Clinical trial NCT00463294: Coronary Artery Bypass Surgery (CABG) Off or On Pump Revascularization Study
Official title: CABG Off or On Pump Revascularization Study (CORONARY)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: the Efficacy and Safety of Off-pump CABG
Keywords: CABG
On-pump
Off-pump
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: McMaster University
name: University of Oxford
name: Instituto Dante Pazzanese de Cardiologia
name: Fu Wai Hospital, Beijing, China
name: Universidad de La Frontera
name: Fundación Cardiovascular de Colombia
name: Charles University, Czech Republic
name: Hopital Jean Minjoz
name: Centre for Chronic Disease Control, India
name: Ospedale Santa Croce-Carle Cuneo
name: Medical University of Gdansk
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Ankara University
name: Hotel Dieu Hospital
name: Centre hospitalier de l'Université de Montréal (CHUM)
name: SAL Hospital, Ahmedabad, India
First posted: 2007-04-20
Enrollment: 4752
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: I. Main Research Question:

* To compare the risks and benefits of Off-pump Coronary artery bypass surgery (CABG) to On-pump CABG and to determine if one is better than the other.
* The purpose of this pilot study is also to see the rate of recruitment with expertise-based randomization across different hospital settings.

II. Small RCT studies and meta-analyses done so far have not been able to conclusively say which of the procedure is better. A large randomized study is required to establish the risks and benefits associated with both the off-pump and on-pump CABG surgical procedures.

III. The study will look at which of the two techniques reduce major risks associated with CABG.

Detailed description: Rationale and purpose of the study:

Coronary artery bypass grafting (CABG) surgery prolongs life-expectancy in patients with severe ischemic heart disease, especially those with left main, triple vessel disease or single/double vessel disease with stenosis of the proximal left anterior descending (LAD) artery. The perioperative mortality is about 2% with an additional 5% to 7% suffering complications such as myocardial infarction, stroke, renal failure, etc. The technique of operating on a beating heart (off-pump) for coronary artery bypass grafting surgery has been recently developed in the past few years in an effort to decrease the above perioperative complications typically related to cardiopulmonary bypass associated with on-pump CABG. While registries suggest that off-pump CABG may be superior, these data cannot fully control for differences in patient characteristics, which influence patient selection for specific procedures. The benefits of off-pump CABG compared with conventional on-pump CABG are unclear. The investigators therefore propose a large simple, international multicentre randomized controlled trial to definitively evaluate the efficacy and safety of off-pump CABG in the treatment of patients undergoing coronary artery surgery funded by CIHR, this pilot study will be a preliminary step towards a full trial.

Sample size:

The investigators examined the outcomes in the Canadian off-pump CABG Registry to identify a group of patients who represent a higher risk of cardiovascular events. Utilizing the inclusion criteria described below, this group of patients has accumulated the vast majority of outcomes in the Registry and represent more than 50% of patients in the Registry, therefore minimizing the sample size but still being representative. The cumulative event rate at 30 days (first co-primary outcome) for on-pump CABG is estimated as being 8.6% and the investigators expect a 33% relative risk reduction (RRR) for the off-pump CABG group. The sample calculated for the whole trial is 4700 patients.

Design/Methodology:

Trial design: This is a pilot randomized controlled trial comparing off-pump CABG versus on-pump CABG in 60 patients who will be undergoing isolated CABG.

Interventions: Patients eligible for CABG will be randomized to receive either an Off-pump CABG surgery or On-pump CABG surgery.

Randomization: After obtaining informed written consent patients will be allocated to either off-pump CABG or on-pump CABG by calling a 24-hour randomization telephone number. An expertise-based randomization will be used wherein a surgeon who is an expert in Off-pump surgery will operate on patients randomized to receive Off-pump surgery. Patients randomized to receive On-pump CABG will be operated on by a surgeon who is an expert in on-pump CABG surgery. To minimize bias stratified block randomization will used. For this pilot study randomization will be stratified to 3 centres and random block of 4 or 6.

The data adjudicators will be blinded to the study. Due to the nature of intervention, the operating surgeon, anesthetist, perfusionist, other operation room staff, intensive-care unit staff will not be blinded in this study.

Setting:

Patients will have either been seen in the emergency, outpatient or ICU and diagnosed with having single, double or triple coronary artery occlusion requiring an isolated CABG.

Study interventions:

Interventions: Patients eligible for CABG will be randomized to receive either an Off-pump CABG surgery or On-pump CABG surgery. A surgeon who is an expert in the assigned technique will perform the procedure.

Primary outcomes:

* The occurrence of the composite of total mortality, stroke, nonfatal MI, or new renal failure at 30 days post CABG surgery AND
* The occurrence of the composite of total mortality, stroke, nonfatal MI, new renal failure, or repeat coronary revascularization (i.e. coronary artery bypass surgery or percutaneous coronary intervention) over 5 years after randomization.

The secondary outcomes

* The assessment of total costs and resources consumption at 30 days after CABG surgery AND
* The assessment of total costs and resources consumption at 5 years after CABG surgery

Measurements:

The investigators will ascertain all events of interest through periodic and regular follow-up utilizing standardized definitions for all events, appropriate supporting documents will be obtained centrally.

* CV death: all deaths are considered cardiovascular unless a specific non-cardiovascular cause is evident (e.g. malignancy).
* Stroke: new acute focal neurological deficit (except for subarachnoid hemorrhage which may not be focal) thought to be of vascular origin with signs or symptoms lasting greater than 24 hours.
* MI perioperative (within 24 hours of surgery): new pathologic Q waves with documented new wall motion abnormalities other than septal OR cardiac markers ³ 10 x ULN.
* MI non-perioperative (later than 24 hours after surgery): ECG changes consistent with infarction (new significant Q waves in two contiguous leads in the absence of previous LVH or conduction abnormalities) or evolving ST-segment to T-wave changes in two contiguous leads or new left bundle branch block or ST segment elevation requiring thrombolysis or PCI AND cardiac markers (troponins or CKMB) in the necrosis range. Post-PCI MI are included into non-perioperative MI group but are defined as new pathologic Q waves with documented new wall motion abnormalities other than septal OR cardiac markers ³ 3 x ULN within 24 hours of PCI.
* Renal failure: doubling of serum creatinine from pre-op baseline or requirement for renal replacement therapy (eg, dialysis, continuous hemofiltration, renal transplant). Hemofiltration or dialysis only during cardio-pulmonary bypass does not constitute a requirement for renal replacement therapy. Patients who receive dialysis within 1 month of the surgery are not eligible for this endpoint.
* Repeated coronary revascularization: new CABG procedure or PCI associated with documented ischemia by stress testing (ECG, ECHO, or nuclear) AND graft failure or new culprit lesion (³ 70% luminal stenosis).

For other endpoints, the investigators have defined:

* Recurrence of angina: new or chronic onset of typical chest pain with documented ischemia by stress testing (ECG, ECHO, or nuclear).
* Blood transfusions: all blood bank products transfused within 24 hours of the CABG surgery.
* Total mortality: all causes of mortality

Plan for data analysis:

The intention to treat principle, in which all participants will be included in their assigned treatment groups regardless of adherence, will guide all analyses. In the principle analysis, the time to the first occurrence of one of the components of the cluster of (cardiac death, stroke, nonfatal MI, new renal failure) will be presented by Kaplan-Meier survival curves and the comparisons between the two treatment groups will be performed by a log-rank test. The treatment effect as measured by the hazard ratio and 95% confidence interval will be derived by the Cox proportional hazards model. The investigators will also calculate the absolute risk reductions and the associated 95% confidence intervals, as well as the number needed to treat (NNT) with off-pump CABG to prevent one major cardiovascular event. Participants who prematurely discontinue follow-up before a major cardiovascular event will be censored as to their last follow-up data; this number is expected to be \<1% given the relatively short period of follow-up after surgery.

In secondary analyses the investigators will determine and compare the incidence of major cardiovascular events (cardiac death, stroke, nonfatal MI, new renal dialysis) and revascularization procedures (i.e. coronary artery bypass surgery and percutaneous coronary intervention) using the same strategy. The effect of the two operative techniques on different sub-groups (i.e. patients with diabetes, renal failure, congestive heart failure, cerebrovascular disease, as well as patient left ventricular function, gender and ages will be conducted by stratified analysis through a Cox proportional hazards model. The test of interaction between each subgroup factor and the treatment group will be done by including a product term in the model already containing treatment and the subgroup factor. The length of hospital stay and length of ICU/CCU stay will be compared using a student's t-test. An events adjudication committee (blind to surgical allocation) will centrally review all suspected major outcomes listed above.

The investigators will also do subgroup analysis on different sub-groups (i.e. patients with diabetes, renal failure, congestive heart failure, cerebrovascular disease, as well as patient left ventricular function, gender and ages will be examined for consistency and coherence)

Eligibility criteria: Inclusion Criteria:

Patients who have been diagnosed with coronary artery disease (single, double or triple disease) will be eligible if they:

1. require isolated CABG with median sternotomy
2. are able to give their informed written consent
3. are\> 21 years of age and
4. have one or more of the following risk factors:

   * ≥ 70 years
   * peripheral vascular disease (previous peripheral bypass or amputation or ABI \<0.80)
   * Cerebrovascular disease (history of stroke, TIA)
   * Renal insufficiency (creatinine above upper limit of normal)
   * \>60 years of age and one of the following:

     * diabetes (oral hypoglycemic agent and/or insulin)
     * urgent revascularization (waiting in hospital)
     * LV ejection fraction \<35%
     * current or recent smoker.
   * 55-59 years of age and two of the following:

     * diabetes (oral hypoglycemic agent and/or insulin)
     * urgent revascularization (waiting in hospital)
     * LV ejection fraction \<35%
     * current or recent smoker.

Exclusion Criteria:

Patients will be excluded if they have one of the following:

1. concomitant cardiac procedure associated with CABG,
2. contra-indications to off-pump CABG or on-pump CABG (calcified aorta, intramuscular LAD, calcified coronaries, small target vessels)
3. concomitant life-threatening disease likely to limit life expectancy to less than 2 years,
4. prior enrollment in this trial
5. emergency CABG surgery (immediate revascularization for hemodynamic instability) OR
6. redo CABG.

Primary outcomes:
measure: First Co-Primary Outcome
timeFrame: 30 days post CABG surgery
measure: Second co-primary outcome
timeFrame: 5 years after CABG
Secondary outcomes:
measure: The assessment of total costs and resources consumption at 30 days after CABG surgery
timeFrame: 30 days after CABG surgery
measure: The assessment of total costs and resources consumption at 5 years after CABG surgery
timeFrame: 5 years after CABG surgery
Other outcomes:
Locations:
city: Rio Negro
country: Argentina
facility: Fundacion Medica de rio negro y neuquen
city: Sao Paulo,
country: Brazil
facility: Beneficencia Portuguesa de Sao Paulo
state: CEP
city: Sao Paulo
country: Brazil
facility: Instituto Dante Pazzanese de Cardiologia
state: CEP
city: Porto Alegre
country: Brazil
facility: Hospital Sao Francisco Complexo Hospitalar Santa Casa
state: RS
city: Curitiba Parana
country: Brazil
facility: Irmande Santa Casa De Misericordia De Curtiba
city: Sao Jose do Rio Preto
country: Brazil
facility: Braile Clinica de Servicos de Assistencia Medico
city: Sao Paulo
country: Brazil
facility: Irmandade da Santa Casa de Misericordia de Sao Paulo
city: Sao Paulo
country: Brazil
facility: Federal University of Sao Paulo School of Medicine
city: Sao Paulo
country: Brazil
facility: Instituto do Coracao do Hospital das Clinicas da
city: Sao Paulo
country: Brazil
facility: Hospital Mario Covas
city: Sao Paulo
country: Brazil
facility: Santa Casa de Misericordia de Marilia
city: São Paulo
country: Brazil
facility: Associação do Sanátorio Sírio
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Montreal
country: Canada
facility: Hotel-Dieu du CHUM
state: Quebec
city: Temuco
country: Chile
facility: Hospital Regional Temuco
state: IX Region
city: Santiago
country: Chile
facility: Instituto Nacional del Torax
city: Beijing
country: China
facility: ChaoYang Hospital
city: Beijing
country: China
facility: FuWai Hospital
city: Nanjing
country: China
facility: Nanjing First Hospital
city: Bogota
country: Colombia
facility: Fundacion Cardioinfantil
city: Cali
country: Colombia
facility: Fundacion Valle Del Lili
city: Hradec Kralove
country: Czech Republic
facility: Charles University Hospital
city: Ostrava-Poruba
country: Czech Republic
facility: Kardiochirurgicke centrum
city: Pilsen
country: Czech Republic
facility: University Hospital Pilsen
city: Prague
country: Czech Republic
facility: Fakultni nemocnice Kralovske Vinohrady (FNKV)
city: Praha
country: Czech Republic
facility: University Hospital Motol
city: Trinec
country: Czech Republic
facility: Nemocnice Podlesi
city: Besancon
country: France
facility: Service de chirurgie thoracique et cardio-vasculaire
city: Hyderabad
country: India
facility: Nizam's Institute of Medical Sciences
state: Andhra Pradesh
city: Ahmedabad
country: India
facility: SAL Hospital and Medical Institute
state: Gujarat
city: Cochin
country: India
facility: Amrita Institute of Medical Sciences and Research Center
state: Kerala
city: Coimbatore
country: India
facility: G.Kuppuswamy Naidu Memorial Hospital
state: TamilNadu
city: Ahmedabad
country: India
facility: SAL Hospital
city: Chennai Tamil Nadu
country: India
facility: International Center of Cardiovascular and Thoracic Diseases
city: Lucknow
country: India
facility: Sanjay Gandhi PGIMS
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
city: Noida
country: India
facility: Escorts Heart Institute and Research Centre
city: Cuneo
country: Italy
facility: Ospedale S. Croce
city: Milano
country: Italy
facility: Ospedale Niguarda - Ca Granda
city: Krakow
country: Poland
facility: Jagiellonian University
city: Ankara
country: Turkey
facility: Alp Aslan
city: Ankara
country: Turkey
facility: Erol Senor
city: Ankara
country: Turkey
facility: Ruchan Akar
city: Ankara
country: Turkey
facility: Sertap Aykut Aka
city: Ankara
country: Turkey
facility: Volkan Sinci
city: Basildon
country: United Kingdom
facility: Basildon and Thurrock University Hospital NHS FT
state: Essex
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
state: EU
city: Oxford
country: United Kingdom
facility: The John Radcliffe Hospital
Study officials:
affiliation: McMaster University
name: Lamy Andre, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Population Health Research Institute
name: Salim Yusuf, MD, DPhil
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Oxford
name: David Taggart, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hebert M, Lamy A, Noiseux N, Stevens LM; CORONARY Investigators. Impact of early quantitative morbidity on 1-year outcomes in coronary artery bypass graft surgery. Interact Cardiovasc Thorac Surg. 2022 Mar 31;34(4):523-531. doi: 10.1093/icvts/ivab316.
citation: Conen D, Wang MK, Devereaux PJ, Whitlock R, McIntyre WF, Healey JS, Yuan F, Yusuf S, Lamy A. New-Onset Perioperative Atrial Fibrillation After Coronary Artery Bypass Grafting and Long-Term Risk of Adverse Events: An Analysis From the CORONARY Trial. J Am Heart Assoc. 2021 Jun 15;10(12):e020426. doi: 10.1161/JAHA.120.020426. Epub 2021 May 29.
citation: Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Straka Z, Piegas LS, Avezum A, Akar AR, Lanas Zanetti F, Jain AR, Noiseux N, Padmanabhan C, Bahamondes JC, Novick RJ, Tao L, Olavegogeascoechea PA, Airan B, Sulling TA, Whitlock RP, Ou Y, Gao P, Pettit S, Yusuf S; CORONARY Investigators. Five-Year Outcomes after Off-Pump or On-Pump Coronary-Artery Bypass Grafting. N Engl J Med. 2016 Dec 15;375(24):2359-2368. doi: 10.1056/NEJMoa1601564. Epub 2016 Oct 23.
citation: Lamy A, Tong W, Devereaux PJ, Gao P, Gafni A, Singh K, Taggart D, Straka Z, Akar AR, Piegas L, Ou Y, Yusuf S. The cost implications of off-pump versus on-pump coronary artery bypass graft surgery at one year. Ann Thorac Surg. 2014 Nov;98(5):1620-5. doi: 10.1016/j.athoracsur.2014.06.046. Epub 2014 Sep 24.
citation: Garg AX, Devereaux PJ, Yusuf S, Cuerden MS, Parikh CR, Coca SG, Walsh M, Novick R, Cook RJ, Jain AR, Pan X, Noiseux N, Vik K, Stolf NA, Ritchie A, Favaloro RR, Parvathaneni S, Whitlock RP, Ou Y, Lawrence M, Lamy A; CORONARY Investigators. Kidney function after off-pump or on-pump coronary artery bypass graft surgery: a randomized clinical trial. JAMA. 2014 Jun 4;311(21):2191-8. doi: 10.1001/jama.2014.4952.
citation: Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E, Straka Z, Piegas LS, Akar AR, Jain AR, Noiseux N, Padmanabhan C, Bahamondes JC, Novick RJ, Vaijyanath P, Reddy SK, Tao L, Olavegogeascoechea PA, Airan B, Sulling TA, Whitlock RP, Ou Y, Pogue J, Chrolavicius S, Yusuf S; CORONARY Investigators. Effects of off-pump and on-pump coronary-artery bypass grafting at 1 year. N Engl J Med. 2013 Mar 28;368(13):1179-88. doi: 10.1056/NEJMoa1301228. Epub 2013 Mar 11.
citation: Garg AX, Devereaux PJ, Yusuf S, Cuerden MS, Parikh CR, Coca SG, Walsh M, Cook RJ, Whitlock RP, Noiseux N, Novick RJ, Ou Y, Lamy A; CORONARY Investigators. Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY): kidney substudy analytic protocol of an international randomised controlled trial. BMJ Open. 2012 Apr 18;2(2):e001080. doi: 10.1136/bmjopen-2012-001080. Print 2012.
citation: Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E, Straka Z, Piegas LS, Akar AR, Jain AR, Noiseux N, Padmanabhan C, Bahamondes JC, Novick RJ, Vaijyanath P, Reddy S, Tao L, Olavegogeascoechea PA, Airan B, Sulling TA, Whitlock RP, Ou Y, Ng J, Chrolavicius S, Yusuf S; CORONARY Investigators. Off-pump or on-pump coronary-artery bypass grafting at 30 days. N Engl J Med. 2012 Apr 19;366(16):1489-97. doi: 10.1056/NEJMoa1200388. Epub 2012 Mar 26.
citation: Lamy A, Devereaux PJ, Prabhakaran D, Hu S, Piegas LS, Straka Z, Paolasso E, Taggart D, Lanas F, Akar AR, Jain A, Noiseux N, Ou Y, Chrolavicius S, Ng J, Yusuf S. Rationale and design of the coronary artery bypass grafting surgery off or on pump revascularization study: a large international randomized trial in cardiac surgery. Am Heart J. 2012 Jan;163(1):1-6. doi: 10.1016/j.ahj.2011.10.007.