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Three Part Question

In [patients undergoing coronary artery surgery] does [off pump surgery compared to on pump surgery] reduce the incidence of [postoperative atrial fibrillation]?

Clinical Scenario

You are about to attend a cardiothoracic conference in Leipzig and you are interested in possible intra-operative interventions that you could perform to reduce the incidence of atrial fibrillation. You have seen papers on bi-atrial pacing, posterior pericardotomy, and ventral cardiac denervation which you think may reduce the incidence of AF. You present this to a colleague who tells you that you don't need to bother with any of these manoeuvres which have very little evidence for them as there is outstanding evidence that off pump surgery alone will greatly reduce your incidence of AF. You are sceptical of his view and therefore resolve to look up the evidence for this.

Search Strategy

Medline 1966-July 2004 using the Ovid interface.
[exp Cardiovascular surgical procedures/ OR cardiovascular surgical procedures.mp OR exp Thoracic surgery/ OR Thoracic surgery.mp OR exp Coronary Artery bypass/ OR coronary artery bypass surgery.mp OR CABG.mp OR coronary surgery.mp OR cardiac surgery.mp OR revascularization.mp ] AND [exp off-pump coronary artery surgery/OR exp beating heart surgery/ OR OPCAB.mp OR off-pump.mp OR off pump.mp OR midcab.mp OR midcabg.mp OR opcab$.mp] AND [exp postoperative atrial fibrillation/OR atrial tachyarrhythmias.mp OR exp atrial fibrillation OR postoperative atrial fibrillation.mp OR supraventricular arrhythmia.mp OR supraventricular arrhythmias.mp OR AF.mp] OR [meta-analysis.af AND exp Thoracic surgery/ ] LIMIT to human studies.

Search Outcome

One hundred and seven papers were found of which 7 were deemed to be relevant. In addition cross-checking references, suggestions from Journal Club members and hand checking Cardiothoracic Journals published this year revealed a further 9 papers. The relevant papers are presented in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Reston et al 2003 USA	Meta-analysis of RCTs and cohort studies comparing OPCAB with standard CABG. Searched 21 databases up to Jan 2003. 180 studies reviewed, 10 RCTs, 5 prospective and 38 retrospective cohort studies found. 28 studies were included in their analysis of Atrial fibrillation	Meta-analysis (Level 1a)	Odds of AF in OPCAB group compared to CABG group	Odds of AF was 0.69 (95%CI-0.58-0.81) in favour of OPCAB. P=0.00001 Of the RCTs only the effect was even bigger in favour of OPCAB	A significant heterogeneity was found between studies for AF indicating significant disagreement between studies but the reasons for this were not clear PRAGUE-4 trial, Brompton Trial and Smart trial not included
			Stroke (38 studies)	Odds of Stroke was 0.55 (0.44 – 0.76) in favour of OPCAB
			Mid term Mortality (7 studies)	Odds of mortality was 0.49 (0.29 – 0.82) in favour of OPCAB
Puskas et al 2003 USA and JAMA 2003	RCT comparing OPCAB (N=98) with CABG (N=99). Patients only excluded if in cardiogenic shock or needing an IABP	Single Blind PRCT (Level 1b)	Incidence of AF	OPCAB group 16/98 (16%). CABG group 22/99 (22%). P=0.367	4 patients crossed over in this study. 3 OPCAB deaths and 2 CABG deaths 1 year angiography data is yet to be completed
Lee et al 2003 Hawaii	60 patients randomized to OPCAB (N=30) or CABG (N=30)	PRCT (level 2b)	Incidence of AF	OPCAB group 7/30 (23% +/- 43%). CABG group 11/30 (39% +/- 50%). P=NS	Small study , methods for AF measurement not described
Parolari et al 2003 Italy	Meta-analysis of RCTs comparing OPCAB with CABG Search of Medline Pubmed, CCTR, Cochrane register of unpublished trials up to May 2002 1300 abstracts found , 16 RCTs found and 8 selected for inclusion.	Meta-analysis (level 1a)	Combined endpoint of mortality stroke and MI	OPCAB group 7/532 (1.3%). CABG group 17/558 (3%). P=0.08 Odds 0.48 (0.21 – 1.09)	Several RCTs not found that were included in the meta-analyses above
Athanasiou et al 2004 UK	Meta-analysis of all observational studies comparing OPCAB and CABG in patients over 70 years of age. Medline search for studies published between 1999-2003 8 non-randomized trials included, with 764 OPCAB and 2253 CABG patients.	Meta-analysis (level 2a)	Incidence of AF	OPCAB group 168/764 (22%). CABG group 641/2253 (28%). Odds 0.70 (0.56 – 0.86)	Unclear why studies were not sought prior to 1999 or why authors of RCTs were not contacted in order to obtain their data in their over 70s groups, which would have lead to much greater numbers from studies with superior methodology
van Dijk D et al 2001 Holland and NEJM 2003	Multicentre PRCT Comparing OPCAB (N=142) with CABG (N=139) Exclusion for reoperation, poor EF, MI<6weeks,	Single Blind PRCT (level 1b)	Incidence of AF	OPCAB group 28/142 (20%). CABG group 29/139 (21%). p=0.79
			Event free survival	OPCAB group 132/142 (93%). CABG group 131/139 (94%)
Muneretto et al 2003 Italy	176 patients randomized to total arterial OPCAB (N=88) or CABG (N=88) High risk patients were excluded	PRCT (level 1b)	Incidence of AF	OPCAB group 19/88 (21.6%). CABG group 31/88 (35.2%). p=0.06	Methods for measurement of AF not given
Salamon et al 2003 USA	2,569 patients undergoing OPCAB and CABG, Gp I : 252 OPCAB pts Gp II : 1470 CABG pts Gp III : 841 CABG pts with similar no grafts to Gp I GpIV: 847pts prior to prophylactic B-Blockade	Retrospective Cohort study (level 2b)	Incidence of AF	Gp I, OPCAB group 8.8%. Gp II, CABG group 11.6%. Gp III : Graft matched CABG 9.4%. GpIV : no B-Blocker CABG 28%	Retrospective cohort study, therefore the definitions of AF may have varied and there were significant differences in demographics between all groups.
Ascione et al 2000 UK and Circulation 2000	Pooled Meta-analysis of BHACAS 1 and 2 studies 200 OPCAB and 201 CABG patients Excluded patients with EF<30%, MI<1mth, repeat CABG,	Pooled Meta-analysis (level 1a)	Incidence of AF	OPCAB group 25/200 (13%). CABG group 74/201 (37%). P<0.0001 Odds 0.34 (0.23-0.51)	Selection bias. Continuous Holter ECG monitoring not done after first 72 hours
			30 day Death or first cardiac event	OPCAB group 33/200 (17%). CABG group 42/201 (21%). Odds 0.78 (0.49 – 1.22)

Comment(s)

Reston et al performed a comprehensive and well balanced meta-analysis in 2003 of the short term and mid-term outcomes of 'off-pump coronary bypass surgery' (OPCAB) versus conventional coronary arterial bypass surgery (CABG). Using comprehensive search strategies and strict entry criteria, they selected 28 studies from 180 reviewed papers that reported the incidence of AF in these patients. They found that there was a highly significant reduction in AF in the OPCAB group (Odds ratio of 0.69 in favour of OPCAB). There was however significant heterogeneity (or disagreement that cannot be explained by chance) between these studies that they could not account for. However if only the randomized controlled trials were included, the difference was increased rather than decreased. They did caution that most studies excluded patients such as non-elective surgery, reoperation, renal failure and impaired ejection fraction. While Reston et al also found significant benefits in terms of Stroke, MI and mortality, a meta-analysis by Van der Heijden et al in 2004 that assessed only RCTs disagreed with their meta-analysis, finding that there was no significant difference in the combined end-point of MI, death or stroke. Although this study did not look at AF it is interesting to note that this meta-analysis also included The Octopus study, the SMART study and an RCT from Hawaii. Thus this calls into question whether the meta-analysis by Reston et al is already outdated. In addition yet another meta-analysis by Parolari et al in 2003, also found no difference in this composite outcome measure of stroke, MI, or death. Again this meta-analysis did not extract data on AF but calls into question the findings by Reston due to the marked difference in their findings. Ascione and Angelini performed a pooled meta-analysis of BHACAS 1 and 2. They showed that the incidence of AF reduced from 37% to 13% which was a highly significant finding. This was despite showing no difference in mortality or cardiac events. A meta-analysis by Athanasiou et al in 2004 specifically asked the question of whether OPCAB reduced the incidence of AF in Elderly patients undergoing coronary arterial surgery. They found that in the 8 studies that they identified, the incidence in the OPCAB group was 22% but in the CABG group it was 28% which was significant. However this study had many flaws. It only included cohort studies from 1999 to 2003 identified from Medline although the reasons for this narrow timeframe was not explained More importantly no attempt was made to contact the authors of the many RCTs in this area to ask for their data on AF in the over 70s age group. Thus this is a small meta-analysis of non-randomized patients only Of the Recent Randomized trials not included in the Reston meta-analysis, The SMART Trial of 200 patients randomized to either OPCAB or CABG found no significant difference in AF but with an incidence of 16% in the OPCAB group and 22% in the CABG group there was a trend towards reduced incidence in OPCAB surgery. In contrast the PRAGUE-4 trial that randomised 400 patients to OPCAB or CABG found no difference at all in the incidence of AF. The OPCAB group had an incidence of 20% compared to an incidence of 24% in the CABG group. Unfortunately the PRCT by Khan, Pepper et al published in the New England Journal of Medicine in 2004 and a PRCT by Taggart et al in 2004 published in circulation did not report their findings of post-operative AF. The OCTOPUS trial found no difference in AF between the two groups with a 20% incidence in the OPCAB group and a 21% incidence in the CABG group. Muneretto et al performed a PRCT in 176 patients comparing total arterial OPCAB with total arterial CABG. They found that the incidence of AF was 22% in the OPCAB group and 35% in the CABG group which showed a strong trend towards a lower incidence in the OPCAB group but had a p value of 0.06. Gerola performed an RCT in 2004 in Brazil in 160 patients and found a low incidence of AF in both groups. The finding of 9% in the OPCAB group and 5% in the CABG group was far lower than other studies, and calls into question the measurement of AF in their study, which was not described in the protocol. Lee et al in 2003 performed a small RCT in 60 patients, and found an incidence of AF of 23% in OPCAB group and 39% in the CABG , but this was not statistically significant. Although not an RCT, Salamon et al performed a retrospective cohort study in 2003 that specifically looked at whether OPCAB reduced the incidence of AF. The 252 patients having OPCAB had an incidence of 8.8%, whereas the incidence of AF in 1470 CABG pts receiving prophylactic B-Blockers was 11.6%. When a matched group for number of grafts was found the CABG AF frequency of AF reduced to 9.4%. It should be remembered that there are many weaknesses inherent to the retrospective cohort design of this study including intergroup demographic differences and possible variation in AF definition. Therefore although we found further Cohort studies we excluded these from this topic. Thus in summary 3 meta-analyses were found that assessed AF in OPCAB versus CABG. They all found a significant reduction in AF with OPCABG. 6 further RCTs were identified that were published after several of these meta-analyses. None of them identified a significant difference individually however if you summate their findings there was a 17.8% AF rate in the OPCAB group (114/642) but a 23% rate of AF in the CABG group (144/620). This corresponds to an odds of 0.76 (Using a random effects model) with a probability of 1.6% that the results are non-significant. This finding therefore agrees with the already performed Meta-analyses that found significant differences. Our summary of the recent RCTs gives a Number needed to treat of 20 to avoid one incidence of AF.

Clinical Bottom Line

OPCAB reduces the incidence of postoperative atrial fibrillation with a number needed to treat of 20 to prevent one case of AF.

References

1. Reston JT, Tregear S.J., Turkelson CM. Meta-analysis of Short-term and Mid-term Outcomes Following Off-Pump Coronary Artery Bypass Grafting. Ann Thorac Surg 2003;76:1510-1515.
2. van Dijk D, Jansen EW, Hijman R, Nierich AP, Diephuis JC, Moons KG, Lahpor JR, Borst C, Keizer AM, Nathoe HM, Grobbee DE, de Jaegere PP, Kalkman CJ, Octopus Study Group. Cognitive outcome after off-pump and on-pump coronary artery bypass graft surgery: a randomized trial. JAMA 2002;287:1405-1412.
3. Puskas JD, Williams WH, Duke PG, Staples JR, Glas KE, Marshall JJ, Leimbach M, Huber P, Garas S, Sammons BH, McCall SA, Petersen RJ, Bailey DE, Chu H, Mahoney EM, Weintraub WS, Guyton RA. Off-pump coronary artery bypass grafting provides complete revascularization with reduced myocardial injury, transfusion requirements, and length of stay: a prospective randomized comparison... J Thorac Cardiovasc Surg 2003;125:797-808.
4. Lee JD, Lee SJ, Tsushima WT, Yamauchi H, Lau WT, Popper J, Stein A, Johnson D, Lee D, Petrovitch H, Dang CR. Benefits of off-pump bypass on neurologic and clinical morbidity: a prospective randomized trial. Ann Thorac Surg 2003;76:18-25.
5. Parolari A, Alamanni F, Cannata A, Naliato M, Bonati L, Rubini P, Veglia F, Tremoli E, Biglioli P. Off-pump versus on-pump coronary artery bypass: meta-analysis of currently available randomized trials. Ann Thorac Surg 2003;76:37-40.
6. Angelini GD, Taylor FC, Reeves BC, Ascione R. Early and midterm outcome after off-pump and on-pump surgery in Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 and 2): a pooled analysis of two randomized controlled trials. Lancet 2002;359:1194-1199.
7. Athanasiou T, Aziz O, Mangoush O, Weerasinghe A, Al-Ruzzeh S, Purkayastha S, Pepper J, Amrani M, Glenville B, Casula R. Do Off-pump Techniques Reduce the incidence of Postoperative Atrial Fibrillation in Elderly Patients Undergoing Coronary Artery Bypass grafting? Ann Thorac Surg 2004;77:1567-1574.
8. Khan NE, De Souza A, Mister R, Flather M, Clague J, Davies S, Collins P, Wang D, Sigwart U, Pepper J. A randomized comparison of off-pump and on-pump multivessel coronary-artery bypass surgery. NEJM 2004;350:21-28.
9. Selvanayagam JB, Petersen SE, Francis JM, Robson MD, Kardos A, Neubauer S, Taggart DP. Effects of off-pump versus on-pump coronary surgery on reversible and irreversible myocardial injury: a randomized trial using cardiovascular magnetic resonance imaging and biochemical markers. Circulation 2004;109:345-350.
10. van Dijk D, Nierich AP, Jansen EW, Nathoe HM, Suyker WJ, Diephuis JC, van Boven WJ, Borst C, Buskens E, Grobbee DE, Robles De Medina EO, de Jaegere PP, Octopus Study Group. Early outcome after off-pump versus on-pump coronary bypass surgery: results from a randomized study. Circulation 2001;104:1761-1766.
11. Muneretto C, Bisleri G, Negri A, Manfredi J, Metra M, Nodari S, Dei CL Off-pump coronary artery bypass surgery technique for total arterial myocardial revascularization: a prospective randomized study. Ann Thorac Surg 2003;76:778-782.
12. Salamon T, Michler RE, Knott KM, Brown DA. Off-Pump Coronary Artery Bypass Grafting Does not Decrease the Incidence of Atrial Fibrillation. Ann Thorac Surg 2003;75:505-507.
13. Puskas JD, Williams WH, Mahoney EM, Huber PR, Block PC, Duke PG, Staples JR, Glas KE, Marshall JJ, Leimbach ME, McCall SA, Petersen RJ, Bailey DE, Weintraub WS, Guyton RA. Off-pump vs conventional coronary artery bypass grafting: early and 1-year graft patency, cost, and quality-of-life outcomes: a randomized trial. JAMA 2004;291:1841-1849.
14. Nathoe H, van Dijk D, Jansen E, Suyker W, Diephuis J, van Boven WJ, De la Riviere AB, Borst C, Grobbee D, Buskens E, de Jaegere P. A comparison of ON-pump Coronary Bypass Surgery in Low risk patients. NEJM 2003;348:394-402.
15. Ascione R, Caputo M, Calori G, Lloyd CT, Underwood MJ, Angelini GD. Predictors of Atrial Fibrillation After Conventional and Beating Heart Coronary Surgery. Circulation 2000;102:1530-1535.