Off‐pump versus on‐pump coronary artery bypass grafting for ischaemic heart disease

Christian H Møller; Luit Penninga; Jørn Wetterslev; Daniel A Steinbrüchel; Christian Gluud

doi:10.1002/14651858.CD007224.pub2

. 2012 Mar 14;2012(3):CD007224. doi: 10.1002/14651858.CD007224.pub2

Off‐pump versus on‐pump coronary artery bypass grafting for ischaemic heart disease

Christian H Møller ^1,^✉, Luit Penninga ², Jørn Wetterslev ³, Daniel A Steinbrüchel ¹, Christian Gluud ⁴

Editor: Cochrane Heart Group

PMCID: PMC11809671 PMID: 22419321

Abstract

Background

Coronary artery bypass grafting (CABG) is performed both without and with cardiopulmonary bypass, referred to as off‐pump and on‐pump CABG respectively. However, the preferable technique is unclear.

Objectives

To assess the benefits and harms of off‐pump versus on‐pump CABG in patients with ischaemic heart disease.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 1, 2011), MEDLINE (OVID, 1950 to February 2011), EMBASE (OVID, 1980 to February 2011), Science Citation Index Expanded on ISI Web of Science (1970 to February 2011) and CINAHL (EBSCOhost, 1981 to February 2011) on 2 February 2011. No language restrictions were applied.

Selection criteria

Randomised clinical trials of off‐pump versus on‐pump CABG irrespective of language, publication status and blinding were selected for inclusion.

Data collection and analysis

For statistical analysis of dichotomous data risk ratio (RR) and for continuous data mean difference (MD) with 95% confidence intervals (CI) were used. Trial sequential analysis (TSA) was used for analysis to assess the risk of random error due to sparse data and to multiple updating of accumulating data.

Main results

Eighty‐six trials (10,716 participants) were included. Ten trials (4,950 participants) were considered to be low risk of bias. Pooled analysis of all trials showed that off‐pump CABG increased all‐cause mortality compared with on‐pump CABG (189/5,180 (3.7%) versus 160/5144 (3.1%); RR 1.24, 95% CI 1.01 to 1.53; P =.04). In the trials at low risk of bias the effect was corroborated (154/2,485 (6.2%) versus 113/2,465 (4.5%), RR 1.35,95% CI 1.07 to 1.70; P =.01). TSA showed that the risk of random error on the result was unlikely. Off‐pump CABG resulted in fewer distal anastomoses (MD ‐0.28; 95% CI ‐0.40 to ‐0.16, P <.00001). No significant differences in myocardial infarction, stroke, renal insufficiency, or coronary re‐intervention were observed. Off‐pump CABG reduced post‐operative atrial fibrillation compared with on‐pump CABG, however, in trials at low risk of bias, the estimated effect was not significantly different.

Authors' conclusions

Our systematic review did not demonstrate any significant benefit of off‐pump compared with on‐pump CABG regarding mortality, stroke, or myocardial infarction. In contrast, we observed better long‐term survival in the group of patients undergoing on‐pump CABG with the use of cardiopulmonary bypass and cardioplegic arrest. Based on the current evidence, on‐pump CABG should continue to be the standard surgical treatment. However, off‐pump CABG may be acceptable when there are contraindications for cannulation of the aorta and cardiopulmonary bypass. Further randomised clinical trials should address the optimal treatment in such patients.

Keywords: Humans; Coronary Artery Bypass; Coronary Artery Bypass/adverse effects; Coronary Artery Bypass/methods; Coronary Artery Bypass/mortality; Coronary Artery Bypass, Off‐Pump; Coronary Artery Bypass, Off‐Pump/adverse effects; Coronary Artery Bypass, Off‐Pump/methods; Coronary Artery Bypass, Off‐Pump/mortality; Myocardial Ischemia; Myocardial Ischemia/mortality; Myocardial Ischemia/surgery; Randomized Controlled Trials as Topic

Plain language summary

Coronary artery bypass surgery performed with versus without cardiac arrest and cardiopulmonary bypass in patients with ischaemic heart disease

Patients with ischaemic heart disease due to narrowing of coronary arteries can be treated with coronary artery bypass surgery. Coronary artery bypass surgery has traditionally been performed with cardiopulmonary bypass and an arrested heart. Development of cardiac stabilisers have made it possible to conduct the operation on the beating heart and thereby avoid cardiac arrest and cardiopulmonary bypass. By avoiding cardiac arrest and cardiopulmonary bypass, it was hoped that complications seen after coronary artery bypass could be reduced. Systematic review of 86 randomised clinical trials including 10,716 patients and statistical analyses of the data showed that coronary artery bypass surgery performed on the beating heart results in an increased risk of death. No firm evidence for benefit or harm was found regarding the outcome measures myocardial infarction, stroke, atrial fibrillation, renal insufficiency, or coronary reintervention. Our data raises a warning regarding coronary artery bypass surgery on the beating heart and cardiac arrest and cardiopulmonary bypass seem less risky. In patients with contraindications for cannulation of the aorta and cardiopulmonary bypass coronary artery bypass surgery on the beating heart may be a solution but we need randomised clinical trials in these patients to identify the most beneficial approach.

Background

Description of the condition

Ischaemic heart disease is defined as insufficient blood supply to the myocardium due to atherosclerosis in the coronary arteries. Classic symptoms of the disease are angina pectoris and myocardial infarction. According to the World Health Organisation in 2005 about 7.6 million people died due to ischaemic heart disease and around 100 million may have suffered from myocardial infarction (WHO 2007).

Description of the intervention

Ischaemic heart disease can be treated with medical therapy, percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG). In the US alone, 645,000 PCI procedures and 261,000 CABG procedures were performed in 2005 (DeFrances 2007). The choice of intervention depends on the degree of disease and symptoms, as well as patient comorbidity.

Revascularisation during CABG is obtained by creating new routes for the blood (bypasses) around narrowed and blocked arteries. These blockages are due to atherosclerosis. The bypasses are most commonly created by using a vein from the leg (the saphenous vein), an artery from the inside of the chest wall (the internal mammary artery), or an artery from the hand (the radial artery). The vein bypasses are attached (anastomosed) at one end to the aorta and at the other end to the coronary artery beyond the blockage. The internal mammary artery is directly anastomosed to the coronary artery and the radial artery can either be used as vein grafts are used, or anastomosed at one end to the internal mammary artery and at the other end to the coronary artery.

The traditional way of performing CABG is to use cardiopulmonary bypass to provide an artificial circulation, so that the coronary artery bypass can be performed while the heart is stopped (cardioplegic arrest) ('on‐pump' CAGB). However, since the early 1990s the number of CABG procedures performed without using cardiopulmonary bypass has increased (off‐pump CABG). During this procedure the heart is not stopped and coronary anastomoses are performed on the beating heart using different stabilisation systems (Connolly 2000). By avoiding cardiac arrest and cardiopulmonary bypass, it was hoped that complications seen after coronary artery bypass could be reduced.

CABG relieves symptoms and may be life saving (Yusuf 1994). However, the operation is associated with complications, including myocardial, pulmonary, renal, coagulation, and cerebral adverse outcomes (Nalysnyk 2003; Selim 2007). Many of these complications have been attributed to cardiopulmonary bypass and aortic cross clamping. There has been increased interest in off‐pump CABG in order to avoid these adverse effects. Stabilisation systems have constantly improved and revascularisation of all coronary arteries without the use of cardiopulmonary bypass is now technically possible. However, performing coronary anastomosis on the beating heart may affect the quality of the anastomosis, as well as lead to incomplete revascularisation because of technical inability to perform the bypasses (Lim 2006).

Why it is important to do this review

Several randomised trials comparing off‐pump versus on‐pump CABG have been conducted, but results have varied and most trials have been underpowered to reach a conclusion on clinically relevant outcome measures. Previous meta‐analyses of randomised trials did not find statistically significant differences between off‐pump and on‐pump CABG regarding mortality, myocardial infarction and coronary re‐intervention (Cheng 2005; Parolari 2003a; Sedrakyan 2006; van der Heijden 2004; Wijeysundera 2005). However, some of these meta‐analyses did find a statistically significant reduction of blood transfusion (Cheng 2005; Wijeysundera 2005), postoperative atrial fibrillation (Sedrakyan 2006), stroke (Sedrakyan 2006), inotropic agent requirements (Cheng 2005; Wijeysundera 2005), wound infection (Sedrakyan 2006), ventilation time (Cheng 2005), intensive care unit length of stay (Cheng 2005), and hospital length of stay (Cheng 2005) favouring off‐pump CABG. However, most of these secondary outcome measures are inconsistently reported and the meta‐analyses are based on trials with varying methodological quality, leaving ample room for outcome reporting bias, systematic error ('bias'), and random error ('play of chance') (Keus 2010). Since our systematic reviews from 2008 (Møller 2008a), new trial evidence has emerged (BBS 2011; DOORS 2009; MASS III 2009; ROOBY 2009) and hence an updated systematic review is required .

Objectives

To assess the benefits and harms of off‐pump versus on‐pump CABG in patients with ischaemic heart disease.

Methods

Criteria for considering studies for this review

Types of studies

We considered for inclusion randomised clinical trials irrespective of language, publication status, or blinding. Prospective cohort studies and quasi‐randomised studies were excluded.

Types of participants

We included participants with ischaemic heart disease treated with first‐time isolated CABG.

Types of interventions

We included trials comparing off‐pump versus on‐pump CABG irrespective of access to the thorax (full or partial, sternotomy or thoracotomy). Co‐intervention was accepted if used equally in both intervention arms. CABG combined with valve surgery or other cardiac procedures were excluded as well as CABG with on‐pump beating heart. Hybrid and robot‐assisted procedures were excluded.

Types of outcome measures

Primary outcomes

All‐cause mortality.
Myocardial infarction.
Stroke.

Secondary outcomes

Coronary re‐intervention (coronary artery bypass grafting or percutaneous coronary intervention).
Post‐operative atrial fibrillation.
Renal insufficiency.
Adverse events. We classified adverse events as serious or non‐serious. Serious adverse events were defined as any outward medical occurrence that was life threatening, resulted in death or persistent or significant disability, or any medical event, which might have jeopardised the patient, or required intervention to prevent it (ICH‐GCP 1997). All other adverse events (i.e., any medical occurrence not necessarily having a casual relationship with the treatment, but did, however, cause a dose reduction or discontinuation of the treatment) were considered as non‐serious.
Quality of life.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 1, 2011), MEDLINE (OVID, 1950 to February 2011), EMBASE (OVID, 1980 to February 2011), Science Citation Index Expanded on ISI Web of Science (1970 to February 2011) and CINAHL (EBSCOhost, 1981 to February 2011). The databases were searched on 2 February 2011. No language restrictions were applied. The search strategies are given in Appendix 1. The Cochrane sensitive‐maximising RCT filter was used Lefebvre 2011.

Searching other resources

We used the reference lists of the identified trials to identify further trials. Previous meta‐analyses and systematic reviews were screened to identify additional trials.

Data collection and analysis

We conducted the review according to The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Selection of studies

Two of the three authors (CM and LP or DS) independently assessed trial eligibility. We listed excluded trials with the reasons for their exclusion (Characteristics of excluded studies).

Data extraction and management

Two authors independently extracted data from the trials (CM and LP). Disagreements were solved by discussion or in consultation with a third author (CG). The following data were extracted: first author or trial name; country of origin; trial design; number of participants; inclusion and exclusion criteria; characteristics of patients: age, diabetes mellitus, left ventricular ejection fraction, patients with three‐vessel coronary disease, and number of distal anastomoses; type of cardioplegia; patient temperature during cardiopulmonary bypass; dose of heparin in off‐pump CABG; reversal of heparin effects with protamine in off‐pump CABG; surgical conversion rate; duration of follow‐up; sample size calculation; intention‐to‐treat analysis; methodological quality (as described below), and primary and secondary outcomes for the trial.

Data extraction was done by two reviewers independently and entered into RevMan 5.

Assessment of risk of bias in included studies

We assessed the methodological quality of the trials independently without masking the studies. We followed the instructions described in detail in The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Because of the risk of overestimation of intervention effects in randomised trials with inadequate methodological quality (Kjaergard 2001; Moher 1998; Schulz 1995; Wood 2008), we looked at the influence of methodological quality of the trials results by evaluating the reported randomisation, blinding, and follow‐up procedures in each trial. If information was not available in the published trial, we contacted the authors in order to assess the trials correctly. Authors were asked to give information about how the allocation sequence was generated and afterward concealed until the time of randomisation. Furthermore, we assessed if outcome assessment was conducted blinded. We assessed the risk of bias of the randomised clinical trials using the following components: generation of allocation sequence, allocation concealment, blinding, follow‐up, and selective outcome reporting.

Generation of the allocation sequence

Low risk of bias, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing dice was considered as low risk of bias if a person who was not otherwise involved in the recruitment of participants performed the procedure.
Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described. (The authors were contacted and attempts were made to find out the allocation method.)
High risk of bias, if a system involving dates, names, or admittance numbers were used for the allocation of patients. These studies are known as quasi‐randomised and were excluded from the review.

Allocation concealment

Low risk of bias, if the allocation of patients involved a central independent unit, on‐site locked computer, or sealed envelopes.
Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.
High risk of bias, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised. Such studies were excluded from the review.

Blinding

Low risk of bias when authors state that outcome measures were assessed by a blinded observer or blinded assessor.
Unclear, when efforts of blinding were unclear.
High risk of bias if the trial was an open‐label trial not using blinded outcome assessment.

Follow‐up

Low risk of bias, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.
Unclear, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.
High risk of bias, if the number or reasons for dropouts and withdrawals were not described.

Selective outcome reporting

Low risk of bias, study protocol is available and all pre‐specified outcomes that are of interest in the review have been reported or the study protocol is not available, but all primary outcomes in the systematic review were reported.
Unclear, insufficient information to permit judgement.
High risk of bias, if not all of the trials pre‐specified primary outcomes were reported, or one or more primary outcomes was reported using measurements, analysis methods or subsets of the data that were not pre‐specified, or one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse event), or one or more the primary outcomes in the systematic review were reported incompletely so that they cannot be entered in a meta‐analysis, or the trial report failed to include results for a key outcome that would be expected to have been reported for such a trial.

Trials with low risk of bias regarding the components generation of allocation sequence, allocation concealment, blinding, follow‐up, and selective outcome reporting were considered trials with low risk of bias. All other trials were considered to be trials with high risk of bias (systematic error).

Data synthesis

We used the statistical software RevMan 5 provided by the Cochrane Collaboration RevMan 2008. We calculated risk ratios (RR) with 95% confidence intervals (CI) for dichotomous variables and mean differences with 95% CI for continuous variables, using both the random‐effects model and the fixed‐effect model with a significant level of less than or equal to P≤0.05. In cases of discrepancies between the two models both results were reported. Otherwise only the result from the random‐effects model were reported. Data were analysed according to the intention‐to‐treat principle.

We tested for heterogeneity with the Cochrane Q test and measured inconsistency (I²; the percentage of total variance across trials that is due to heterogeneity rather than chance) of treatment effects across the primary and secondary outcomes (Higgins 2002).

Trial sequential analysis

In a single trial, interim analyses increase the risk of type I error. To avoid an increase of overall type I error, monitoring boundaries can be applied to decide whether a single randomised trial could be terminated early because of the p‐value being sufficiently small (Lan 1983). Because no reason exists why the standards for a meta‐analysis should be less rigorous than those for a single trial, analogous monitoring boundaries can be applied to cumulative meta‐analysis, called trial sequential monitoring boundaries (Pogue 1998; Wetterslev 2008). For meta‐analyses with statistically significantly results, we calculated the required heterogeneity‐adjusted information size (the meta‐analysis sample size) and applied trial sequential monitoring boundaries in order to determine whether the evidence in our meta‐analyses are reliable and conclusive or at risk of random error (Thorlund 2009;Thorlund 2011; Wetterslev 2008).

Subgroup analysis and investigation of heterogeneity

We performed subgroup analyses on trials with low risk of bias for randomisation and blinding compared to trials with low risk of bias for randomisation but unclear/high‐risk of bias for blinding as well as trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding. Futhermore, we performed subgroup analysis on type of stabilisation system and dose of heparin in the off‐pump group and temperature during cardiopulmonary bypass and type of cardioplegic solution in the on‐pump group. Intervention effects in the subgroups were compared by test of subgroup difference using inverse variance and fixed‐effect models.

Sensitivity analysis

We assessed the effect of missing outcome data on all‐cause mortality by applying a number of different scenarios to the intention‐to‐treat analyses. These scenarios were defined as the following for the outcome mortality:

1. Good outcome analysis: assumed that none of the participants with missing data were dead.

2. Poor outcome analysis: assumed that all of the participants with missing data were dead.

3. Extreme‐case favouring off‐pump CABG: assumed that none of the participants with missing data in the off‐pump group were dead, whereas all of those in the on‐pump group were dead.

4. Extreme‐case favouring on‐pump CABG: assumed that none of the participants with missing data in the on‐pump group were dead, whereas all of those in the off‐pump group were dead.

Results

Description of studies

Results of the search

Our search strategy identified 2254 publications, out of which about half were duplicates. In addition, through a search of abstracts from the most recent meeting in the American Heart Association we identified new results from one trial. Of 1074 screened publications 875 were excluded based on title or abstract (Figure 1). After full‐text assessment, 86 trials described in 159 publications were included in the systematic review (Characteristics of included studies) and 24 publications were excluded as they did not fulfil our inclusion criteria or were quasi‐randomised (Characteristics of excluded studies). Through a search for trials in clinicaltrials.gov and www.controlled‐trials.com registries we identified six ongoing trials (NCT00558779; NCT00719667; NCT00999089; NCT00463294; ISRCTN29161170; NCT00259493). Results from one larger trial has not yet been published in full‐text but only presented at meetings and in abstracts (DOORS 2009). Our systematic review also contains data from 3.7 years follow‐up in the BBS trial (BBS 2011).

Included studies

Sixty‐six trials were conducted in Europe, nine in North America, three in South America, two in Australia, four in Asia, one in North Africa, and one in the Middle East. The number of participants in each trial ranged from 20 to 2203. The total number of participants in our review is 10,716 participants. The included trials were characterised by a relatively low mean age of the participants, low representation of women, and low representation of participants with impaired left ventricle ejection fraction (Table 1). Mean age in the review was 63.5 years (range 48 to 76 years). In 78 trials reporting the number of women included, the proportion of women was 1903/10,432 (18%) (Table 1). In one trial, only participants with acute ST elevation myocardial infarction were included (Fattouch 2009). Few other trials included exclusively subsets of high‐risk patients (BBS 2011; Carrier 2003). In three trials off‐pump CABG was performed through an anterolateral thoracotomy (Gu 1998; Gulielmos 1999; Guler 2001). In two trials off‐pump CABG was compared with on‐pump CABG performed with a minimal extracorporeal circulation system (Formica 2009; Mazzei 2007). Epidural analgesia was used in the off‐pump group in two trials (Blacher 2005; OCTOPUS 2001). Furthermore, severity of ischaemic heart disease of included participants was inconsistently reported (Table 1). However, in trials with low risk of bias in all five bias domains mainly patients with two or three vessel disease were included. In five of these trials, the number of participants with three vessel disease were reported, including 2702 (70%) participants (BBS 2011; DOORS 2009; OCTOPUS 2001; PROMISS 2010; ROOBY 2009).

1. Characteristics of included trials.

Source, year	Country	No. of patients	Mean age, y	Women, %	EF<30%, %	Severity of IHD	Intention to treat analysis	Follow‐up
Al‐Ruzzeh 2003	United Kingdom	20	64	15	0	NA	Unclear	4 days
Al‐Ruzzeh 2006	United Kingdom	168	63	17	0	2 or 3VD	Yes	6 months
Alwan 2004	France	70	64	30	0	NA	Yes	in‐hospital/30 day mort
Anderson 2005	Sweden	50	67	22	0	NA	No	in‐hospital
Ascione 2005	United Kingdom	20	62	15	0	3VD	Yes	in‐hospital
Ascione 2006	United Kingdom	40	63	13	0	NA	Yes	in‐hospital
Baker 2001	Australia	66	64	18	0	NA	Yes	6 month
BBS 2010	Denmark	341	76	36	0	3VD	Yes	3 years
BHACAS I + II 2002	United Kingdom	401	62	18	0	NA	Yes	>6 years
Blacher 2005	Brazil	28	62	36	0	NA	Yes	in‐hospital
Caputo 2002	United Kingdom	40	63	10	0	NA	Yes	in‐hospital
Carrier 2003	Canada	65	70	23	NA	NA	No	in‐hospital/30 day mort
Cavalca 2006	Italy	50	66	24	0	NA	No	in‐hospital
Celik 2005	Turkey	60	67	32	0	NA	Yes	10 days
Covino 2001	Italy	37	NA	11	NA	1 or 2VD	Unclear	in‐hospital
Czerny 2000	Austria	30	64	23	NA	NA	No	in‐hospital
Czerny 2001	Austria	80	64	16	0	2 or 3VD	Yes	13 months
Diegeler 2000	Germany	40	65	NA	0	2 or 3VD	Yes	in‐hospital
DOORS 2009	Denmark	900	74	23	5	3VD 80%	Yes	30 days
Dorman 2004	United States	52	63	44	NA	NA	Yes	in‐hospital
Fattouch 2009	Italy	128	62	31	14	NA	Unclear	Mean 36 months
Formica 2009	Italy	60	66	32	0	2 or 3 VD	Yes	in‐hospital
Gasz 2004	Hungary	20	63	25	NA	NA	Yes	in‐hospital
Gasz 2005	Hungary	30	NA	NA	NA	NA	Unclear	In‐hospital
Gerola 2004	Brazil	160	59	34	0	1 or 2VD	Yes	in‐hospital/30 day mort
Gu 1998	Netherlands	62	61	34	NA	1VD	Yes	in‐hospital
Guler 2001	Turkey	58	55	NA	NA	1VD	Yes	2 months
Gulielmos 2000	Germany	40	62	23	0	NA	Yes	3 months
Gönenc 2006	Turkey	42	65	21	NA	NA	Unclear	24 hours
Hernandez 2007	United States	201	NA	20	NA	3VD 55%	Yes	6 months
Jares 2007	Czech Republic	20	64	30	NA	NA	Yes	24 hours
JOCRI 2005	Japan	147	60	15	0	2 or 3VD	Yes	> 30 days
Khan 2004	United Kingdom	103	63	13	1	NA	Yes	3 months
Kherani 2003	United States	46	NA	NA	NA	NA	Unclear	30 days
Kochamba 2000	United States	58	59	22	NA	1 or 2VD	Yes	in‐hospital
Kunes 2007	Czech Republic	34	68	24	NA	NA	Yes	7 days
Lee 2003	United States	60	66	18	NA	NA	Yes	12 months
Legare 2004	Canada	300	63	20	0	3VD 70%	Yes	3.8 years
Lingaas 2004	Norway	120	65	22	0	3VD 50%	Yes	12 months
Malik 2006	India	50	58	16	0	NA	Unclear	in‐hospital
Mandak 2008	Czech Republic	40	67	18	NA	NA	Yes	in‐hospital
Mantovani 2010	Sweden	25	66	32	0	1 or 2VD	No	19 months
Mariscalco 2006	Italy	70	65	19	NA	NA	Yes	in‐hospital
MASS III 2010	Brazil	308	60	21	0	2 or 3VD	Yes	5 years
Matata 2000	United Kingdom	20	60	15	0	1 or 2VD	Yes	in‐hospital
Mazzei 2007	Italy	300	66	26	13	2 or 3VD	No	12 months
Medved 2008	Croatia	60	60	28	NA	NA	Yes	in‐hospital
Michaux 2006	Switzerland	50	63	16	NA	3VD 78%	Yes	30 days
Modine	France	71	65	66	0	NA	Yes	in‐hospital
Motallebzadeh 2004	United Kingdom	35	64	9	0	3VD 66%	Yes	in‐hospital
Motallebzadeh 2006	United Kingdom	212	65	11	9	3VD 75%	Yes	6 months
Muneretto 2003	Italy	176	67	39	0	3VD 50% 2VD 41%	Yes	12 months
Nesher 2006	Israel	125	68	25	0	NA	No	in‐hospital
Niranjan 2006	United Kingdom	80	67	18	0	3VD 93%	Yes	in‐hospital
Nour‐El‐Din 2004	Egypt	30	56	10	NA	NA	Unclear	in‐hospital
OCTOPUS 2001	Netherlands	281	61	31	0	3VD 23% 2VD 50%	Yes	5 years
Ozkara 2007	Turkey	44	59	25	0	NA	Yes	in‐hospital
Paparella 2006	Italy	31	NA	NA	NA	NA	No	in‐hospital
Parolari 2003	Italy	25	61	24	0	NA	Yes	in‐hospital
Parolari 2005	Italy	30	65	51	0	NA	Yes	30 days
Parolari 2007	Italy	30	66	20	NA	NA	Yes	30 days
Penttilä 2001	Finland	22	59	NA	0	3VD 41% 2VD 50%	Yes	in‐hospital
PRAGUE‐11 2008	Czech Republic	80	66	20	0	NA	Yes	30 days
PRAGUE‐4 2004	Czech Republic	400	63	19	5	3VD 68%	Yes	12 months
PROMISS	Portugal	147	65	16	NA	3VD 68%	Yes	12 months
Quaniers 2006	Belgium	80	63	10	0	NA	Yes	in‐hospital
Rachwalik 2006	Poland	42	58	29	0	NA	Yes	in‐hospital
Rainio 2007	Finland	20	61	NA	10	NA	No	NA
Raja 2003	Pakistan	300	64	24	NA	NA	Unclear	in‐hospital
Rasmussen 2007	Denmark	35	68	18	0	NA	No	in‐hospital
ROOBY 2009	United States	2203	63	0.5	6	3VD 67% 2VD 27%	Yes	12 months
Sahlman 2003	Finland	50	63	18	NA	NA	Unclear	in‐hospital
Sajja 2007	India	120	60	11	NA	NA	No	in‐hospital/30 day mort
Schmid 2006	Germany	30	68	30	NA	NA	Yes	in‐hospital
Selvanayagam 2004	United Kingdom	60	61	13	0	NA	Yes	in‐hospital
SMART 2003	United States	200	62	23	6	NA	Yes	12 months
Synnergren 2004	Sweden	52	62	35	0	NA	Yes	in‐hospital
Tang 2002	United Kingdom	45	63	20	0	NA	No	in‐hospital
Tatoulis 2006	Australia	100	65	22	0	NA	No	30 days
Vedin 2003	Sweden	74	65	20	0	3VD 66%	Yes	6 months
Velissaris 2003	United Kingdom	54	62	20	0	NA	Yes	in‐hospital
Vural 1995	Turkey	50	48	12	NA	NA	Unclear	2 months
Wandschneider 2000	Austria	119	66	21	NA	NA	No	in‐hospital
Wildhirt 2000	Germany	33	65	19	NA	NA	No	3 days
Zamvar 2002	United Kingdom	60	63	13	5	NA	Yes	10 weeks

	All‐cause mortality	Myocardial infarction	Stroke	Atrial fibrillation	Renal failure
Tp. during CPB
Normothermia	1.43 [0.97, 2.10]	0.97 [0.69, 1.37]	0.82 [0.49, 1.37]	0.94 [0.78, 1.12]	1.06 [0.68, 1.66]
Hypothermia	1.09 [0.81, 1.47]	1.05 [0.71, 1.55]	0.53 [0.32, 0.88]	0.73 [0.64, 0.84]	0.60 [0.34, 1.08]
Test of subgroup difference, P ‐ value	0.27	0.76	0.25	0.03	0.13
I², %	16	0	25	78	56
Type of cardioplegia
Cold blood	1.30 [0.95, 1.79]	0.91 [0.58, 1.42]	0.88 [0.53, 1.47]	0.92 [0.80, 1.05]	0.89 [0.61, 1.31]
Crystalloid	1.26 [0.65, 2.46]	0.87 [0.50, 1.53]	0.48 [0.20, 1.16]	0.71 [0.57, 0.88]	0.78 [0.15, 4.13]
Warm/tepid blood	1.10 [0.70, 1.74]	0.80 [0.42, 1.53]	0.48 [0.13, 1.68]	0.50 [0.37, 0.69]	0.68 [0.18, 2.54]
Ventricular fibrillation	Not estimable	Not estimable		1.00 [0.15, 6.64]
Test of subgroup difference, P ‐ value	0.83	0.96	0.40	0.003	0.92
I², %	0	0	0	78	0
Type of off‐pump stabilizer
Octopus	1.33 [0.95, 1.87]	0.89 [0.62, 1.30]	0.95 [0.58, 1.58]	0.91 [0.79, 1.04]	0.88 [0.61, 1.28]
Cardio Thorac System	1.16 [0.72, 1.87]	0.63 [0.21, 1.90]	0.39 [0.13, 1.14]	0.37 [0.25, 0.53]	Not estimable
Guidant	1.23 [0.57, 2.65]	0.97 [0.34, 2.78]	0.35 [0.08, 1.56]	0.74 [0.57, 0.95]	0.65 [0.15, 2.81]
Test of subgroup difference, P ‐ value	0.89	0.82	0.19	<0.0001	0.69
I², %	0	0	39	73	55
Heparin dose in off‐pump
Heparin dose less than 300 mg/kg	1.29 [0.99, 1.69]	0.97 [0.67, 1.41]	0.85 [0.52, 1.37]	0.80 [0.70, 0.91]	0.88 [0.60, 1.28]
Heparin dose 300 mg/kg or more	0.70 [0.29, 1.69]	1.39 [0.90, 2.14]	0.21 [0.02, 1.83]	0.89 [0.48, 1.68]	0.33 [0.01, 7.62]
Test of subgroup difference, P ‐ value	0.19	0.22	0.22	0.73	0.55
I², %	41	34	33	0	0

Source/ trial name	Heparin dose, IU/kg	Protamine reversal	Type of stabiliser	Tp. during CPB	Cardioplegia	Conversion to, n
Source/ trial name	Heparin dose, IU/kg	Protamine reversal	Type of stabiliser	Tp. during CPB	Cardioplegia	off‐pump	on‐pump
Al‐Ruzzeh 2003	150	yes	Octopus	NR	cold blood	0	0
Al‐Ruzzeh 2006	150	yes	Octopus	32°C	cold blood	0	0
Alwan 2004	300	NR	Octopus	37°C	warm blood	0	0
Anderson 2005	100	NR	NR	cooled or allowed to drift to 34°C	cold blood	0	0
Ascione 2005	100	yes	CardioThoracic	32‐34°C	warm blood	0	0
Ascione 2006	100	yes	CardioThoracic	32‐34°C	warm blood	0	0
Baker 2001	150	NR	Octopus	allowed to drift to 34°C	tepid blood	unclear	unclear
BBS 2010	100	Not routinely	Octopus	normothermia	cold blood	6	8
BHACAS I 1999	100	yes	CardioThoracic	34‐36°C	warm blood	0	2
BHACAS II 2002	100	yes	CardioThoracic	34‐36°C	warm blood	0	0
Blacher 2005	150*	yes	CardioThoracic	32°C	isotherm blood	0	0
Caputo 2002	100	yes	NR	34‐36°C	warm blood	0	0
Carrier 2003	NR	NR	NR	33°C	blood	1	5
Cavalca 2006	300	yes	Octopus	32‐33°C	cold blood	0	1
Celik 2005	150	unclear	NR	30‐34°C	blood	0	0
Covino 2001	NR	NR	NR	NR	NR	unclear	unclear
Czerny 2000	300	yes	CardioThoracic	normothermia	cold blood	0	1
Czerny 2001	300	yes	CardioThoracic	normothermia	cold blood	0	9
Diegeler 2000	NR	NR	NR	32°C	NR	0	0
DOORS 2009	ACT 400	Yes	NR	normothermia	cold blood/crystaloid	NR	NR
Dorman 2004	20,000 IU	yes	Octopus	32°C	blood	0	2
Fattouch 2009	NR	NR	Octopus	32	warm blood	0	1
Formica 2009	150	NR	Octopus	35°C	cold blood	0	0
Gasz 2004	NR	NR	NR	NR	NR	0	0
Gasz 2005	NR	NR	Octopus	moderate hypothermic	cold crystalloid	0	0
Gerola 2004	200	NR	NR	28°C	cold blood	0	0
Gu 1998	100	no	CardioThoracic	30‐32°C	cold crystalloid	0	0
Guler 2001	NR	NR	NR	drifted to 34.5°C +/‐1.22	isotherm blood	0	0
Gulielmos 2000	500	yes	CardioThoracic/ Octopus	normo	crystaloid	0	0
Gönenc 2006	100	unclear	NR	NR	unclear	0	0
Hernandez 2007	300	yes	Genzyme/octopus	28° to 32°C	Cold blood	0	8
Jares 2007	100	½ dosis	NR	normothermic	NR	0	0
JOCRI 2005	NR	NR	NR	32‐34°C	tepid blood	0	1
Khan 2004	150	no	Octopus	32°C	cold blood	0	2
Kherani 2003	NR	NR	NR	NR	NR	unclear	unclear
Kochamba 2000	100	yes	NR	34°C	NR	0	0
Kunes 2007	200	yes	NR	normo	cold crystaloid	0	0
Lee 2003	NR	NR	Guidant	mild hypo	cold blood	0	0
Legare 2004	100	yes	Octopus	allowed to drift to 32°C	cold blood	1	20
Lingaas 2004	100	ACT 150‐200	Octopus	28‐32°C	cold crystaloid	0	7
Malik 2006	100	1:½	Octopus	moderate hypo	cold blood	0	0
Mandak 2008	100	NR	Guidant/octopus	normothermia	cold blood	0	0
Mantovani 2010	150	NR	NR	>34°C	cold blood	0	1
Mariscalco 2006	NR	NR	NR	32°C	cold blood	0	0
MASS III 2010	150	no	Octopus	32‐34°C	Cold‐blood	NR	NR
Matata 2000	300	3mg/kg	Octopus	normothermia	NR	0	0
Mazzei 2007	150	NR	Guidant	NR	normothermic blood	0	6
Medved 2008	150	yes	Octopus	32°C	ventricular fibrillation	0	0
Michaux 2006	NR	NR	Octopus	normothermia	cold blood	0	2
Modine 2010	100	Yes	Octopus	33°C	cold blood	0	0
Motallebzadeh 2004	150	NR	CardioThoracic	32°C	cold blood	0	0
Motallebzadeh 2006	150	NR	CardioThoracic	32°C	cold blood	0	0
Muneretto 2003	NR	NR	Guidant	33°C	cold blood	0	8
Nesher 2006	200	partial	Octopus	allowed to drift to 32°C	tepid blood	unclear	unclear
Niranjan 2006	150	yes	Guidant	32°C	cold blood	0	0
El‐din 2004	150	yes	Octopus	30‐32°C	cold blood	0	0
OCTOPUS 2001	NR	NR	Octopus	allowed to drift to 32°C	cold crystaloid	5	10
Ozkara 2007	150	1:½	NR	(28‐32°C) or (32‐35°C)	cold blood	0	0
Paparella 2006	300	1:1	Octopus	34°C	cold blood	0	1
Parolari 2003	NR	NR	Octopus	32‐34°C	cold blood	0	0
Parolari 2005	300	3 mg/kg	NR	32‐34°C	cold blood	0	0
Parolari 2007	300	3 mg/kg	NR	32‐34°C	cold blood	0	0
Penttilä 2001	100	50‐100 mg	Octopus	33°C	blood 33°C, aspartate/ glutamate	0	0
PRAGUE‐11 2008	150	yes	Guidant	normothermia	cold crystaloid	0	0
PRAGUE‐4 2004	100	yes	Guidant	normothermia	cold crystaloid	13	31
PROMISS 2010	200	1:1	Octopus/Guidant	allowed to drift to 34°C	34°C blood	1	2
Quaniers 2006	300/100	yes	Octopus	active normo 37°C	cold crystaloid	0	0
Rachwalik 2006	NR	NR	Octopus	normothermia	blood	0	0
Rainio 2007	300	yes	Octopus	36°C	cold blood	0	0
Raja 2003	100	yes	Octopus	32°C	cold crystaloid	unclear	unclear
Rasmussen 2007	ACT>300	yes		normothermi	cold (4 C) blood	0	1
ROOBY 2009	NR	NR	NR	NR	NR	40	137
Sahlman 2003	NR	NR	NR	35°C	cold crystaloid	0	0
Sajja 2007	NR	NR	Octopus	32°C‐ 36°C	cold blood	0	0
Schmid 2006	150	01:01	NR	normothermia	cold crystalloid	0	0
Selvanayagam 2004	300	NR	NR	34°C	cold crystalloid	0	1
SMART 2003	NR	NR	Octopus	32‐34°C	cold blood	1	3
Synnergren 2004	100	no	NR	34°C	cold blood	0	0
Tang 2002	100	NR	NR	32°C	cold blood	0	0
Tatoulis 2006	100	no	NR	35‐37°C	blood (20‐25°C)	unclear	unclear
Vedin 2003	150	NR	NR	34‐35°C	cold blood	0	3
Velissaris 2003	NR	NR	Octopus	35°C	cold blood	0	0
Vural 1995	5,000 IU	yes	NR	mild hypo	cold crystalloid	0	0
Wandschneider 2000	NR	NR	CardioThoracic /Octopus	allowed to drift to 33.4°C	cold blood	0	11
Wildhirt 2000	NR	NR	Octopus	29‐31°C	blood	0	1
Zamvar 2002	NR	NR	NR	NR	NR	0	0

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	74	10324	Risk Ratio (M‐H, Random, 95% CI)	1.24 [1.01, 1.53]
1.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Random, 95% CI)	1.35 [1.07, 1.70]
1.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	27	2841	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.47, 1.70]
1.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	38	2533	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.45, 1.72]
2 Myocardial infarction	54	8547	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.79, 1.26]
2.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.61, 1.36]
2.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	18	1982	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.77, 2.09]
2.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	27	1615	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.31, 1.69]
3 Stroke	60	9044	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.54, 1.06]
3.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.61, 1.36]
3.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	22	2509	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.20, 1.07]
3.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	29	1585	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.13, 1.15]
4 Coronary reintervention (CABG or PCI)	18	5214	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.94, 1.65]
4.1 Trials with low risk of bias	7	3881	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.91, 1.68]
4.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	6	977	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.60, 2.35]
4.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	5	356	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.37, 131.28]
5 Postoperative atrial fibrillation	33	4404	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.63, 0.96]
5.1 Trials with low risk of bias	6	1700	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.59, 2.03]
5.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	13	1804	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.53, 0.96]
5.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	14	900	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.53, 0.86]
6 Renal insufficiency	21	4806	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.62, 1.20]
6.1 Trials with low risk of bias	6	3502	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.64, 1.31]
6.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	9	923	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.16, 1.82]
6.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	6	381	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.20, 2.36]
7 Distal anastomoses	57	7071	Mean Difference (IV, Random, 95% CI)	‐0.28 [‐0.40, ‐0.16]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	74	10324	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.95, 1.41]
1.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [1.06, 1.68]
1.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	27	2841	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.42, 1.25]
1.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	38	2533	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.45, 1.49]
2 Myocardial infarction	54	8547	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.80, 1.26]
2.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.73, 1.27]
2.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	18	1982	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.82, 2.10]
2.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	27	1615	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.31, 1.44]
3 Stroke	60	9044	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.53, 0.99]
3.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.63, 1.32]
3.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	22	2509	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.22, 0.95]
3.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	29	1585	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.13, 1.08]
4 Coronary reintervention (CABG or PCI)	18	5214	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.96, 1.66]
4.1 Trials with low risk of bias	7	3881	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.91, 1.68]
4.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	6	977	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.62, 2.26]
4.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	5	356	Risk Ratio (M‐H, Fixed, 95% CI)	7.0 [0.37, 131.28]
5 Postoperative atrial fibrillation	33	4404	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.72, 0.88]
5.1 Trials with low risk of bias	6	1700	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.83, 1.14]
5.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	13	1804	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.58, 0.82]
5.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	14	900	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.53, 0.86]
6 Renal insufficiency	21	4806	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.61, 1.17]
6.1 Trials with low risk of bias	6	3502	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.64, 1.29]
6.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	9	923	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.16, 1.69]
6.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	6	381	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.20, 2.34]
7 Distal anastomoses	57	7071	Mean Difference (IV, Fixed, 95% CI)	‐0.46 [‐0.48, ‐0.43]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	66	7563	Risk Ratio (IV, Fixed, 95% CI)	1.20 [0.95, 1.53]
1.1 Normothermia	17	2360	Risk Ratio (IV, Fixed, 95% CI)	1.43 [0.97, 2.10]
1.2 Hypothermia	49	5203	Risk Ratio (IV, Fixed, 95% CI)	1.09 [0.81, 1.47]
2 Myocardial infarction	50	6199	Risk Ratio (IV, Fixed, 95% CI)	1.01 [0.78, 1.30]
2.1 Normothermia	14	2138	Risk Ratio (IV, Fixed, 95% CI)	0.97 [0.69, 1.37]
2.2 Hypothermia	36	4061	Risk Ratio (IV, Fixed, 95% CI)	1.05 [0.71, 1.55]
3 Stroke	54	6625	Risk Ratio (IV, Fixed, 95% CI)	0.66 [0.46, 0.94]
3.1 Normothermia	14	2130	Risk Ratio (IV, Fixed, 95% CI)	0.82 [0.49, 1.37]
3.2 Hypothermia	40	4495	Risk Ratio (IV, Fixed, 95% CI)	0.53 [0.32, 0.88]
4 Postoperative atrial fibrillation	31	4299	Risk Ratio (IV, Fixed, 95% CI)	0.80 [0.72, 0.89]
4.1 Normothermia	8	1069	Risk Ratio (IV, Fixed, 95% CI)	0.94 [0.78, 1.12]
4.2 Hypothermia	23	3230	Risk Ratio (IV, Fixed, 95% CI)	0.73 [0.64, 0.84]
5 Renal insufficiency	19	2397	Risk Ratio (IV, Fixed, 95% CI)	0.86 [0.60, 1.22]
5.1 Normothermia	4	879	Risk Ratio (IV, Fixed, 95% CI)	1.06 [0.68, 1.66]
5.2 Hypothermia	15	1518	Risk Ratio (IV, Fixed, 95% CI)	0.60 [0.34, 1.08]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	60	6718	Risk Ratio (IV, Fixed, 95% CI)	1.24 [0.97, 1.58]
1.1 Cold blood cardioplegia	31	3364	Risk Ratio (IV, Fixed, 95% CI)	1.30 [0.95, 1.79]
1.2 Cold crystalloid cardioplegia	13	1587	Risk Ratio (IV, Fixed, 95% CI)	1.26 [0.65, 2.46]
1.3 Warm/tepid/isotherm blood cardioplegia	15	1707	Risk Ratio (IV, Fixed, 95% CI)	1.10 [0.70, 1.74]
1.4 Ventricular fibrillation	1	60	Risk Ratio (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Myocardial infarction	45	5135	Risk Ratio (IV, Fixed, 95% CI)	0.87 [0.64, 1.19]
2.1 Cold blood cardioplegia	23	2473	Risk Ratio (IV, Fixed, 95% CI)	0.91 [0.58, 1.42]
2.2 Cold crystalloid cardioplegia	10	1444	Risk Ratio (IV, Fixed, 95% CI)	0.87 [0.50, 1.53]
2.3 Warm/tepid/isotherm blood cardioplegia	11	1158	Risk Ratio (IV, Fixed, 95% CI)	0.80 [0.42, 1.53]
2.4 Ventricular fibrillation	1	60	Risk Ratio (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Stroke	47	5480	Risk Ratio (IV, Fixed, 95% CI)	0.72 [0.47, 1.09]
3.1 Cold blood cardioplegia	27	3100	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.53, 1.47]
3.2 Cold crystalloid cardioplegia	11	1415	Risk Ratio (IV, Fixed, 95% CI)	0.48 [0.20, 1.16]
3.3 Warm/tepid/isotherm blood cardioplegia	9	965	Risk Ratio (IV, Fixed, 95% CI)	0.48 [0.13, 1.68]
4 Postoperative atrial fibrillation	29	4221	Risk Ratio (IV, Fixed, 95% CI)	0.80 [0.72, 0.89]
4.1 Cold blood cardioplegia	18	2262	Risk Ratio (IV, Fixed, 95% CI)	0.92 [0.80, 1.05]
4.2 Cold crystalloid cardioplegia	5	1181	Risk Ratio (IV, Fixed, 95% CI)	0.71 [0.57, 0.88]
4.3 Warm/tepid/isotherm blood cardioplegia	5	718	Risk Ratio (IV, Fixed, 95% CI)	0.50 [0.37, 0.69]
4.4 Ventricular fibrillation	1	60	Risk Ratio (IV, Fixed, 95% CI)	1.0 [0.15, 6.64]
5 Renal insufficiency	18	2337	Risk Ratio (IV, Fixed, 95% CI)	0.87 [0.61, 1.24]
5.1 Cold blood cardioplegia	11	1154	Risk Ratio (IV, Fixed, 95% CI)	0.89 [0.61, 1.31]
5.2 Cold crystalloid cardioplegia	2	681	Risk Ratio (IV, Fixed, 95% CI)	0.78 [0.15, 4.13]
5.3 Warm/tepid/isotherm blood cardioplegia	5	502	Risk Ratio (IV, Fixed, 95% CI)	0.68 [0.18, 2.54]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	38	4598	Risk Ratio (IV, Fixed, 95% CI)	1.27 [0.98, 1.64]
1.1 Octopus	24	2629	Risk Ratio (IV, Fixed, 95% CI)	1.33 [0.95, 1.87]
1.2 Cardio Thoracic System	8	873	Risk Ratio (IV, Fixed, 95% CI)	1.16 [0.72, 1.87]
1.3 Guidant	6	1096	Risk Ratio (IV, Fixed, 95% CI)	1.23 [0.57, 2.65]
2 Myocardial infarction	32	4137	Risk Ratio (IV, Fixed, 95% CI)	0.87 [0.62, 1.22]
2.1 Octopus	23	2862	Risk Ratio (IV, Fixed, 95% CI)	0.89 [0.62, 1.30]
2.2 Cardio Thoracic System	6	619	Risk Ratio (IV, Fixed, 95% CI)	0.63 [0.21, 1.90]
2.3 Guidant	3	656	Risk Ratio (IV, Fixed, 95% CI)	0.97 [0.34, 2.78]
3 Stroke	33	4170	Risk Ratio (IV, Fixed, 95% CI)	0.76 [0.49, 1.17]
3.1 Octopus	20	2568	Risk Ratio (IV, Fixed, 95% CI)	0.95 [0.58, 1.58]
3.2 Cardio Thoracic System	9	886	Risk Ratio (IV, Fixed, 95% CI)	0.39 [0.13, 1.14]
3.3 Guidant	4	716	Risk Ratio (IV, Fixed, 95% CI)	0.35 [0.08, 1.56]
4 Postoperative atrial fibrillation	23	3670	Risk Ratio (IV, Fixed, 95% CI)	0.80 [0.71, 0.90]
4.1 Octopus	16	2443	Risk Ratio (IV, Fixed, 95% CI)	0.91 [0.79, 1.04]
4.2 Cardio Thoracic System	3	511	Risk Ratio (IV, Fixed, 95% CI)	0.37 [0.25, 0.53]
4.3 Guidant	4	716	Risk Ratio (IV, Fixed, 95% CI)	0.74 [0.57, 0.95]
5 Renal insufficiency	15	1999	Risk Ratio (IV, Fixed, 95% CI)	0.87 [0.61, 1.24]
5.1 Octopus	11	1459	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.61, 1.28]
5.2 Cardio Thoracic System	2	60	Risk Ratio (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Guidant	2	480	Risk Ratio (IV, Fixed, 95% CI)	0.65 [0.15, 2.81]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	47	6033	Risk Ratio (IV, Fixed, 95% CI)	1.24 [0.96, 1.60]
1.1 Heparin dose less than 300 mg/kg	36	4513	Risk Ratio (IV, Fixed, 95% CI)	1.31 [1.00, 1.71]
1.2 Heparin dose 300 mg/kg or more	11	1520	Risk Ratio (IV, Fixed, 95% CI)	0.70 [0.29, 1.69]
2 Myocardial infarction	37	4864	Risk Ratio (IV, Fixed, 95% CI)	1.13 [0.85, 1.50]
2.1 Heparin dose less than 300 mg/kg	27	3550	Risk Ratio (IV, Fixed, 95% CI)	0.97 [0.67, 1.41]
2.2 Heparin dose 300 mg/kg or more	10	1314	Risk Ratio (IV, Fixed, 95% CI)	1.39 [0.90, 2.14]
3 Stroke	36	4191	Risk Ratio (IV, Fixed, 95% CI)	0.79 [0.49, 1.27]
3.1 Heparin dose less than 300 mg/kg	28	3678	Risk Ratio (IV, Fixed, 95% CI)	0.85 [0.52, 1.37]
3.2 Heparin dose 300 mg/kg or more	8	513	Risk Ratio (IV, Fixed, 95% CI)	0.21 [0.02, 1.83]
4 Postoperative atrial fibrillation	22	3145	Risk Ratio (IV, Fixed, 95% CI)	0.80 [0.70, 0.91]
4.1 Heparin dose less than 300 mg/k	18	2934	Risk Ratio (IV, Fixed, 95% CI)	0.80 [0.70, 0.91]
4.2 Heparin dose 300 mg/kg or more	4	211	Risk Ratio (IV, Fixed, 95% CI)	0.89 [0.48, 1.68]
5 Renal insufficiency	15	1609	Risk Ratio (IV, Fixed, 95% CI)	0.86 [0.59, 1.26]
5.1 Heparin dose less than 300 mg/k	14	1577	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.60, 1.28]
5.2 Heparin dose 300 mg/kg or more	1	32	Risk Ratio (IV, Fixed, 95% CI)	0.33 [0.01, 7.62]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	74	10323	Risk Ratio (M‐H, Random, 95% CI)	1.41 [1.09, 1.83]
1.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Random, 95% CI)	1.57 [1.16, 2.12]
1.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	27	2841	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.48, 2.04]
1.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	38	2532	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.68, 2.50]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	19	7111	Risk Ratio (M‐H, Random, 95% CI)	1.28 [1.03, 1.58]
1.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Random, 95% CI)	1.35 [1.07, 1.70]
1.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	7	1557	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.40, 2.08]
1.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	3	604	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.34, 2.06]
2 Myocardial infarction	22	6858	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.78, 1.27]
2.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.61, 1.36]
2.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	9	1534	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.70, 2.00]
2.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	4	374	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.30, 2.55]
3 Stroke	13	5592	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.61, 1.25]
3.1 Trials with low risk of bias	9	4950	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.61, 1.36]
3.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	3	592	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.18, 1.65]
3.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.07, 16.38]
4 Coronary reintervention (CABG or PCI)	10	4601	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.93, 1.62]
4.1 Trials with low risk of bias	7	3881	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.91, 1.68]
4.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	3	720	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.60, 2.35]
4.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Postoperative atrial fibrillation	31	4304	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.63, 0.96]
5.1 Trials with low risk of bias	6	1700	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.59, 2.03]
5.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	13	1804	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.53, 0.96]
5.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	12	800	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.53, 0.86]
6 Renal insufficiency	9	3889	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.64, 1.24]
6.1 Trials with low risk of bias	5	3221	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.65, 1.33]
6.2 Trials with low risk of bias for randomisation but high risk of bias for blinding	2	480	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.15, 2.81]
6.3 Trials with unclear risk of bias for randomisation and unclear/high risk of bias for blinding	2	188	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.20, 2.36]
7 Distal anastomoses	57	7071	Mean Difference (IV, Random, 95% CI)	‐0.28 [‐0.40, ‐0.16]

Methods	Trial design: Parallel 2 groups     Sample size estimation: Unclear     Follow up: 4 days     Intention to treat: Unclear     Surgical conversion: Not described
Participants	Country: UK     Inclusion criteria: Primary isolated CABG     Exclusion criteria: Ejection fraction at or below 30%, renal failure (creatinine level at or above 180 umol/L or active renal replacement therapy), concomitant cardiac surgery requiring CPB, or emergency surgery following angiographic intervention     Demografics:   Off‐pump: Age = 63.8+/‐8.4, 3 vessel disease = , diabetes = , Ejection fraction < 30% = 0, 30‐50% = 30%, distal anastomosis = 3.5+/‐0.2   On‐pump: Age = 63.9+/‐10.9, 3 vessel disease = , diabetes = , Ejection fraction < 30% = 0, 30‐50% = 30%, distal anastomosis = 3.4+/‐0.2
Interventions	Off‐pump: 10     On‐pump: 10
Outcomes	Primary: Inflammatory markers (white cell counts, CD 11b, and interleukin 8)
Notes	Clinical data reported     E‐mailed: 07.02.2007 and responded. No overlaps between Al‐ruzzeh 2003 and 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer program using minimisation and block randomisation.
Allocation concealment (selection bias)	Unclear risk	Unclear
Blinding (performance bias and detection bias)   All outcomes	High risk	Not blinded
Selective reporting (reporting bias)	Unclear risk	None of the outcomes reported
Adequate follow‐up?	Low risk	No withdrawals
Funding	Unclear risk	Not reported

Methods	Trial design: Parallel 2 groups     Sample size estimation: Adequate; alpha= 0.05, beta = 0.8, absolute difference in angiographic patency 5%, Expected patency 96%     Follow up: 6 month (85% as regard angiography patency 3 month postoperatively)     Intension to treat analysis: Yes
Participants	Country: UK     Inclusion criteria: Primary isolated coronary artery bypass surgery     Exclusion criteria: Ejection fraction < 30%, renal failure (at or above 180 umol or active renale replacement therapy), concomitant cardiac surgery, emergency operation, isolated single vessel disease. Refused to have postoperative angiography. Unable to effectively communicate in English     Demografics:   Off‐pump: Age = 63.1 +/‐ 9.6 , 3 vessel disease = , diabetes = 21%, Ejection fraction < 30% = 0% , 30‐50% = 23%, distal anastomosis = ?   On‐pump: Age = 63.1 +/‐ 11.0, 3 vessel disease = , diabetes = 24% , Ejection fraction < 30% = 0% , 30‐50% = 21% , distal anastomosis = ?
Interventions	Off‐pump: 84     On‐pump: 84
Outcomes	Primary: Angiographic patency and neurocognitive function     Secondary: Clinical outcome and health related quality of life
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Generated with minimisation in an Excell program
Allocation concealment (selection bias)	Low risk	Surgeon was told immediately before the procedure
Blinding (performance bias and detection bias)   All outcomes	Low risk	Patient, staff and researcher were blinded
Selective reporting (reporting bias)	Low risk	Protocol not published, but data about mortality, stroke and myocardial infarction reported
Adequate follow‐up?	Low risk	Adequate reported
Funding	Unclear risk	Not reported

Methods	Trial design: Parallel 2 groups     Sample size estimation: Unclear, alpha 0.05, beta= 0.80, detection of 0.5ug/L difference in cardiac troponin I concentration, no standard deviation given     Follow up: In‐hospital and 30 day mortality     Intention to treat: Yes     Surgical conversion: No
Participants	Country: France     Inclusion criteria: first‐time elective CABG     Exclusion criteria: aortic incompensation, ejection fraction below 30 %, concomitant heart valve disease, unstable angina, re‐operation     Demografics:   Off‐pump: Age =61+/‐11 , 3 vessel disease = , diabetes = 34 %, Ejection fraction < 30% = 0, 30‐50% = , distal anastomosis = 2.3+/‐1.1   On‐pump: Age = 66+/‐7, 3 vessel disease = , diabetes = 31 %, Ejection fraction < 30% = 0, 30‐50% = , distal anastomosis = 2.5+/‐0.8
Interventions	Off‐pump: 35     On‐pump: 35
Outcomes	Primary: Cardiac Troponin I concentration
Notes	Left main coronary artery stenosis: 6 in off‐pump group and 9 in on‐pump group   E‐mailed 05.03.2007: responded 12.03.2007; concealment sealed envelopes   E‐mailed 13.03.2007: no response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer generated randomisation table
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding (performance bias and detection bias)   All outcomes	High risk	Not blinded
Selective reporting (reporting bias)	High risk	Stroke not reported
Adequate follow‐up?	Low risk	No patients lost to follow‐up
Funding	Unclear risk	Not reported

Methods	Trial design: Parallel 2 groups     Sample size estimation: Unclear     Follow up: In‐hospital     Intention to treat: No (*see notes)     Surgical conversion: No
Participants	Country: Stockholm, Sweden     Inclusion criteria: First‐time elective CABG, suitable for OPCAB     Exclusion criteria: Known diabetes mellitus or other endocrinological disorders, a history of heart failure or severely reduced myocardial or kidney function     Demografics:   Off‐pump: Age =64+/‐9 , 3 vessel disease = , diabetes = 0, Ejection fraction < 30% = , 30‐50% = , distal anastomosis = 2.8+/‐0.9   On‐pump: Age = 69+/‐11, 3 vessel disease = , diabetes = 0, Ejection fraction < 30% = 0, 30‐50% = , distal anastomosis = 2.5+/‐1.1
Interventions	Off‐pump: 25     On‐pump: 25     Excluded: 3 off‐pump to 2 on‐pump
Outcomes	Primary: Whole blood glucose     Secondary: Exogenous insulin, several other endocrinological parameters
Notes	* 2 patients in each group excluded due to preoperative fasting blood glucose above 6.1 mmol/L. 1 patients in the OPCAB group excluded due to extended ICU stay due to pulmonary complication     E‐mailed 19.06.2007: No response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Unclear
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding (performance bias and detection bias)   All outcomes	High risk	Not blinded
Selective reporting (reporting bias)	Unclear risk	All other patients had uneventful postoperative courses. Specific clinical outcomes not reported
Adequate follow‐up?	High risk	2 patients in each group excluded due to preoperative fasting blood glucose above 6.1 mmol/L. 1 patients in the OPCAB group excluded due to extended ICU stay due to pulmonary complication.
Funding	Unclear risk	Not reported

Methods	Trial design: Parallel 3 groups     Sample size estimation: 20 subjects in each group was chosen for the study to have approximately 90% power to detect a target difference between group of 1 standard deviation or greater at a significance level of 5 %     Follow up: In‐hospital     Intention to treat: Yes     Surgical conversion: No
Participants	Country: United Kingdom     Inclusion criteria: First‐time CABG     Exclusion criteria: Cardiac ejection fraction less than 30%, recent myocardial infarction (<1 month), type II diabetes mellitus, respiratory or renal impairment, coagulopathy, and previous cerebrovascular accidents.     Demografics:   Off‐pump: Age = 62.7+/‐10.6, 3 vessel disease = , diabetes = , Ejection fraction < 30% = 0, 30‐50% = , distal anastomosis = ?   On‐pump: Age = 62.9+/‐6.9, 3 vessel disease = , diabetes = , Ejection fraction < 30% = 0, 30‐50% = , distal anastomosis = ?
Interventions	Off‐pump: 20     On‐pump: 20
Outcomes	Primary: Troponin I, Inflammatory markers (IL 6 and 8, C3a), Renal tubular damage (NAG), free haemoglobin, Protein S 100 (neurological damage)   Secondary: Clinical outcomes (death, major complications)
Notes	Randomised into 3 groups (conventional CABG with CPB, off‐pump CABG, off‐pump CABG with RVAD) only CABG with CPB and off‐pump CABG are included in the review     E‐mailed 22.06.2007: responded 22.06.2007 no mortality, stroke, MI or re‐intervention in any groups Funding source: Edwards Lifesciences Europe provided A‐med catheters and a grant for purchasing reagents
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Generated in advance of starting the study
Allocation concealment (selection bias)	Low risk	Sequentially numbered, sealed, opaque envelopes
Blinding (performance bias and detection bias)   All outcomes	High risk	No blinded
Selective reporting (reporting bias)	Low risk	Data about mortality, stroke and myocardial infarction reported
Adequate follow‐up?	Low risk	No patients lost to follow‐up
Funding	Unclear risk	Not reported

Methods	Trial design: Parallel 4 groups     Sample size estimation: Unclear     Follow up: 3 month     Intention to treat: Yes     Surgical conversion: No
Participants	Country: Germany     Inclusion criteria: Referred for single left internal mammary artery bypass to the left anterior descending artery, due to CAD. Patients suffering from double or multi‐vessel coronary disease, with only LAD amenable for surgery were included     Exclusion criteria: Left ventricular ejection fraction less than 30 %, impair lung or renale function, unstable angina, major calcification of the ascending aorta and body mass index above 30 kg /m2, myocardial infarction within 2 weeks. Patients receiving dipyridamole, anticoagulants or immunosuppression. Previous cardiac operation     Demografics:   Off‐pump: Age = , 3 vessel disease = , diabetes = , Ejection fraction < 30% = , 30‐50% = , distal anastomosis = 1   On‐pump: Age = , 3 vessel disease = , diabetes = , Ejection fraction < 30% = , 30‐50% = , distal anastomosis = 1
Interventions	Off‐pump: 20     On‐pump: 20
Outcomes	Primary: Inflammatoty response (IL 1, IL 6, TnT, CKMB), In a secund publication psychosomatic outcome
Notes	The trial had 4 groups: sternotomy + CPB, sternotomy ‐ CPB, minithoracotomy + CPB, minithoracotomy ‐ CPB. 10 patients in each group. ONLY LIMA TO LAD     E‐mailed 12.03.2007 and 20.03.2007: allocation sequence and concealment by random generated list and sealed envelopes. No incidences of atrial fibrillation, stroke , myocardial infarction or deaths in any groups
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random generated list
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding (performance bias and detection bias)   All outcomes	High risk
Selective reporting (reporting bias)	High risk	Myocardial infarction not reported
Adequate follow‐up?	Low risk	No patients lost to follow‐up
Funding	Unclear risk	Not reported

Methods	Trial design: 2x2 factorial     Sample size estimation: Unclear     Follow up: In‐hospital     Intention to treat: Yes     Surgical conversion: No
Participants	Country: United Kingdom     Inclusion criteria: First time CABG requiring at least 3 bypass grafts and with a good to moderate ejection fraction     Exclusion criteria: known inflammatory diseases, existing infections, emergent surgery, use of long‐term corticosteroids and non‐steroidal antiinflammatory drugs, anti‐platelet agents in the week prior to surgery, known coagulopathy/long‐term anticoagulation with warfarin or heparin, severe pre‐existing renal dysfunction (creatinine > 200umol/L) or lung dysfunction (forced vital capacity or forced expiratory volume in 1 s <80% of predicted), LVEF < 40%     Demografics:   Off‐pump: Age = 67.6, 3 vessel disease = 93%, diabetes = 10%, Ejection fraction < 30% = 0, 30‐50% = 20%, distal anastomosis = 3,75   On‐pump: Age = 66.2, 3 vessel disease = 93%, diabetes = 17.5%, Ejection fraction < 30% = 0, 30‐50% = 12.5%, distal anastomosis = 3.93
Interventions	Off‐pump: 40     On‐pump: 40
Outcomes	Effect of cell saver as regard blood transfusion
Notes	20 patient in each group received autotransfusion from a cell saver     E‐mailed 12.03.2007: No response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Card allocation
Allocation concealment (selection bias)	Low risk	Non‐transparent envelopes
Blinding (performance bias and detection bias)   All outcomes	High risk
Selective reporting (reporting bias)	High risk	Myocardial infarction not reported
Adequate follow‐up?	Low risk	No patients lost to follow‐up
Funding	Low risk	British Heart Foundation

Methods	Trial design: Parallel 2 groups.     Sample size estimation: Unclear     Follow up: In‐hospital     Intention to treat: Yes     Surgical conversion: No
Participants	Country: Finland     Inclusion criteria: Patient with coronary artery disease suitable CABG without CPB     Exclusion criteria: Ongoing ischaemia, acute myocardial infarction less than 1 month previously, poorly controlled diabetes, serum creatinine >150 umol/L, chronic atrial fibrillation, aortic or mitral valvular disease     Demografics:   Off‐pump: Age = 59.5 , 3 vessel disease = 36%, diabetes = , Ejection fraction < 30% =0 , 30‐50% = 1, distal anastomosis = 2.8   On‐pump: Age = 59.2, 3 vessel disease = 45%, diabetes = , Ejection fraction < 30% = 0, 30‐50% = 0, distal anastomosis = 3.3
Interventions	Off‐pump: 11     On‐pump: 11
Outcomes	Myocardial energy metabolism (lactate and pH, ATP degradation products ) and Troponin I and CK‐MB
Notes	E‐mailed 12.03.2007: responded 15.03.2007 allocation seq and concealment card and sealed envelopes   E‐mailed 20.03.2007: No response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Card allocation
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding (performance bias and detection bias)   All outcomes	High risk
Selective reporting (reporting bias)	Low risk	Data about mortality, stroke and myocardial infarction reported
Adequate follow‐up?	Low risk	No patients lost to follow‐up
Funding	Low risk	Inari and Reijo Holopainen Foundation

Methods	Trial design: Parallel 2 groups Sample size estimation: Unclear     Follow up: In‐hospital     Intention to treat: No     Surgical conversion: 11 patient converted from off‐pump to on‐pump
Participants	Country: Austria     Inclusion criteria: Cardiac surgery for coronary heart disease     Exclusion criteria: Valve operation, combined procedures, emergency operations, renal insufficiency or any kind of neurologic symptoms     Demografics:   Off‐pump: Age = 65 , 3 vessel disease = ? , diabetes = ?, Ejection fraction < 30% = ? , 30‐50% =? , distal anastomosis = ?   On‐pump: Age = 66, 3 vessel disease = ?, diabetes = ?, Ejection fraction < 30% =? , 30‐50% = ?, distal anastomosis = 3.10
Interventions	Off‐pump: 41     On‐pump: 67
Outcomes	Primary: Cerebral outcomes (clinical and protein S100 release)
Notes	11 patients randomised to off‐pump, were converted to on‐pump and withdrawn from the trial     E‐mailed 13.03.2007: No response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Unclear
Allocation concealment (selection bias)	Unclear risk	Unclear
Blinding (performance bias and detection bias)   All outcomes	High risk
Selective reporting (reporting bias)	Low risk	Data about mortality, stroke and myocardial infarction reported
Adequate follow‐up?	High risk	11 patients randomised to off‐pump, were converted to on‐pump and withdrawn from the trial
Funding	Unclear risk	Not reported

Study	Reason for exclusion
Akila, 2007	Not a randomised trial
Autschbach 2001	On‐pump beating heart (microaxial pump)
Bingyang 2007	No off‐pump group
Diegeler 1998	Not a randomised trial
Geishardt 2005	Author contacted but never responded. No data available
Gerritsen 2006	Not a randomised trial
Greilich 2008	Not a randomised trial
Güden 2003	Quasi‐randomisation
Jalal 2007	Not a randomised trial
Jansen 1997	Not a randomised trial
Jansen 1998	Not a randomised trial
Kalisnik 2007	Not a randomised trial
Krejca 1999	On‐pump beating heart
Lonn 1999	On‐pump beating heart (Axial blood flow pump)
Naseri 2009	Not a randomised trial
Ooi 2008	Not a randomised trial
Parolari 2005a	Unclear reporting of excluded patients and clinical outcomes. Author did not repond on request of additional information
Rastan 2005	On‐pump beating heart
Reber 2008	On‐pump beating heart
Syed 2004	Quasi‐randomisation
Tugtekin 2007	Retrospective study
Vallely 2009	Not a randomised trial
Vassiliades 2002	No on‐pump group
Wan 2004	On‐pump beating heart

Trial name or title	CRISP
Methods
Participants	5420
Interventions	This study is an international, multicentre open randomised controlled trial, across 40 centres: 20 in the UK and 20 overseas. Trial patients will be randomised to:   1. CABG without cardiopulmonary bypass, i.e. off‐pump CABG (OPCABG) on the beating heart, via a median sternotomy incision   2. CABG with cardiopulmonary bypass i.e. on‐pump CABG (ONCABG) on a chemically arrested heart, via a median sternotomy incision     Total duration of follow‐up is 1 year post‐surgery.
Outcomes	The primary outcome is a composite endpoint of death or serious morbidity (CRISPS). This is made up of the following:   1. Death after cardiac surgery within 30 days of the operation from any cause   2. New onset renal failure requiring renal replacement therapy up to and including 30 days of the operation   3. Myocardial infarction up to and including 30 days of the operation   4. Stroke up to and including 30 days of the operation   5. Prolonged ventilation greater than or equal to 96 hours during the index hospital admission   6. Sternal wound dehiscence requiring non‐pharmacological intervention up to and including 30 days of the operation 1. Duration of intensive care stay   2. Duration of hospital stay   3. Survival, free from death or serious morbidity at one year   4. Resource use (hospital and other healthcare resources) during one year   5. Quality of life at one year: Rose Angina Questionnaire (short), EuroQol EQ‐5D, the Coronary Revascularisation Outcome Questionnaire (CROQ; UK patients only)   6. Cost‐effectiveness     Data will be collected on events between discharge and 30 days at a routine follow‐up appointment 4 ‐ 8 weeks after discharge. Questionnaires will be completed by the patient before surgery, at the 4 ‐ 8 week follow‐up appointment, and will be posted to patients for completion at 1 year post‐surgery.
Starting date	01/01/2009
Contact information	research.services@admin.ox.ac.uk
Notes	Anticipated end date 01/01/2011   Status of trial

Trial name or title	Graft Patency Following Off‐Pump CABG Vs. On‐Pump CABG Using 64 MDCT Bypass Graft CT Angiography
Methods
Participants	350
Interventions	The purpose of this study is to compare graft patency rates following coronary artery bypass graft surgery performed by beating heart vs. conventional techniques using cardiac CT scanning to evaluate the bypass grafts.
Outcomes	Primary Outcome Measures: Graft patency as determined by bypass graft CT angiography at 3 months and 12 months following surgery     Secondary Outcome Measures: Length of Hospital Stay   Blood Loss   Operative Time   Post‐op Complications   Quality of Life Assessment
Starting date	01/12/2005
Contact information	kariss@thc.on.ca
Notes	Estimated Study Completion Date: October 2007

Trial name or title	CORONARY
Methods
Participants	4700
Interventions	Coronary artery bypass graft (CABG) surgery with or without cardio‐pulmonary bypass (CPB) machine:   1. Experimental group: CABG without use of CPB   2. Control group: CABG with the use of CPB
Outcomes	1. The occurrence of the composite of total mortality, stroke, nonfatal myocardial infarction [MI], or new renal failure at 30 days post CABG surgery   2. The occurrence of the composite of total mortality, stroke, nonfatal MI, new renal failure, or repeat coronary revascularisation (i.e. coronary artery bypass surgery or percutaneous coronary intervention) over 5 years after randomisation
Starting date	01/10/2007
Contact information	lamya@mcmaster.ca
Notes	Estimated Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)

Trial name or title	Surgical Manipulation of the Aorta and Cerebral Infarction
Methods
Participants	200
Interventions	The purpose of the study is to compare two surgical strategies for coronary artery bypass grafting with respect to the occurrence of cerebral infarctions made visible by magnetic resonance imaging
Outcomes	Primary Outcome Measures: occurrence and number of cerebral infarctions assessed by magnetic resonance imaging [ Time Frame: 2‐7 days after surgery ]     Secondary Outcome Measures: mortality [ Time Frame: within hospital stay following surgery ]   stroke [ Time Frame: within hospital stay following surgery ]   delirium [ Time Frame: within hospital stay following surgery ]   neurocognitive performance [ Time Frame: within hospital stay following surgery ]   multi‐organ failure [ Time Frame: within hospital stay following surgery ]   myocardial infarction [ Time Frame: within hospital stay following surgery ]   completeness of revascularisation [ Time Frame: within hospital stay following surgery ]
Starting date	01/10/2007
Contact information	reents_w@klinik.uni‐wuerzburg.de
Notes	Estimated Study Completion Date: May 2010

PERMALINK

Off‐pump versus on‐pump coronary artery bypass grafting for ischaemic heart disease

Christian H Møller

Luit Penninga

Jørn Wetterslev

Daniel A Steinbrüchel

Christian Gluud

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Generation of the allocation sequence

Allocation concealment

Blinding

Follow‐up

Selective outcome reporting

Data synthesis

Trial sequential analysis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

1. Characteristics of included trials.

Risk of bias in included studies

2.

3.

Effects of interventions

4.

All‐cause mortality

5.

1.1. Analysis.

2.1. Analysis.

6.

7.1. Analysis.

8.1. Analysis.

9.1. Analysis.

7.

3.1. Analysis.

4.1. Analysis.

5.1. Analysis.

6.1. Analysis.

2. Test of subgroup variance.

12.1. Analysis.

Myocardial infarction

8.

1.2. Analysis.

2.2. Analysis.

3.2. Analysis.

4.2. Analysis.

5.2. Analysis.

6.2. Analysis.

10.2. Analysis.

Trial name or title	German Off Pump Coronary Artery Bypass in Elderly Study (GOPCABE)
Methods
Participants	2000
Interventions	The coronary bypass operation without use of the heart‐lung machine (off‐pump=OPCAB) reduces the combined endpoint in comparison with the conventional coronary bypass operation (on‐pump).
Outcomes	Primary Outcome Measures: All cause mortality [ Time Frame: 1 month and 12 month ] [ Designated as safety issue: Yes ]   Myocardial infarction [ Time Frame: 1 month and 12 month ] [ Designated as safety issue: No ]   Stroke [ Time Frame: 1 month and 12 month ] [ Designated as safety issue: No ]   Any revascularisation [ Time Frame: 1 month and30 month ] [ Designated as safety issue: No ]   renal failure [ Time Frame: 1 month and 12 month ] [ Designated as safety issue: No ]     Secondary Outcome Measures: ventilation time [ Time Frame: post op ] [ Designated as safety issue: No ]   blood transfusion [ Time Frame: post op ] [ Designated as safety issue: No ]   length of stay in intensive‐care unit [ Time Frame: post op ] [ Designated as safety issue: No ]
Starting date	01/07/2008
Contact information	a.diegeler@herzchirurgie.de
Notes	Estimated Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

Trial name or title	Arrested Versus Beating Heart Techniques in Coronary Revascularisation
Methods
Participants	616
Interventions	Comparing the 3 surgical approaches: Conventional Coronary Artery Bypass Grafting (CCAB), with extracorporeal circulation and cardioplegic arrest; Off‐Pump Coronary Artery Bypass Grafting (OPCAB), avoids extracorporeal circulation and global myocardial ischaemia; and Pump‐Assisted Coronary Artery Bypass Grafting (PACAB), with an unloaded and beating heart. The hypothesis addressed by the study is that the surgical invasiveness increases in the order: OPCAB, PACAB, CCAB.
Outcomes	Primary Outcome Measures: All cause mortality [ Time Frame: 1, 6, 12, 24, 48 month ] [ Designated as safety issue: Yes ]   Myocardial infarction [ Time Frame: 1, 6, 12, 24, 48 month ] [ Designated as safety issue: Yes ]   Stroke [ Time Frame: 1, 6, 12, 24, 48 month ] [ Designated as safety issue: Yes ]   Low‐output syndrome [ Time Frame: in hospital ] [ Designated as safety issue: No ]   duration of ventilation >= 24h [ Time Frame: in hospital ] [ Designated as safety issue: No ]   New requirement of haemodialysis [ Time Frame: in hospital ] [ Designated as safety issue: No ]     Secondary Outcome Measures: Completeness of revascularization [ Time Frame: in hospital ] [ Designated as safety issue: No ]   Re‐revascularization of the target vessel (PCI and/or CABG) [ Time Frame: 1, 6, 12, 24, 48 month ] [ Designated as safety issue: No ]   Resource use (operative time, duration of stay in the intensive care unit, total hospital stay) [ Time Frame: in hospital ] [ Designated as safety issue: No ]
Starting date	01/01/2003
Contact information	Principal Investigator: Jochen Boergermann, MD Martin‐Luther‐University Halle‐Wittenberg
Notes	Estimated Study Completion Date: