidence for some physicians to conclude
that diabetic patients with multivessel disease in need of revascularization are best
handled by CABG. But a consensus has not yet been reached because these findings have not
been uniformly confirmed by registries and other studies. With the recent introduction of
coated stents that significantly reduce or eliminate restenosis, a prevailing belief is that
adequate revascularization can be achieved by PCI even in diabetic individuals. New
developments in percutaneous techniques should translate to improved prognosis to offset the
advantage of CABG seen in the BARI study. Since these new drug eluting stents are not yet
approved and are not likely to be on the market for several years, a small window of time
exists to gather the evidence to support the strategy that provides optimal
revascularization in diabetic individuals.

DESIGN NARRATIVE:

FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal
Management of Multivessel Disease) is a multicenter, two-arm, open label, prospective,
randomized superiority trial with equal allocation, of 5 years duration with a minimum of 3
years of follow-up. The main objective of the study is to evaluate whether PCI with
drug-eluting stenting (PCI/DES) is more or less effective than the existing standard of
care, CABG. The study population will consist of 2,400 adults with diabetes mellitus (Type 1
or Type 2) with angiographically confirmed multivessel CAD and morphology amenable to either
PCI or CABG, with indication for revascularization based upon symptoms or angina and/or
objective evidence of myocardial ischemia. Patients who consent will be randomized on a 1:1
basis either to CABG or multivessel stenting using drug-eluting stents, and followed at 30
days, 1 year, and then annually for at least 3 years, but up to 5 years. A registry of 2000
patients will also be recruited concurrently, comprised of eligible non-consenting patients
for the randomized trial. Eligible patients will be randomized to receive either CABG or
multivessel stenting using drug-eluting stents. Patients randomized to the PCI/DES arm will
receive, at the discretion of the primary physician or interventionalists, either CYPHER
Sirolimus eluting stent (Cordis Corporation, Warren, NJ, USA) or the TAXUS
paclitaxel-eluting stent (Boston Scientific Corporation, Natick, MA, USA). However, it is
intended that only one type of drug-eluting stent be used in a given patient during the
course of the trial. The primary outcome of the study is the composite of all-cause
mortality, nonfatal myocardial infarction, and stroke at the end of the 5-year patient
accrual and follow-up period (minimum follow-up is 3 years). The main secondary endpoint
that will be assessed is the 1-year major adverse cardiac and cerebrovascular event (MACCE)
rates, including the first of one of the following: death, myocardial infarction, stroke, or
repeat revascularization. Additional secondary endpoints include: all-cause and
cardiovascular mortality at 1, 2, and 3 years; rates of individual MACCE endpoints at 30
days post-procedure; quality of life at 30 days, 6 months, and annually post-procedure; long
term costs and cost-effectiveness.

Inclusion Criteria:

- Diabetes mellitus (Type 1 or Type 2), defined according to the American Diabetes
Association as either:

1. presence of classic symptoms of diabetes mellitus with unequivocal elevation of
plasma glucose (2-hour post-prandial or random of greater than 200 mg/dL
(11mmol/L) or

2. fasting plasma glucose elevation on more than one occasion of at least 126 mg/dL
(7mmol/L)

- Currently undergoing pharmacological or non-pharmacological treatment for diabetes

- Angiographically confirmed multivessel CAD [critical (greater than or equal to 70%)
lesions in at least two major epicardial vessels and in at least two separate
coronary artery territories (LAD, LCX, RCA)] amenable to either PCI or CABG

- Angiographic characteristics amendable to both PCI/DES and CABG

- Indication for revascularization based upon symptoms of angina and/or objective
evidence of myocardial ischemia

Exclusion Criteria:

- Severe congestive heart failure (class III or IV according to New York Heart
Association [NYHA] or pulmonary edema)

- Prior CABG surgery

- Prior valve surgery

- Prior PCI with stent implantation within 6 months of study entry

- Stroke within 6 months of study entry; if stroke occured more than 6 months prior to
study entry, must have significant residual neurologic involvement, as reflected in a
Rankin Score of greater than 1

- Prior history of significant bleeding (within 6 months of study entry) that may occur
during CABG or PCI/DES related anticoagulation

- In-stent restenosis of a target vessel

- Two or more chronic total occlusions in major coronary territories

- Left main stenosis (at least 50% diameter stenosis)

- Acute ST-elevation MI (Q-wave) within 72 hours of study entry requiring
revascularization

- Abnormal creatine kinase level (greater than twice the normal limit); or abnormal
CK-MB level at study entry

- Planned simultaneous surgical procedure unrelated to coronary revascularization
(e.g., valve repair/replacement, aneurysmectomy, carotid endarterectomy, or carotid
stent)

- Cannot undergo either CABG or PCI/DES because of a coexisting medical condition

- Significant leukopenia, neutropenia, thrombocytopenia, anemia, or known bleeding
diathesis

- Intolerance to aspirin or both clopidogrel and ticlopidine

- Dementia with a score of less than 20 on the Mini Mental Status Examination (MMSE)

- Extra-cardiac illness that is expected to limit survival to less than 5 years (e.g.,
oxygen-dependent chronic obstructive pulmonary disease, active hepatitis, significant
hepatic failure, or severe kidney disease)

- Pregnant

- Currently enrolled in another clinical trial

- Unable to attend required follow-up visits