Drug-Eluting Stents vs. Bare Metal Stents In Saphenous Vein Graft Angioplasty

VA Cooperative Studies Program #571 is designed to prospectively evaluate the efficacy of
drug-eluting stents (DES) in reducing aortocoronary saphenous vein bypass graft (SVG) failure
when compared to bare metal stents (BMS) in patients undergoing stenting of de novo SVG
lesions.

SVGs often develop luminal stenoses that are most commonly treated with stent implantation.
Approximately 60,000-100,000 percutaneous SVG interventions are performed annually in the
USA. Two types of coronary stents are currently available: bare metal stents and drug eluting
stents. Bare metal stents are the standard of care for the percutaneous treatment of SVG
lesions, but are limited by high rates of in-stent restenosis (as high as 51% after 12
months) often leading to repeat percutaneous or surgical SVG treatments. Drug-eluting stents
have been shown to significantly reduce in-stent restenosis and the need for repeat target
vessel and lesion revascularization in native coronary arteries, yet their efficacy in SVGs
is not well studied, with conflicting results from various small studies. The proposed
Cooperative Studies Program study will be the first large prospective, randomized,
multicenter, blinded clinical trial comparing DES and BMS in SVG lesions. It will provide
critical knowledge to assist the cardiac interventionalist in selecting the optimum stent
type for these challenging lesions.

Patients undergoing clinically-indicated stenting of de novo SVG lesions will be randomized
in a 1:1 ratio to DES or BMS. To ensure blinding to the type of stent used, of the patients
who do not present with an acute coronary syndrome and do not require 12 months of dual
antiplatelet therapy, those who receive DES will receive 11 months of clopidogrel and those
who receive BMS will receive 11 months of matching placebo. After stenting, patients will be
followed clinically for a minimum of one year to determine the 12-month incidence of target
vessel failure (TVF, primary study endpoint). TVF will be defined as the composite of cardiac
death, target vessel myocardial infarction and target vessel revascularization, and is the
primary clinical endpoint used in all FDA-approved DES pivotal trials. Coronary angiography
and intervention during follow-up will only be performed if clinically-indicated (no
mandatory angiographic follow-up). Secondary endpoints include: 1) clinical outcomes other
than TVF (procedural success; post-procedural myocardial infarction; post-procedural
bleeding; all cause death and cardiac death; follow-up myocardial infarction; stent
thrombosis; target lesion revascularization; target vessel revascularization; non-target
vessel revascularization; the composite endpoint of death, myocardial infarction, and target
vessel revascularization (patient-oriented composite endpoint according to the FDA guidance
document on DES studies); the composite endpoint of cardiac death, target vessel myocardial
infarction, and target lesion revascularization (device-oriented composite endpoint for
target lesion failure); and stroke); and 2) incremental cost-effectiveness of DES relative to
BMS. A tertiary endpoint is in-stent neointima proliferation as measured by intravascular
ultrasonography.

Based on published studies, the investigators estimate the 12-month TVF rate in the BMS arm
to be 30%. The investigators hypothesize that DES will reduce TVF to 18% (40% relative
reduction). Assuming two-year accrual and one interim assessment, a total sample size of
about 520 patients will be needed to detect this difference with 90% power, using a two-sided
5% significance level. Assuming an intake rate of 1 patient per month per VA Medical Center,
the investigators will need 22 participating sites. However, the investigators will begin the
study with 25 sites to protect against a site dropout rate of 10%.

Percutaneous treatment of SVG lesions is of particular importance to the VA system because
many Veterans have undergone and continue to undergo coronary artery bypass graft surgery.
Every year, approximately 12-15% of percutaneous coronary interventions performed within the
VA system are performed in SVGs, at a cost of approximately $15,000-$20,000 per procedure;
DES are currently used in approximately half of SVG interventions. Because of (a) the high
prevalence and high cost of SVG stenting, (b) DES cost two- to three- fold more than BMS and
often require prolonged ( 12 months) thienopyridine administration to prevent late stent
thrombosis, and (c) DES may have increased risk for late and very late stent thrombosis, a
catastrophic complication with high mortality, the proposed study will have considerable
impact on the clinical practice of SVG lesion stenting, patient satisfaction, and financial
burden of health care systems (both within and outside the VA), regardless of whether the
results are positive (DES offer significantly superior health benefits to patients than BMS),
or negative (DES do not offer significantly superior health benefits to patients than BMS).
Due to decreasing profits and increasing competition, DES manufacturers are not planning to
ever fund a SVG DES study. The VA system with its Cooperative Studies Program is uniquely
suited to conduct the proposed study.

Inclusion Criteria:

- Age 18 years

- Need for percutaneous coronary intervention of a 50-99% de novo SVG lesion that is
between 2.25 and 4.5 mm in diameter and that is considered to cause clinical or
functional ischemia

- Intent to use a distal embolic protection device

- Agrees to participate and to take prescribed medications as instructed

- Has provided informed consent and agrees to participate

Exclusion Criteria:

- Planned non-cardiac surgery within the following 12 months

- Presentation with an ST-segment elevation acute myocardial infarction

- Target SVG is the last remaining vessel or is the "left main" equivalent

- Any previous percutaneous treatment of the target lesion (with balloon angioplasty,
stent, intravascular brachytherapy etc)

- Any previous percutaneous treatment of the target vessel (of a lesion different than
the target lesion) within the prior 12 months

- Hemorrhagic diatheses, or refusal to receive blood transfusions

- Warfarin administration required for the next 12 months and patient considered to be
at high risk of bleeding with triple anticoagulation/antiplatelet therapy

- Recent positive pregnancy test, breast-feeding, or possibility of a future pregnancy
(defined as no prior hysterectomy or as <5 years elapsing since last menstrual period)

- Coexisting conditions that limit life expectancy to less than 12 months

- History of an allergic reaction or significant sensitivity to drugs such as sirolimus,
paclitaxel, zotarolimus, or everolimus included in various DES. History of an allergic
reaction or significant sensitivity to L-605 cobalt chromium alloy (cobalt, silicon,
chromium, tungsten, manganese, iron, nickel), F562 cobalt chromium alloy (cobalt,
chromium, nickel), 316L surgical stainless steel (iron, chromium, nickel, and
molybdenum), or MP35N cobalt-based alloy (cobalt, nickel, chromium, molybdenum,
titanium, iron, silicon, and manganese), or components of the platinum chromium alloy
stent.

- Allergy to clopidogrel in patients who do not present with an acute coronary syndrome
(ACS), where ACS is defined as cardiac ischemic symptoms occurring at rest and 1 of
the following 3 criteria: electrocardiographic changes suggestive of ischemia
(ST-segment elevation or depression 1 mm in 2 contiguous leads, or new left bundle
branch block, or posterior myocardial infarction); positive biomarker indicating
myocardial necrosis (troponin I or T or creatine kinase-MB greater than the upper
limit of normal); or coronary revascularization performed during hospitalization
triggered by the cardiac ischemic symptoms

- Participating in another interventional randomized trial (required condition for all
CSP studies) for which dual enrollment with DIVA is not approved