Coronary Artery Bypass Surgery (CABG) Off or On Pump Revascularization Study

the Efficacy and Safety of Off-pump CABG Clinical Trial

— CORONARY  

Official title:

CABG Off or On Pump Revascularization Study (CORONARY)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00463294
• Other study ID #: PHRI-065
• Status: Completed
• Phase: Phase 3
• First received: April 18, 2007
• Last updated: September 15, 2016
• Start date: October 2007
• Est. completion date: September 2016

Study information

• Verified date: September 2016
• Source: Population Health Research Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Ethics Review Committee
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4752
• Est. completion date: September 2016
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• the Efficacy and Safety of Off-pump CABG

Intervention

Procedure:
• Coronary Artery Bypass Graft with the use of CPB
Coronary Artery Bypass Graft (CABG) using median sternotomy, CPB, cardioplegia and complete cross-clamp and no associated or concomitant surgical procedures
• Coronary Artery Bypass Graft without the use of CPB
Coronary Artery Bypass Graft (CABG) with no associated or concomitant surgical procedures, using median sternotomy and without CPB and cardioplegia

Locations

Country	Name	City	State
Argentina	Fundacion Medica de rio negro y neuquen	Rio Negro
Brazil	Irmande Santa Casa De Misericordia De Curtiba	Curitiba Parana
Brazil	Hospital Sao Francisco Complexo Hospitalar Santa Casa	Porto Alegre	RS
Brazil	Braile Clinica de Servicos de Assistencia Medico	Sao Jose do Rio Preto
Brazil	Federal University of Sao Paulo School of Medicine	Sao Paulo
Brazil	Hospital Mario Covas	Sao Paulo
Brazil	Instituto Dante Pazzanese de Cardiologia	Sao Paulo	CEP
Brazil	Instituto do Coracao do Hospital das Clinicas da	Sao Paulo
Brazil	Irmandade da Santa Casa de Misericordia de Sao Paulo	Sao Paulo
Brazil	Santa Casa de Misericordia de Marilia	Sao Paulo
Brazil	Associação do Sanátorio Sírio	São Paulo
Brazil	Beneficencia Portuguesa de Sao Paulo	Sao Paulo,	CEP
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Hamilton General Hospital	Hamilton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Hotel-Dieu du CHUM	Montreal	Quebec
Canada	Montreal Heart Institute	Montreal	Quebec
Canada	Toronto General Hospital	Toronto	Ontario
Chile	Instituto Nacional del Torax	Santiago
Chile	Hospital Regional Temuco	Temuco	IX Region
China	ChaoYang Hospital	Beijing
China	FuWai Hospital	Beijing
China	Nanjing First Hospital	Nanjing
Colombia	Fundacion Cardioinfantil	Bogota
Colombia	Fundacion Valle Del Lili	Cali
Czech Republic	Charles University Hospital	Hradec Kralove
Czech Republic	Kardiochirurgicke centrum	Ostrava-Poruba
Czech Republic	University Hospital Pilsen	Pilsen
Czech Republic	Fakultni nemocnice Kralovske Vinohrady (FNKV)	Prague
Czech Republic	University Hospital Motol	Praha
Czech Republic	Nemocnice Podlesi	Trinec
France	Service de chirurgie thoracique et cardio-vasculaire	Besancon
India	SAL Hospital	Ahmedabad
India	SAL Hospital and Medical Institute	Ahmedabad	Gujarat
India	International Center of Cardiovascular and Thoracic Diseases	Chennai Tamil Nadu
India	Amrita Institute of Medical Sciences and Research Center	Cochin	Kerala
India	G.Kuppuswamy Naidu Memorial Hospital	Coimbatore	TamilNadu
India	Nizam's Institute of Medical Sciences	Hyderabad	Andhra Pradesh
India	Sanjay Gandhi PGIMS	Lucknow
India	All India Institute of Medical Sciences	New Delhi
India	Escorts Heart Institute and Research Centre	Noida
Italy	Ospedale S. Croce	Cuneo
Italy	Ospedale Niguarda - Ca Granda	Milano
Poland	Jagiellonian University	Krakow
Turkey	Alp Aslan	Ankara
Turkey	Erol Senor	Ankara
Turkey	Ruchan Akar	Ankara
Turkey	Sertap Aykut Aka	Ankara
Turkey	Volkan Sinci	Ankara
United Kingdom	Basildon and Thurrock University Hospital NHS FT	Basildon	Essex
United Kingdom	Royal Infirmary of Edinburgh	Edinburgh	EU
United Kingdom	The John Radcliffe Hospital	Oxford

Sponsors (17)

Lead Sponsor

Collaborator

Population Health Research Institute

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Ankara University, Centre for Chronic Disease Control, India, Centre hospitalier de l'Université de Montréal (CHUM), Charles University, Czech Republic, Fu Wai Hospital, Beijing, China, Fundación Cardiovascular de Colombia, Hopital Jean Minjoz, Hotel Dieu Hospital, Instituto Dante Pazzanese de Cardiologia, McMaster University, Medical University of Gdansk, Ospedale Santa Croce-Carle Cuneo, SAL Hospital, Ahmedabad, India, Universidad de la Frontera, University of Oxford

Countries where clinical trial is conducted

Argentina,  Brazil,  Canada,  Chile,  China,  Colombia,  Czech Republic,  France,  India,  Italy,  Poland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	First Co-Primary Outcome	The occurrence of the composite of total mortality, stroke, nonfatal MI, or new renal failure at 30 days post CABG surgery	30 days post CABG surgery	No
Primary	Second co-primary outcome	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.	5 years after CABG	No
Secondary	The assessment of total costs and resources consumption at 30 days after CABG surgery		30 days after CABG surgery	No
Secondary	The assessment of total costs and resources consumption at 5 years after CABG surgery		5 years after CABG surgery	No