Clinical trial NCT00159991: Copenhagen Arterial Revascularization Randomized Patency and Outcome Trial
Official title: Arterial Revascularization for Coronary Bypass Surgery: A Randomized Trial Comparing the Outcome After Using LIMA + Vein Grafts Versus Total Arterial Revascularization With LIMA + RIMA + Radial Artery Grafts
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Coronary Arteriosclerosis
Ischemic Heart Disease
Angina Pectoris
Keywords: Coronary artery bypass grafting
Total arterial revascularization
Internal mammary artery grafting
Radial artery grafting
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Danish Heart Foundation
name: Lundbeck Foundation
name: Copenhagen Hospital Corporation
First posted: 2005-09-12
Enrollment: 331
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: There is a remarkable lack of randomized trials concerning the potential benefit of using arterial conduits for coronary bypass surgery. This is the purpose of the present trial. Exclusive use of arterial conduits might result in improved conduit viability, reduced risk of recurrent angina, myocardial infarction and other cardiac events, reduced need for antianginal medication, improved functional status and possibly improved long term survival. The patients will be followed for ten years after surgery.

Detailed description: I: Background

There is a remarkable lack of randomized studies concerning the potential benefit of using arterial grafts for coronary revascularization. Numerous observational reports consistently confirm, that the use of a LIMA-LAD grafts is not associated with increased peroperative mortality or morbidity and will result in an approximately 10% improved survival at 10 years postoperatively.

The average patency for LIMA-LAD grafts is 80%-85% after 10 years. 50% of the vein grafts are occluded. LIMA-LAD grafting reduces the risk of of late myocardial infarction, other cardiac events and reoperation, however the effect on recurrent angina or need of antianginal medication is less certain.

The question, whether bilateral IMA grafting has long term benefits compared to single IMA grafts is controversial. Numerous observational retrospective studies fail to demonstrate convincingly, that bilateral IMA grafting reduces long term mortality and improves the frequency of late cardiac events and recurrent angina, but these data are difficult to compare due to selection bias. It is not quite clear, if a minimal benefit represents a true difference in outcome, or if two different populations are compared.

Whether an increased degree of arterial revascularization, including radial artery (RA) and IMA grafts, will result in an improved long term survival, reduced risk for recurrent angina, reinfarction, antianginal medication and improved quality of life, is unclear.

A randomized trial has not yet been performed and current observational 5 year follow-up data are promising, but cannot document an anticipated benefit from a more stringent scientific point of view.

II: Hypothesis

Coronary bypass grafting with the use of LIMA + RIMA + RA (total arterial revascularization) vs. LIMA + saphenous vein grafts will result in equal peroperative mortality and morbidity rates and improve long term outcome in terms of improved patency rates, reduced risk of recurrent angina, infarction and other cardiac events, reduced need for antianginal medication, improved functional status and possibly improved long term survival.

III: Aim of the study

Prospective randomized trial comparing coronary bypass grafting with the use of LIMA + RIMA + RA vs. LIMA + saphenous vein grafts in patients with 2 or 3 vessel disease (more than 1 graft anticipated) with respect to:

1. Graft patency rates at 1, 5 and 10 years postoperatively
2. Cardiac event free survival 1, 5 and 10 years postoperatively (risk of hospital readmission due to infarction, suspicion of infarction, unstable angina, arrythmias, heart insufficiency, need for renewed angiography, angioplasty, redo surgery)
3. Peroperative mortality and morbidity
4. Risk of recurrent angina and need for antianginal medication 1, 5 and 10 years postoperatively
5. Data on functional status and social rehabilitation at clinical controls 3 months, 1, 5 and 10 years postoperatively

IV: Design \& methods

1. Design

   Prospective randomized trial. Patients will be randomized into 2 groups:

   Group A: Arterial revascularization with LIMA + RIMA + RA.

   Group B: LIMA and saphenous vein grafts are used as graft material.
2. Inclusion criteria

   * Patients with 2 or 3 vessel coronary artery disease, where more than 1 coronary bypass graft is anticipated.
   * Elective or subacute operation (unstable AP with surgery within a few days)
   * Inclusion is independent of ventricular function, recent MI, degree and type of coronary lesions and secondary risk factors as diabetes, hyperlipidemia, hypertension, lung function, chronic obstructive lung disease, peripheral atherosclerotic disease, kidney function, earlier cerebrovascular disease.
   * Age: \< 70 years.
   * Sufficient collateral blood supply to the hand by the ulnar artery, evaluated by the Allen test.
   * Patients must be able to give informed consent.
3. Exclusion criteria

   * Concurrent malignant disease with expected survival of \< 5 years.
   * Unsuitable saphenous vein grafts evaluated preoperatively.
   * Unsuitable saphenous vein grafts with a diameter \> 6mm evaluated peroperatively.
   * Acute operation (unstable hemodynamics in terms of need of inotropic support, ongoing MI with dynamic ECG changes, cardiogenic shock).
   * Concommitant operation for valve disease or other forms of heart surgery.
   * Redo operations.
4. Surgery, anaesthesia and postoperative care

   Surgery, anaesthesia and postoperative care are performed according to current guidelines at our institution.
5. Endpoints and follow-up

   The study is designed with respect to two primary endpoints:
   1. Distal anastomotic patency rates at 1, 5 and 10 years postoperatively
   2. Cardiac event free survival 1, 5 and 10 years postoperatively (Cardiac event free survival is defined as survival without readmission due to infarction, suspicion of infarction, unstable angina, arrythmias, heart insufficiency, need for renewed angiography, angioplasty, redo surgery)

   Secondary endpoints:
   1. Peroperative mortality and morbidity (frequency of peroperative/ postoperative infarction, arrythmias, use of IABP, inotropic support, pulmonary, renal and cerebral complications, length of stay in the ICU, etc. according to registration schemes).
   2. Risk of recurrent angina and need for antianginal medication 1, 5 and 10 years postoperatively
   3. Data on functional status and social rehabilitation at clinical controls 3 months, 1, 5 and 10 years postoperatively

   According to these endpoints the follow-up is planned as:
   * 3 month clinical control at referring hospitals
   * 1 year control including angiography, which can be performed on an outpatient basis.
   * 5 year control including conventional angiography and computed tomography angiography.
   * 10 year control including computed tomography angiography, which can be performed on an outpatient basis.
6. Statistics

Sample size is calculated with respect to the primary endpoint graft patency at 1 and 5 years. A difference of 10-15% of patency in favour of the radial artery as bypass graft is regarded as clinically relevant. Observational data on radial artery patency indicate patency rates of 90-95% at 1 year and 85% at 5 years, while saphenous vein graft patency is 80-90% at 1 year and 60-70% at 5 years.

To detect such a difference (15% improved patency for RA grafts, 85% vs 70%) with a 90% probability (type 2 error 0.10) and a significance level of 0.05, the sample size for each group would be n=150.

A 15% difference in patency rates at 5 years is in our opinion an assumption that probably overestimates the vein graft patency, which means, that a sample size of 150 patients in each group should guarantee with a high probability a statistically significant outcome.

Eligibility criteria: Inclusion Criteria:

* Patients with 2 or 3 vessel coronary artery disease, where more than 1 coronary bypass graft is anticipated.
* Elective or subacute operation (unstable AP with surgery within a few days)
* Inclusion is independent of ventricular function, recent MI, degree and type of coronary lesions and secondary risk factors as diabetes, hyperlipidemia, hypertension, lung function, chronic obstructive lung disease, peripheral atherosclerotic disease, kidney function, earlier cerebrovascular disease.
* Age: \< 70 years.
* Sufficient collateral blood supply to the hand by the ulnar artery, evaluated by the Allen test.
* Patients must be able to give informed consent.

Exclusion Criteria:

* Concurrent malignant disease with expected survival of \< 5 years.
* Unsuitable saphenous vein grafts evaluated preoperatively.
* Unsuitable saphenous vein grafts with a diameter \> 6mm evaluated preoperatively.
* Acute operation (unstable hemodynamics in terms of need of inotropic support, ongoing MI with dynamic ECG changes, cardiogenic shock).
* Concommitant operation for valve disease or other forms of heart surgery. Redo operations.

Primary outcomes:
measure: Angiographic distal anastomotic patency rates
timeFrame: 1, 5 and 10 years postoperatively
measure: Cardiac event free survival
timeFrame: 1, 5 and 10 years postoperatively
Secondary outcomes:
measure: Peroperative mortality
timeFrame: Until 3 months postoperatively
measure: Postoperative morbidity (frequency of peroperative/ postoperative infarction, arrythmias, use of IABP, inotropic support, pulmonary, renal and cerebral complications, length of stay in the ICU, etc. according to registration schemes).
timeFrame: 3 months postoperatively
measure: Risk of recurrent angina and need for antianginal medication
timeFrame: 1, 5 and 10 years postoperatively
measure: Data on functional status and social rehabilitation at clinical controls
timeFrame: 3 months, 1, 5 and 10 years postoperatively
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Department of Cardiothoracic Surgery, Rigshospitalet
Study officials:
affiliation: Dept. of Cardiothoracic Surgery, Rigshospitalet, Copenhagen
name: Sune Damgaard, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dept. of Cardiothoracic Surgery, Rigshospitalet, Copenhagen
name: Daniel A Steinbrüchel, Professor
role: STUDY_DIRECTOR
affiliation: Dept. of Cardiothoracic Surgery, Rigshospitalet, Copenhagen
name: Jens T Lund, Consultant
role: STUDY_CHAIR
affiliation: Cardiac Cath. Lab., Rigshospitalet, Copenhagen
name: Henning Kelbæk, Consultant
role: STUDY_CHAIR
affiliation: Dept. of Cardiology, Gentofte County Hospital, Copenhagen
name: Jan K Madsen, Consultant
role: STUDY_CHAIR
References:
citation: Damgaard S, Wetterslev J, Lund JT, Lilleor NB, Perko MJ, Kelbaek H, Madsen JK, Steinbruchel DA. One-year results of total arterial revascularization vs. conventional coronary surgery: CARRPO trial. Eur Heart J. 2009 Apr;30(8):1005-11. doi: 10.1093/eurheartj/ehp048. Epub 2009 Mar 6.