Clinical trial NCT01121224: Drug-Eluting Stents vs. Bare Metal Stents In Saphenous Vein Graft Angioplasty
Official title: CSP #571 - Drug-eluting Stents vs. Bare Metal Stents in Saphenous Vein Graft Angioplasty (DIVA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Saphenous Vein Graft Atherosclerosis
Keywords: Saphenous vein graft
Percutaneous coronary intervention
Stents
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2010-05-12
Enrollment: 597
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients who have undergone coronary bypass surgery have had a vein removed from the leg and implanted in the chest to "bypass" blockages in the coronary arteries. These veins are called saphenous vein grafts or SVGs. SVGs often develop blockages that can cause chest pain and heart attacks. SVG blockages can be opened by using small balloons and stents (metal coils that keep the artery open). Two types of stents are currently used: bare metal stents (BMS) and drug-eluting stents (DES). Both BMS and DES are made of metal. DES are also coated with a drug that releases into the wall of the blood vessel to prevent scar tissue from forming and re-narrowing the vessel. Both stents have advantages and disadvantages: DES require taking special blood thinners (called thienopyridines, such as clopidogrel or prasugrel) longer than bare metal stent and could have more bleeding but are also less likely to renarrow. Both BMS and DES are routinely being used in SVGs, but it is not known which one is better. Neither bare metal (except for an outdated model) nor drug-eluting stents are FDA approved for use in SVGs. The purpose of CSP#571 is to compare the outcomes after DES vs. BMS use in SVGs.

In CSP#571 patients who need stenting of SVG blockages will be randomized to receive DES or BMS in a 1:1 ratio. Per standard practice, patients will receive 12 months of an open label thienopyridine if they have acute coronary syndrome (ACS), or if they have another clinical reason for needing the medication. Patients without ACS who receive DES also need to take 12 months of a thienopyridine whether or not they are in the study, but non-ACS patients who receive a BMS do not. In order to make sure patients do not know which stent they received, non-ACS patients who received BMS will receive 1 month of open label thienopyridine followed by 11 months of blinded placebo, while those who received DES will receive 1 month of open label thienopyridine followed by 11 months of blinded clopidogrel, which is a thienopyridine.

All study patients will be followed in the clinic for at least 1 year after their stenting procedure to see if there is a difference in the rate of cardiac death, heart attack, or any procedure that is required in order to increase the flow of blood to and from the heart between the BMS and DES groups.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Target Vessel Failure (TVF), Defined as the Composite of Cardiac Death
timeFrame: 12 months
measure: Number of Participants With Target Vessel Failure (TVF), Defined as the Target Vessel Myocardial Infarction
timeFrame: 12 months
measure: Number of Participants With Target Vessel Failure (TVF), Defined as the Target Vessel Revascularization
timeFrame: 12 months
Secondary outcomes:
measure: Incremental Cost-effectiveness of DES Relative to BMS
timeFrame: 12 months
measure: Procedural Success
timeFrame: Discharge from Index Hospitalization (an average of 36 hours)
measure: Number of Participant Deaths (All Cause and Cardiac). All Deaths Will be Considered Cardiac Unless an Unequivocal Non-cardiac Cause Can be Established.
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Number of Participants With Myocardial Infarction (MI)
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Number of Participants With Definite Stent Thrombosis as Defined Using the Academic Research Consortium (ARC) Definition
timeFrame: 12 months
measure: Number of Participants With Target Vessel Revascularization (TVR)
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Patient-Oriented Composite Endpoint Will be Used as Secondary Outcome
timeFrame: 12 months
measure: In Patients Who Clinically Require Follow-up Angiography, Two Angiographic Endpoints Will be Assessed: (a) In-segment Binary Restenosis and (b) Angiographic Late In-segment Luminal Loss.
timeFrame: 12 months
measure: Number of Participants With Stroke
timeFrame: 12 months
measure: Incremental Cost-effectiveness Ratios (ICERs) for Subgroups of Patients, Such as Those With Highest Risk of Restenosis, Tallies of Cost by Type, and a Cost-outcomes Analysis Such as Cost Per Restenosis Avoided.
timeFrame: 12 months
measure: In-stent Neointima Proliferation as Measured by Intravascular Ultrasonography
timeFrame: 12 months
measure: Number of Participants With Target Lesion Revascularization (TLR)
timeFrame: 12 months
measure: Number of Participants With Target Vessel Myocardial Infarction
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Number of Participants With Any Revascularization
timeFrame: 12 months
measure: Number of Participants With Definite or Probable Stent Thrombosis
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Procedural Complications (Post-procedural Myocardial Infarction and Post-procedural Bleeding)
timeFrame: Discharge from Index Hospitalization (an average of 36 hours)
measure: Device-oriented Composite Endpoint of Target Lesion Failure Will be Used as a Secondary Outcome
timeFrame: 12 months
measure: Number of Participants With Target Lesion Revascularization (TLR)
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Number of Participants With Non-Target Revascularization
timeFrame: 12 months
measure: Number of Participants With Non-Target Revascularization
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Patient-oriented (for Target Lesion Failure) Composite Endpoints Will be Used as Secondary Outcomes as Proposed by Cutlip et al, and as Recommended in the Draft FDA Guidance for Industry Statement.
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Device-oriented (for Target Lesion Failure) Composite Endpoints Will be Used as Secondary Outcomes as Proposed by Cutlip et al, and as Recommended in the Draft FDA Guidance for Industry Statement.
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Number of Participants With Stroke
timeFrame: Entire Duration of Follow-up (median 2.7 years)
measure: Quality Adjusted Life Years of DES Relative to BMS
timeFrame: 12 months
measure: Quality Adjusted Life Years for Subgroups of Patients
timeFrame: 12 months
measure: In Patients Who Clinically Require Follow-up Angiography, Two Angiographic Endpoints Will be Assessed: (a) In-segment Binary Restenosis and (b) Angiographic Late In-segment Luminal Loss.
timeFrame: 12 months
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Southern Arizona VA Health Care System, Tucson, AZ
state: Arizona
city: Little Rock
country: United States
facility: Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR
state: Arkansas
city: San Francisco
country: United States
facility: San Francisco VA Medical Center, San Francisco, CA
state: California
city: Denver
country: United States
facility: VA Eastern Colorado Health Care System, Denver, CO
state: Colorado
city: Washington
country: United States
facility: Washington DC VA Medical Center, Washington, DC
state: District of Columbia
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System, Gainesville, FL
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Indianapolis
country: United States
facility: Richard L. Roudebush VA Medical Center, Indianapolis, IN
state: Indiana
city: Lexington
country: United States
facility: Lexington VA Medical Center, Lexington, KY
state: Kentucky
city: New Orleans
country: United States
facility: Southeast Louisiana Veterans Health Care System, New Orleans, LA
state: Louisiana
city: West Roxbury
country: United States
facility: VA Boston Healthcare System West Roxbury Campus, West Roxbury, MA
state: Massachusetts
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System, Ann Arbor, MI
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Columbia
country: United States
facility: Harry S. Truman Memorial, Columbia, MO
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis VA Medical Center John Cochran Division, St. Louis, MO
state: Missouri
city: New York
country: United States
facility: Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
state: New York
city: Asheville
country: United States
facility: Asheville VA Medical Center, Asheville, NC
state: North Carolina
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center, Cleveland, OH
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma City VA Medical Center, Oklahoma City, OK
state: Oklahoma
city: Memphis
country: United States
facility: Memphis VA Medical Center, Memphis, TN
state: Tennessee
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System Seattle Division, Seattle, WA
state: Washington
Study officials:
affiliation: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
name: Emmanouil S Brilakis, MD PhD
role: STUDY_CHAIR
affiliation: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
name: Subhash Banerjee, MD
role: STUDY_CHAIR
References:
citation: Xenogiannis I, Rangan BV, Uyeda L, Banerjee S, Edson R, Bhatt DL, Goldman S, Holmes DR Jr, Rao SV, Shunk K, Mavromatis K, Ramanathan K, Bavry AA, McFalls EO, Garcia S, Thai H, Uretsky BF, Latif F, Armstrong E, Ortiz J, Jneid H, Liu J, Aggrawal K, Conner TA, Wagner T, Karacsonyi J, Ventura B, Alsleben A, Lu Y, Shih MC, Brilakis ES. In-Stent Restenosis in Saphenous Vein Grafts (from the DIVA Trial). Am J Cardiol. 2022 Jan 1;162:24-30. doi: 10.1016/j.amjcard.2021.09.024. Epub 2021 Nov 1.
citation: Latif F, Uyeda L, Edson R, Bhatt DL, Goldman S, Holmes DR Jr, Rao SV, Shunk K, Aggarwal K, Uretsky B, Bolad I, Ziada K, McFalls E, Irimpen A, Truong HT, Kinlay S, Papademetriou V, Velagaleti RS, Rangan BV, Mavromatis K, Shih MC, Banerjee S, Brilakis ES. Stent-Only Versus Adjunctive Balloon Angioplasty Approach for Saphenous Vein Graft Percutaneous Coronary Intervention: Insights From DIVA Trial. Circ Cardiovasc Interv. 2020 Feb;13(2):e008494. doi: 10.1161/CIRCINTERVENTIONS.119.008494. Epub 2020 Feb 5.
citation: Brilakis ES, Edson R, Bhatt DL, Goldman S, Holmes DR Jr, Rao SV, Shunk K, Rangan BV, Mavromatis K, Ramanathan K, Bavry AA, Garcia S, Latif F, Armstrong E, Jneid H, Conner TA, Wagner T, Karacsonyi J, Uyeda L, Ventura B, Alsleben A, Lu Y, Shih MC, Banerjee S; DIVA Trial Investigators. Drug-eluting stents versus bare-metal stents in saphenous vein grafts: a double-blind, randomised trial. Lancet. 2018 May 19;391(10134):1997-2007. doi: 10.1016/S0140-6736(18)30801-8. Epub 2018 May 11.