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H. Takagi et al. / Interactive CardioVascular and Thoracic Surgery
Figure 1: Meta-analysis of repeat revascularization rates following off-pump vs on-pump CABG using the Mantel-Haenzel method in the fixed-effects model. CI: confidence interval.
weight or larger trials), however, was able to demonstrate a statistically significant benefit to on-pump CABG, likely due to a relatively small number of events of interest. In a meta-analysis [4] of 41 randomized trials, significantly fewer distal anastomoses were performed after off-pump surgery (weighted mean difference, –0.29; 95% CI, –0.46 to –0.13). In addition, our previous meta-analysis [6] of six randomized trials demonstrated a significant increase in overall graft occlusion (risk ratio [RR], 1.27; 95% CI, 1.03–1.56; P = 0.0234; risk difference [RD], 3.0%; 95% CI, 0.6–5.4%; P = 0.0129), especially in venous graft occlusion (RR, 1.28; 95% CI, 1.06–1.54; P = 0.0094; RD, 4.0%; 95% CI, 0.2–7.8%; P = 0.0396), with off-pump relative to on-pump CABG. Fewer bypass grafts [1] (or distal anastomoses [2–4]) and lower graft patency [3, 5, 6] in off-pump than on-pump CABG could explain higher repeat revascularization rates following off-pump CABG demonstrated in the present meta-analysis. Further, higher repeat revascularization rates are probably due to increased recurrent angina and may impair quality of life. Because no criteria for indication of repeat revascularization were predefined in all the included trials, further analyses should be required.
SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. Conflict of interest: none declared.
REFERENCES [1] Wijeysundera DN, Beattie WS, Djaiani G, Rao V, Borger MA, Karkouti K et al. Off-pump coronary artery surgery for reducing mortality and morbidity: meta-analysis of randomized and observational studies. J Am Coll Cardiol 2005;46:872–82. [2] Cheng DC, Bainbridge D, Martin JE, Novick RJ; Evidence-Based Perioperative Clinical Outcomes Research Group. Does off-pump coronary artery bypass reduce mortality, morbidity, and resource utilization when compared with conventional coronary artery bypass? A meta-analysis of randomized trials. Anesthesiology 2005;102:188–203. [3] Lim E, Drain A, Davies W, Edmonds L, Rosengard BR. A systematic review of randomized trials comparing revascularization rate and graft patency of off-pump and conventional coronary surgery. J Thorac Cardiovasc Surg 2006;132:1409–13.
[4] Møller CH, Penninga L, Wetterslev J, Steinbrüchel DA, Gluud C. Clinical outcomes in randomized trials of off- vs on-pump coronary artery bypass surgery: systematic review with meta-analyses and trial sequential analyses. Eur Heart J 2008;29:2601–16. [5] Parolari A, Alamanni F, Polvani G, Agrifoglio M, Chen YB, Kassem S et al. Meta-analysis of randomized trials comparing off-pump with onpump coronary artery bypass graft patency. Ann Thorac Surg 2005;80: 2121–5. [6] Takagi H, Tanabashi T, Kawai N, Kato T, Umemoto T. Off-pump coronary artery bypass sacrifices graft patency: meta-analysis of randomized trials. J Thorac Cardiovasc Surg 2007;133:e2–3. [7] Feng ZZ, Shi J, Zhao XW, Xu ZF. Meta-analysis of on-pump and off-pump coronary arterial revascularization. Ann Thorac Surg 2009;87:757–65.
eComment. Stroke rate after surgical myocardial revascularization Author: Jamil Hajj-Chahine Department of Cardio-Thoracic surgery, University Hospital of Poitiers, Poitiers, France doi: 10.1093/icvts/ivt375 © The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. I read with great interest the paper by Takagi et al. in which they tried to answer an important question: Does off-pump coronary artery bypass grafting (CABG) increase the risk of repeat coronary revascularization when compared with on-pump CABG? [1]. Data from this meta-analysis confirm that the decreased benefits from on-pump CABG is attributable to the higher incidence of fewer bypass grafts and lower graft patency yielding incomplete and repeat revascularization with this technique. In this valuable meta-analysis, I think that there is yet another topic to be discussed. Proponents of off-pump CABG have claimed that this technique limits the rate of postoperative stroke by avoiding aortic cannulation/decannulation, micro-gaseous and small particulate emboli from the pump circuit and aortic cross-clamping. Offpump technique does not totally eliminate the necessity for aortic clamping. However, in beating heart operations with no-touch aorta technique, cerebral embolic load is completely reduced by avoiding aortic cross-clamping. Yet, there is still the hazard for neurological insult related to periods of hypotension during manipulation of the heart. Three large clinical trials have been conducted recently comparing outcomes in cardiac surgery patients using off-pump and on-pump strategy. The Randomized On/Off Bypass (ROOBY) trial [2] is a single-blinded randomized trial involving 2203 patients in 18 Veterans Affairs medical centres. There was no significant difference between off-pump and on-pump CABG in the rate of the 30-day stroke (1.3% and 0.7%, respectively; P = 0.28). Recently, the results of the Coronary Artery Bypass Surgery Off or On Pump Revascularization Study (CORONARY) [3] has been published. This prospective study involved 4752 patients randomized to either on- or off-pump CABG in 79 centres and 19 countries. The use of off-pump CABG, as compared with on-pump CABG, did not reduce the rate of non-fatal stroke (1.0% vs 1.1%, respectively; P = 0.89) at 30 days or at one year (1.5% vs 1.7%, respectively; P = 0.24). Diegeler et al. reported their results from the German Off-Pump Coronary Artery
H. Takagi et al. / Interactive CardioVascular and Thoracic Surgery Bypass Grafts in Elderly Patients (GOPCADE) trial [4]. This trial attempts to define the potential benefits of OPCAB in an elderly group (aged more than 75 years) with multiple comorbidities. The study involved 2539 patients from 12 centres. There was no significant difference between patients who underwent off-pump surgery and those who underwent on-pump surgery in terms of rate of stroke (2.2% vs 2.7%, respectively; P = 0.47) at 30 days or at one year after randomization (3.5% vs 4.4%, respectively; P = 0.26). Of note, the higher stroke rate in the last trial is attributed to the increased operative risk of the study population. None of these large randomized trial could demonstrate any superiority of offpump CABG over on-pump CABG in terms of reduced risk of CABG-related stroke. Nevertheless, data regarding quality of the proximal aorta and cross-clamping technique of the aorta are lacking in these trials. Preoperative and intraoperative screening can identify extensive atherosclerosis of the ascending aorta. Selective use of offpump no-touch aorta CABG in this group of high-risk patients can prevent adverse neurologic injury. Conflict of interest: none declared References [1] Takagi H, Mizuno Y, Niwa M, Goto SN, Umemoto T; for the ALICE (AllLiterature Investigation of Cardiovascular Evidence) Group. A meta-analysis of randomized trials for repeat revascularization following off-pump versus onpump coronary artery bypass grafting. Interact CardioVasc Thorac Surg 2013;17:878–81. [2] Shroyer AL, Grover FL, Hattler B, Collins JF, McDonald GO, Kozora E et al.; Veterans Affairs Randomized On/Off Bypass (ROOBY) Study Group. On-pump versus off-pump coronary-artery bypass surgery. N Engl J Med 2009;361:1827– 37. [3] Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E et al.; CORONARY Investigators. Effects of off-pump and on-pump coronary artery bypass grafting at 1 year. N Engl J Med 2013;368:1179–88. [4] Diegeler A, Borgermann J, Kappert U, Breuer M, Boning A, Ursulescu A et al.; GOPCABE Study Group. Off-pump versus on-pump coronary artery bypass grafting in elderly patients. N Engl J Med 2013;368:1189–98.
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elective or emergency surgery)? Differences in the design and patient population exist in the studies. Did the patients have a similar distribution of coronary artery disease in both arms in the studies? What about the grafts that were used? Did all surgeons use similar grafts (left mammary artery, right mammary artery, radial artery, composite arterial grafts or vein grafts) and did they use the same graft for the same target lesion? Was the number of anastomoses planned in the two groups similar? Did the patients receive the same number of grafts during off-pump and on-pump? Fewer anastomoses were performed to the lateral territory of the heart during off-pump so there is incomplete revascularization. Finally, fewer grafts were performed in the off-pump group in most trials. The technical details were left to the discretion of the operating surgeon so there is a great variability. Doing coronary anastomoses on the beating heart is more challenging and may result in poorer quality and in an increased risk of early occlusion. Is expressing count data (number of grafts) ideal as a mean value owing to the necessary distributional assumption? Was the surgical experience of surgeons who participated in the studies at the same level? Another important issue that is relevant with graft patency is the anticoagulation agents that were used after on-pump and off-pump. Did the patients receive the same anticoagulation agents? Lower anticoagulation might explain the difference in patency rates in the off-pump group. There were no predefined criteria for indication of repeat revascularization which is very important. We would also like to define our expectations from a meta-analysis. The detection of a true treatment effect is useful for clinical use but the decision what to do requires the magnitude of the treatment effect. An advantage of the meta-analysis is the ability to reach a more accurate treatment effect with reduced uncertainty (tight confidence intervals) [2]. We can see that the confidence intervals in some trials in this meta-analysis are not tight so there is uncertainty. Meta-analysts should focus on a group of biases that are clustered under the term ’significance-chasing biases’; these include publication bias, selective outcome reporting bias, selective analysis reporting bias and fabrication bias [3]. A number of tests have been developed to detect and exclude publication bias, but these tests may be affected by any type of significance-chasing bias and may also be affected by the diversity across the study-specific effects [4]. A careful meta-analysis protocol is essential for a more accurate and focused analysis (’The PRISMA statement’ [5]). Off-pump is a technically challenging surgical procedure and remains a very important tool for specific groups of patients. Conflict of interest: none declared
Authors: Christos Tourmousoglou and Spiros Lalos Department of Cardiothoracic Surgery, Hippokratio General Hospital, Athens, Greece doi: 10.1093/icvts/ivt445 © The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. We read with great interest the paper by Tagaki et al. in which the authors concluded that off-pump coronary artery bypass grafting (CABG) may increase repeat revascularization by 38% over on-pump CABG. We would like to mention some important issues about this meta-analysis and about what we expect from a metaanalysis. Were the inclusion criteria similar in the studies of this meta-analysis? Were the participants at the same or higher surgical risk, as evidenced by: 1) the selection criteria and 2) the baseline characteristics (e.g. age of patients, ejection fraction and
References [1] Takagi H, Mizuno Y, Niwa M, Goto SN, Umemoto T; for the ALICE (AllLiterature Investigation of Cardiovascular Evidence) Group. A meta-analysis of randomized trials for repeat revascularization following off-pump versus onpump coronary artery bypass grafting. Interact CardioVasc Thorac Surg 2013;17:878–81. [2] Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997;127:820–6. [3] Dwan K, Altman DG, Arnaiz JA, Bloom J, Chan AW, Cronin E et al. Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS One 2008;3:e3081. [4] Ioannidis JPA. Meta-research: the art of getting it wrong. Research Synthesis Methods 2010;1:169–184. [5] Liberati A, Altman D, Tetzlaff J, Mulrow C, Gotzsche P, Ioannidis JPA et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009;6:e1000100.
BRIEF COMMUNICATION
e-Comment: Conducting meta-analyses of off-pump versus on-pump coronary artery bypass surgery: where we stand
H. Takagi et al. / Interactive CardioVascular and Thoracic Surgery
Figure 1: Meta-analysis of repeat revascularization rates following off-pump vs on-pump CABG using the Mantel-Haenzel method in the fixed-effects model. CI: confidence interval.
weight or larger trials), however, was able to demonstrate a statistically significant benefit to on-pump CABG, likely due to a relatively small number of events of interest. In a meta-analysis [4] of 41 randomized trials, significantly fewer distal anastomoses were performed after off-pump surgery (weighted mean difference, –0.29; 95% CI, –0.46 to –0.13). In addition, our previous meta-analysis [6] of six randomized trials demonstrated a significant increase in overall graft occlusion (risk ratio [RR], 1.27; 95% CI, 1.03–1.56; P = 0.0234; risk difference [RD], 3.0%; 95% CI, 0.6–5.4%; P = 0.0129), especially in venous graft occlusion (RR, 1.28; 95% CI, 1.06–1.54; P = 0.0094; RD, 4.0%; 95% CI, 0.2–7.8%; P = 0.0396), with off-pump relative to on-pump CABG. Fewer bypass grafts [1] (or distal anastomoses [2–4]) and lower graft patency [3, 5, 6] in off-pump than on-pump CABG could explain higher repeat revascularization rates following off-pump CABG demonstrated in the present meta-analysis. Further, higher repeat revascularization rates are probably due to increased recurrent angina and may impair quality of life. Because no criteria for indication of repeat revascularization were predefined in all the included trials, further analyses should be required.
SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. Conflict of interest: none declared.
REFERENCES [1] Wijeysundera DN, Beattie WS, Djaiani G, Rao V, Borger MA, Karkouti K et al. Off-pump coronary artery surgery for reducing mortality and morbidity: meta-analysis of randomized and observational studies. J Am Coll Cardiol 2005;46:872–82. [2] Cheng DC, Bainbridge D, Martin JE, Novick RJ; Evidence-Based Perioperative Clinical Outcomes Research Group. Does off-pump coronary artery bypass reduce mortality, morbidity, and resource utilization when compared with conventional coronary artery bypass? A meta-analysis of randomized trials. Anesthesiology 2005;102:188–203. [3] Lim E, Drain A, Davies W, Edmonds L, Rosengard BR. A systematic review of randomized trials comparing revascularization rate and graft patency of off-pump and conventional coronary surgery. J Thorac Cardiovasc Surg 2006;132:1409–13.
[4] Møller CH, Penninga L, Wetterslev J, Steinbrüchel DA, Gluud C. Clinical outcomes in randomized trials of off- vs on-pump coronary artery bypass surgery: systematic review with meta-analyses and trial sequential analyses. Eur Heart J 2008;29:2601–16. [5] Parolari A, Alamanni F, Polvani G, Agrifoglio M, Chen YB, Kassem S et al. Meta-analysis of randomized trials comparing off-pump with onpump coronary artery bypass graft patency. Ann Thorac Surg 2005;80: 2121–5. [6] Takagi H, Tanabashi T, Kawai N, Kato T, Umemoto T. Off-pump coronary artery bypass sacrifices graft patency: meta-analysis of randomized trials. J Thorac Cardiovasc Surg 2007;133:e2–3. [7] Feng ZZ, Shi J, Zhao XW, Xu ZF. Meta-analysis of on-pump and off-pump coronary arterial revascularization. Ann Thorac Surg 2009;87:757–65.
eComment. Stroke rate after surgical myocardial revascularization Author: Jamil Hajj-Chahine Department of Cardio-Thoracic surgery, University Hospital of Poitiers, Poitiers, France doi: 10.1093/icvts/ivt375 © The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. I read with great interest the paper by Takagi et al. in which they tried to answer an important question: Does off-pump coronary artery bypass grafting (CABG) increase the risk of repeat coronary revascularization when compared with on-pump CABG? [1]. Data from this meta-analysis confirm that the decreased benefits from on-pump CABG is attributable to the higher incidence of fewer bypass grafts and lower graft patency yielding incomplete and repeat revascularization with this technique. In this valuable meta-analysis, I think that there is yet another topic to be discussed. Proponents of off-pump CABG have claimed that this technique limits the rate of postoperative stroke by avoiding aortic cannulation/decannulation, micro-gaseous and small particulate emboli from the pump circuit and aortic cross-clamping. Offpump technique does not totally eliminate the necessity for aortic clamping. However, in beating heart operations with no-touch aorta technique, cerebral embolic load is completely reduced by avoiding aortic cross-clamping. Yet, there is still the hazard for neurological insult related to periods of hypotension during manipulation of the heart. Three large clinical trials have been conducted recently comparing outcomes in cardiac surgery patients using off-pump and on-pump strategy. The Randomized On/Off Bypass (ROOBY) trial [2] is a single-blinded randomized trial involving 2203 patients in 18 Veterans Affairs medical centres. There was no significant difference between off-pump and on-pump CABG in the rate of the 30-day stroke (1.3% and 0.7%, respectively; P = 0.28). Recently, the results of the Coronary Artery Bypass Surgery Off or On Pump Revascularization Study (CORONARY) [3] has been published. This prospective study involved 4752 patients randomized to either on- or off-pump CABG in 79 centres and 19 countries. The use of off-pump CABG, as compared with on-pump CABG, did not reduce the rate of non-fatal stroke (1.0% vs 1.1%, respectively; P = 0.89) at 30 days or at one year (1.5% vs 1.7%, respectively; P = 0.24). Diegeler et al. reported their results from the German Off-Pump Coronary Artery
H. Takagi et al. / Interactive CardioVascular and Thoracic Surgery Bypass Grafts in Elderly Patients (GOPCADE) trial [4]. This trial attempts to define the potential benefits of OPCAB in an elderly group (aged more than 75 years) with multiple comorbidities. The study involved 2539 patients from 12 centres. There was no significant difference between patients who underwent off-pump surgery and those who underwent on-pump surgery in terms of rate of stroke (2.2% vs 2.7%, respectively; P = 0.47) at 30 days or at one year after randomization (3.5% vs 4.4%, respectively; P = 0.26). Of note, the higher stroke rate in the last trial is attributed to the increased operative risk of the study population. None of these large randomized trial could demonstrate any superiority of offpump CABG over on-pump CABG in terms of reduced risk of CABG-related stroke. Nevertheless, data regarding quality of the proximal aorta and cross-clamping technique of the aorta are lacking in these trials. Preoperative and intraoperative screening can identify extensive atherosclerosis of the ascending aorta. Selective use of offpump no-touch aorta CABG in this group of high-risk patients can prevent adverse neurologic injury. Conflict of interest: none declared References [1] Takagi H, Mizuno Y, Niwa M, Goto SN, Umemoto T; for the ALICE (AllLiterature Investigation of Cardiovascular Evidence) Group. A meta-analysis of randomized trials for repeat revascularization following off-pump versus onpump coronary artery bypass grafting. Interact CardioVasc Thorac Surg 2013;17:878–81. [2] Shroyer AL, Grover FL, Hattler B, Collins JF, McDonald GO, Kozora E et al.; Veterans Affairs Randomized On/Off Bypass (ROOBY) Study Group. On-pump versus off-pump coronary-artery bypass surgery. N Engl J Med 2009;361:1827– 37. [3] Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E et al.; CORONARY Investigators. Effects of off-pump and on-pump coronary artery bypass grafting at 1 year. N Engl J Med 2013;368:1179–88. [4] Diegeler A, Borgermann J, Kappert U, Breuer M, Boning A, Ursulescu A et al.; GOPCABE Study Group. Off-pump versus on-pump coronary artery bypass grafting in elderly patients. N Engl J Med 2013;368:1189–98.
881
elective or emergency surgery)? Differences in the design and patient population exist in the studies. Did the patients have a similar distribution of coronary artery disease in both arms in the studies? What about the grafts that were used? Did all surgeons use similar grafts (left mammary artery, right mammary artery, radial artery, composite arterial grafts or vein grafts) and did they use the same graft for the same target lesion? Was the number of anastomoses planned in the two groups similar? Did the patients receive the same number of grafts during off-pump and on-pump? Fewer anastomoses were performed to the lateral territory of the heart during off-pump so there is incomplete revascularization. Finally, fewer grafts were performed in the off-pump group in most trials. The technical details were left to the discretion of the operating surgeon so there is a great variability. Doing coronary anastomoses on the beating heart is more challenging and may result in poorer quality and in an increased risk of early occlusion. Is expressing count data (number of grafts) ideal as a mean value owing to the necessary distributional assumption? Was the surgical experience of surgeons who participated in the studies at the same level? Another important issue that is relevant with graft patency is the anticoagulation agents that were used after on-pump and off-pump. Did the patients receive the same anticoagulation agents? Lower anticoagulation might explain the difference in patency rates in the off-pump group. There were no predefined criteria for indication of repeat revascularization which is very important. We would also like to define our expectations from a meta-analysis. The detection of a true treatment effect is useful for clinical use but the decision what to do requires the magnitude of the treatment effect. An advantage of the meta-analysis is the ability to reach a more accurate treatment effect with reduced uncertainty (tight confidence intervals) [2]. We can see that the confidence intervals in some trials in this meta-analysis are not tight so there is uncertainty. Meta-analysts should focus on a group of biases that are clustered under the term ’significance-chasing biases’; these include publication bias, selective outcome reporting bias, selective analysis reporting bias and fabrication bias [3]. A number of tests have been developed to detect and exclude publication bias, but these tests may be affected by any type of significance-chasing bias and may also be affected by the diversity across the study-specific effects [4]. A careful meta-analysis protocol is essential for a more accurate and focused analysis (’The PRISMA statement’ [5]). Off-pump is a technically challenging surgical procedure and remains a very important tool for specific groups of patients. Conflict of interest: none declared
Authors: Christos Tourmousoglou and Spiros Lalos Department of Cardiothoracic Surgery, Hippokratio General Hospital, Athens, Greece doi: 10.1093/icvts/ivt445 © The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. We read with great interest the paper by Tagaki et al. in which the authors concluded that off-pump coronary artery bypass grafting (CABG) may increase repeat revascularization by 38% over on-pump CABG. We would like to mention some important issues about this meta-analysis and about what we expect from a metaanalysis. Were the inclusion criteria similar in the studies of this meta-analysis? Were the participants at the same or higher surgical risk, as evidenced by: 1) the selection criteria and 2) the baseline characteristics (e.g. age of patients, ejection fraction and
References [1] Takagi H, Mizuno Y, Niwa M, Goto SN, Umemoto T; for the ALICE (AllLiterature Investigation of Cardiovascular Evidence) Group. A meta-analysis of randomized trials for repeat revascularization following off-pump versus onpump coronary artery bypass grafting. Interact CardioVasc Thorac Surg 2013;17:878–81. [2] Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997;127:820–6. [3] Dwan K, Altman DG, Arnaiz JA, Bloom J, Chan AW, Cronin E et al. Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS One 2008;3:e3081. [4] Ioannidis JPA. Meta-research: the art of getting it wrong. Research Synthesis Methods 2010;1:169–184. [5] Liberati A, Altman D, Tetzlaff J, Mulrow C, Gotzsche P, Ioannidis JPA et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009;6:e1000100.
BRIEF COMMUNICATION
e-Comment: Conducting meta-analyses of off-pump versus on-pump coronary artery bypass surgery: where we stand
