1. Outcome Evidence After OPCAB Surgery

2. Overview of Presentation The Editors reviewed evidence related to the following outcomes after CABG surgery performed on- and off pump: Early Mortality Neurocognitive dysfunction Stroke Renal failure Economic comparison between on- and off-pump CABG

3. Prior to this review, the Editors discuss the Complexity of Generating Evidence and following the review, they provide their Conclusions to Date about OPCAB surgery.

4. Contents Complexity of Generating Evidence Early Mortality after CABG –Studies –Self-assessment of departmental performance Neurocognitive dysfunction after CABG Stroke after CABG Renal failure after CABG Economic comparison between on- and off-pump CABG Conclusions to date

5. Coronary Surgery Evolution Probably the most frequently performed surgical procedure worldwide. Since its inception (circa 1967), the quality of anesthesia, anastomosis type and format, myocardial protection, hospital management, medical follow-up, and training has continuously improved. Early and late quality of the surgical product can be represented in mathematical equations (e.g., hazard functions) relating to specific outcome events and intervals.

6. Challenging Established Practice On-Pump: Coronary anastomosis is performed using the extra-corporeal circulation to optimize the manipulation of the heart, the visibility of the coronary vessels, the stability of the anastomotic area, the quality of the anastomosis, and the protection of the heart. Yet, extra-corporeal circulation itself has potential adverse effects.

7. Off-Pump: The off-pump approach allows the anastomotic process, but the variability in approach has created variability in the quality of the surgical process. Imperfect technique has forced surgeons to exclude many patients from the off-pump approach and might have compromised the anastomotic quality. Yet, outcome when performed by off-pump experts is promising

8. Need for Standardization Just as occurred with on-pump coronary surgery, the generation of improved outcome after an off- pump approach in coronary surgery needs to be preceded by a standardization of the off-pump technique. This will allow complete manipulation of the heart, perfect visibility of the coronary vessels, stability of the anastomotic area, and protection of the heart.

9. Need for Standardization Only then can a comparable anastomotic quality be achieved with possible avoidance of some of the deleterious aspects of the extra-corporeal circulation.

10. Issue 1: Is there a fixed risk for CABG? There is a wide spectrum of risk –Low risk for large patient cohorts –Increasing risk for cohort subset, most frequently due to increased co-morbidity and severity of disease Outcome varies with risk Risk of the procedure Distribution of risk General Cohort Increasingly Complex Subgroup

11. Issue 2: How to score risk? Risks have been structured in “ languages of risk ” –(Example: STS risk, EuroSCORE, Parsonnet, etc.) These risk languages can be used to systematically compare on- and off-pump risk Standard Risk Languages (STS, EuroSCORE, Parsonnet) Off-pump approach On-pump approach

12. Issue 3: How certain is an observation? Every observation is associated with a degree of uncertainty around whether that observation in the sample population represents the true value in the total population. In the scientific literature, we usually accept a 5% level of uncertainty. This is expressed as a 95% Confidence Limit or Interval around the observation.

13. Issue 3: How certain is an observation? The degree of uncertainty, or size of the Confidence Interval, is inversely related to the total sample size of the population in which the observation was made. For example, if you derive a value of 0 from a sample of 20 subjects, you are 95% confident that the real value lies between – 17 and 17. In a sample of size of 200, you are 95% confident that the value lies between – 2 and 2.

14. Issue 4: How long should we observe? The interval for a peri-procedural risk should include the interval until the early hazard function stabilizes into a constant risk, independent of hospital discharge. Minimum Study Intervals Following CABG Outcome Study Interval Early Mortality 3 months Stroke 8 days Infarction 8 days Atrial fibrillation 6 days

15. Issue 4: How long should we observe? To balance “ early costs ” with “ late benefits ”, the ideal study interval is 5-10 years. The most costly procedure may be the most beneficial.

16. Issue 5: How large a sample size? Sample size is function of the –α type I error allowed –β type II error allowed –actual predicted risk –expected reduction of risk Predicted Risk 1%2%3%4%10% 10% risk reduction 197,7 50 97,9 24 64,6 49 48,0 11 18,06 4 50% risk reduction 6,2533,10 0 2,04 9 1,52 4 578

17. Issue 5: How large a sample size? For example, what is the estimated sample size of each arm of a clinical trial, if the tolerated α type I error is 0.05 and β type II error is 0.1? Predicted Risk 1%2%3%4%10% 10% risk reduction 197,7 50 97,9 24 64,6 49 48,0 11 18,06 4 50% risk reduction 6,2533,10 0 2,04 9 1,52 4 578

18. Issue 5: How large a sample size? Predicted Risk 1%2%3%4%10% 10% risk reduction 197,7 50 97,9 24 64,6 49 48,0 11 18,06 4 50% risk reduction 6,2533,10 0 2,04 9 1,52 4 578

19. Early Mortality After CABG: Studies Reference: Elimination of cardiopulmonary bypass improves early survival for multi- vessel coronary artery bypass patients. Magee M.J., Jablonski K.A., Stamou S.C., et al. Ann Thorac Surg 2002;73:1196-1203.

20. Early Mortality After CABG: Studies Message: A mathematical model, for hospital mortality after CABG, confirmed several known risk factors. In addition, cardio-pulmonary bypass was independently associated with an increased risk for mortality, with an odds ratio of 1.79 (95% CL 1.2-2.7). Of Interest: Multi-center (N=2), large cohort of OPCAB (N=1983), multi-vessel disease, multivariate logistic regression analysis

21. Early Mortality After CABG: Studies Limitations: Biased selection process of patients (somewhat corrected by propensity scoring), short and biased observation interval (hospital stay)

22. Early Mortality After CABG: Studies Reference: Off-pump coronary artery bypass is associated with improved risk-adjusted outcomes. Plomondon ME, Cleveland JC, Ludwig ST, et al. Ann Thorac Surg. 2001;72:114-119. Message: Centers report a 39% reduction of the STS-risk predicted 30-day mortality in a selected off-pump population. A reduction of only 10% of the STS-predicted 30-day mortality was identified in the on-pump population. Of Interest: Multi-center (N=9), reasonable cohort of OPCAB (N=680), 66% of OPCAB patients had 3-vessel disease, multivariate logistic regression analysis

23. Early Mortality After CABG: Studies Limitations: Biased selection process of patients (somewhat corrected for by an indicator variable), short and biased observation interval (30-day)

24. Early Mortality After CABG: Studies Reference: Off-pump coronary artery bypass grafting decreases risk-adjusted mortality and morbidity. Cleveland J.C., Shroyer L.W., Chen A.Y., et al. Ann Thorac Surg 2001;72:1282-1289. Message: Patients, after STS-risk adjustment, receiving off-pump procedures were less likely to die (adjusted odds- ratio 0.81, 95% CL 0.70-0.91). Of Interest: Multi-center (N=126), large cohort of OPCAB (N=11,717), STS-risk adjustment

25. Early Mortality After CABG: Studies Limitations: Biased selection process of patients, mostly single and two-vessel disease OPCAB patients, short and biased observation interval (30- day)

26. Early Mortality After CABG: Studies Reference: Outcomes experience with off- pump coronary artery bypass surgery in women. Brown P.P., Mack M.J., Simon, A.W., et al. Ann Thorac Surg 2002;74:2113-2119.

27. Early Mortality After CABG: Studies Message: After controlling for patient, procedure, medication, time period and site characteristics, the estimated odds ratio indicates that women undergoing on-pump CABG surgery experienced a 42% higher mortality rate than women undergoing OPCAB (P=0.023).

28. Early Mortality After CABG: Studies Of Interest: Focused on the female population, multi-center (N=78), large cohort of OPCAB (N=2631), multivariate logistic regression risk-adjustment

29. Early Mortality After CABG: Studies Limitations: Biased selection process of patients, short and biased observation interval (hospital stay)

30. Early Mortality After CABG: Studies Reference: Safety and efficacy of off-pump coronary artery bypass grafting. Arom K.V., Flavin T.F., Emery R.W., et al. Ann Thorac Surg 2000;69:704-710.

31. Early Mortality After CABG: Studies Message: No difference in operative mortality is identified after STS-risk predicted grouping in the low (0-2.6% predicted risk, N=216) and medium (2.6-10% predicted risk, N=95) risk group. A significant difference is observed in the high (10- 20% predicted risk, N=39) risk group, with a 73% reduction of the risk versus on-pump. Of Interest: STS-risk grouping in three categories.

32. Early Mortality After CABG: Studies Limitations: One center, limited cohort of patients (N=350), biased selection process of patients, only 1.6 anastomoses per patient in high risk OPCAB patients, short and biased observation interval (hospital stay). The late follow-up section at 1 year has only a 66% completeness of follow- up.

33. Early Mortality After CABG: Self-Assessment VLAD or CRAM Plot - Reference Reference: Monitoring the results of cardiac surgery by variable life-adjusted display. Lovegrove J., Valencia O., Treasure T., et al. Lancet 1997; 350(9085):1128-1130.

34. Early Mortality After CABG: Self-Assessment Message: VLAD provides a graphical display of risk-adjusted survival figures for individual surgeons or units over time and could be modified to monitor performance over a range of treatments and outcomes. Of Interest: Easy calculation, nicely readable, completed within a simple spreadsheet

35. Early Mortality After CABG: Self-Assessment Limitations: Minimum number of patients required, levels of uncertainty not calculated, limited to the quality and interval of the scoring system, does not give information of performance across the spectrum of risk

36. Early Mortality After CABG: Self-Assessment VLAD or CRAM Plot - Calculation Calculate the individual patient ’ s risk, using any scoring system. Express this in lives: 5% predicted risk is 0.05 “ Lives ”. If the patient survives: recalculate value as + 0.05 “ Lives ” If the patient dies in hospital: recalculate value as 1-risk = 1- 0.05 = -0.95 “ Lives ”

37. Early Mortality After CABG: Self-Assessment Cumulate the obtained values In the example patient 6 dies Patient 6 has a 10% predicted risk.

38. Early Mortality After CABG: Self-Assessment VLAD or CRAM Plot - Example

39. Early Mortality After CABG: Self-Assessment Reference: The challenge of departmental quality control in the reengineering towards off-pump coronary artery bypass grafting. Sergeant P., de Worm E., Meyns B., et al. Eur J Cardio-thorac Surg 2001;20:538-543. Message: The graphical depictions provide a cumulative insight in the performance across the spectrum of risk.

40. Early Mortality After CABG: Self-Assessment Of Interest: Easy calculation, nicely readable, completed within a simple spreadsheet Limitations: Provides cumulative insight across risk sectors, but not within individual risk sectors, due to large uncertainties related to low N in high risk categories. Limited to the quality and interval of the scoring system.

41. Early Mortality After CABG: Self-Assessment Performance Across the Spectrum of Risk - Example The cumulative deviation, reduction or increase, of the observed versus the predicted hospital mortality is calculated in a stepwise manner. At each step a 1% higher predicted risk category is added to the population. At the extreme right of the plot the total population is included.

42. Early Mortality After CABG: Self-Assessment Performance Across the Spectrum of Risk - Example Plot the cumulative observed mortality in % versus the cumulative predicted mortality in %. Start with the patients, having a predicted risk between 0 and 1, calculate their observed % mortality and plot versus the predicted mortality.

43. Early Mortality After CABG: Self-Assessment Add the patients with a risk between 1 and 2% and plot again. Plot again at each step of one % of predicted risk. Standard of scoring system

44. Neurocognitive Dysfunction After CABG Reference: Assessment of neurocognitive impairment after off-pump and on-pump techniques for coronary artery bypass graft surgery: prospective randomized controlled trial. Zamvar V., Williams D., Hall J. et al. BMJ 2002;325:1268-1273.

45. Neurocognitive Dysfunction After CABG Message: Patients were considered to have neurocognitive impairment if they showed a deterioration of 1 SD or more in two or more tests. One week postop, 27% in the off-pump and 66% in the on-pump had neurocognitive impairment (P=0.004). Ten weeks postop, 10% of the off- pump and 40% of the on-pump had neurocognitive impairment (P=0.017).

46. Neurocognitive Dysfunction After CABG Of Interest: Randomized trial, limited to triple vessel disease patients, nine standard tests. Limitations: Limited to the first 10 weeks

47. Neurocognitive Dysfunction After CABG Reference: Neuromonitoring and neurocognitive outcome in off-pump versus conventional coronary bypass operation. Diegeler A, Hirsch R., Schneider F., et al. Ann Thorac Surg 2000;69:1162-1166.

48. Neurocognitive Dysfunction After CABG Message: Postoperative CSS scoring was not different between on- and off-pump groups (P=0.2). Psychiatric assessment scoring between on- and off-pump group was significant (P=0.04). Syndrom Kurtz Test (cognition) scoring was highly significant (P=0.0001) in favor of off- pump. The median number of HITS in the on- pump group was 394 versus 11 in the off-pump (P<0.0001).

49. Neurocognitive Dysfunction After CABG Of Interest: Randomized trial, 3 standard neurocognitive tests, investigation using high intensive transient signal processing (HITS) Limitations: Limited to the day 1 and 7 after surgery

50. Neurocognitive Dysfunction After CABG Early Dysfunction Reference: Cognitive outcome after off-pump and on- pump coronary artery bypass graft surgery, a randomized trial. Van Dijk D., Jansen EW., Hijman R., et al. JAMA 2002;287:1405-1412. Message: At 3 months after surgery, cognitive decline occurred in 21% of the on-pump and 29% of the off-pump patients (P=.15). At 12 months, cognitive decline occurred in 31% of the off-pump patients and 34% after on-pump CABG.

51. Neurocognitive Dysfunction After CABG Of Interest: Randomized trial, 11 standard neurocognitive tests, testing at 3 and 12 months Limitations: Largely patients with single and two-vessel disease and low risk for cerebral dysfunction

52. Neurocognitive Dysfunction After CABG Early Dysfunction Reference: Serum S-100 protein release and neuropsychologic outcome during coronary revascularization on the beating heart: a prospective randomized study. Lloyd C.T., Ascione R., Underwood M.J., et al. J Thorac Cardiovasc Surg 2000;119:148- 154.:148-154 Message: There were no significant differences between on-pump and off-pump groups in the magnitude of change across all 7 dimensions of neurocognitive outcome at 12 weeks (P=.18).

53. Neurocognitive Dysfunction After CABG Of Interest: Randomized trial, 7 standard neurocognitive tests, testing at 12 weeks after surgery Limitations: Patients without known neurological abnormality

54. Stroke After CABG Early Stroke Reference: Stroke after conventional versus minimally invasive coronary artery bypass. Stamou S.C., Jablonski K.A., Pfister A.J. Ann Thorac Surg 2002;74:394-399. Message: After adjustment for preoperative risk- variability through propensity score matching, an odds-ratio for stroke of 1.8 is identified in the on- pump versus the off-pump group.

55. Stroke After CABG Of Interest: Propensity matching possible for 72% of the OPCAB patients, OPCAB N=1670 in each group, logistic regression analysis, interesting and very complete model building Limitations:

56. Stroke After CABG Early Stroke Reference: Off-pump coronary artery bypass grafting decreases risk-adjusted mortality and morbidity. Cleveland J.C., Shroyer L.W., Chen A.Y., et al. Ann Thorac Surg 2001;72:1282-1289. Message: Patients, with known cerebrovascular disease, receiving off-pump procedures were less likely to have a stroke (4.6% with conventional CABG and 2.5% in the off-pump group).

57. Stroke After CABG Of Interest: Multi-center (N=126), large cohort of OPCAB (N=1523 with known cerebrovascular disease), acceptable observation interval (30-day). Limitations: Biased selection process of patients, mostly single and two-vessel disease OPCAB patients, no additional risk-adjustment beyond cohort with CVD disease.

58. Stroke After CABG Early Stroke Message: Cardiopulmonary bypass was an independent risk factor for focal neurologic deficit, with an odds ratio of 3.82 (95% confidence interval, 1.4 to 10.3; p=0.005). Aortic manipulation did not significantly influence neurologic outcome in off-pump patients.

59. Stroke After CABG Of Interest: Multi-center (N=2), large cohort of OPCAB (N=1117), acceptable observation interval (hospital stay), multivariable logistic regression for risk-adjustment, adjustment in aortic manipulation. Limitations: Biased selection process of patients (corrected for by using propensity scoring)

60. Stroke After CABG Early Stroke Reference: Safety and efficacy of off-pump coronary artery bypass grafting. Arom K.V., Flavin T.F., Emery R.W., et al. Ann Thorac Surg 2000;69:704-710. Message: Several postoperative events are studied.

61. Stroke After CABG Of Interest: There were no significant differences in the number of patients who suffered from neurological deficits such as permanent stroke (2.0 % on-pump versus 1.4 % off-pump, p=0.42) and transient ischemic attack (0.9 % on-pump versus 0.3 % off-pump, p=0.35). Limitations: One center, limited cohort of patients (N=350), biased selection process of patients, no correction for stroke-risk variability in populations

62. Renal Failure After CABG Reference: Does off-pump coronary surgery reduce morbidity and mortality? Sabik J.F., Gillinov A.M., Blackstone E.H., et al. J Thorac Cardiovasc Surg 2002;124:698-707.

63. Renal Failure After CABG Message: Postoperative mortality, stroke, myocardial infarction and reoperation for bleeding was similar in on- versus off-pump patients. There was significantly more encephalopathy (P=0.02), sternal wound infection (P=0.04), red blood cell use (P=0.002) and renal failure requiring dialysis (P=0.03) in the on-pump patients.

64. Renal Failure After CABG Of Interest: Propensity-matched pairing of datasets, reasonable N OPCAB (406). Limitations: One center, selected patients in original datasets, fewer anastomoses in the off-pump population, even after matching.

65. Renal Failure After CABG Reference: On-pump versus off-pump coronary revascularization: evaluation of renal function. Ascione R., Lloyd C.T., Underwood M.J., et al. Ann Thorac Surg 1999;68:493-498.

66. Renal Failure After CABG Message: The creatinine clearance decreased more (P=0.0004) in the first postoperative 48 hours in the on-pump group. The urinary NAG (N-acetyl-β-glucosaminidase) activity values remained significantly higher (P=0.0272) and the albumin-to-creatinine ratio was worse (P=0.0083), in the postoperative 24-48 hours, in the on-pump versus the off-pump population.

67. Renal Failure After CABG Of Interest: Prospective randomized trial, refined analysis of renal function Limitations: One center, population at low risk for dialysis or severe renal failure.

68. Renal Failure After CABG Reference: Safety and efficacy of off-pump coronary artery bypass grafting. Arom K.V., Flavin T.F., Emery R.W., et al. Ann Thorac Surg 2000;69:704-710.

69. Renal Failure After CABG Message: The incidence of new renal failure was greater in on-pump patients overall, and in each risk group, but without any statistical significance, except in the high risk patients. low risk 4% on-pump 3% off-pump (P=0.49) medium risk10% on-pump 10% off-pump (P=0.79) high risk21% on-pump 3% off-pump (P=0.006)

70. Renal Failure After CABG Of Interest: STS-risk grouping in three categories Limitations: One center, limited cohort of patients (N=350) certainly in high risk, biased selection process of patients, only 1.6 anastomoses per patient in high risk OPCAB patients

71. Economic Comparison Between On- & Off-Pump CABG Reference: Economic outcome of off-pump coronary artery bypass surgery: a prospective randomized study. Ascione R.A., Lloyd C.T., Underwood M.J., et al. Ann Thorac Surg 1999;68:2237-2242.

72. Economic Comparison Between On- & Off-Pump CABG Message: Operative costs were significantly lower in the off-pump group. Bed occupancy and nursing costs account for the largest saving in the off-pump group. Blood loss and transfusion requirements were significantly less in the off- pump group. The costs for the management of postoperative complications were significantly higher in the on-pump group.

73. Economic Comparison Between On- & Off-Pump CABG Of Interest: Prospective randomized trial, detailed cost calculation Limitations: One center, limited cohort of patients in each arm (N=100), limited number of complications

74. Economic Comparison Between On- & Off-Pump CABG Message: Cardiopulmonary bypass was found, in multiple regression models, to be an independent predictor of both increased postoperative length of stay (p<0.0001) and increased hospital stay (P=0.0048).

75. Economic Comparison Between On- & Off-Pump CABG Of Interest: Consecutive series compared with a matched control group of 1000 patients, economic outcome linked to clinical data, multiple regression model for risk-adjustment Limitations: One center, limited number of complications

76. Economic Comparison Between On- & Off-Pump CABG Reference: Off-pump surgery decreases postoperative complications and resource utilization in the elderly. Boyd W.D., Desai N.D., Del Rizzo D.F., et al. Ann Thorac Surg 1999;68:1490-1493. Message: A savings of 14% of the hospital cost was obtained in the off-pump approach. The cost of the procedure was based on the fixed operating room and supply costs plus the variable hospital and ICU bed costs. Professional fees were not included.

77. Economic Comparison Between On- & Off-Pump CABG Of Interest: Consecutive series of elderly (age > 70 years), economic outcome linked to clinical data Limitations: One center, small series (N off- pump = 30, N on-pump = 60), no actual risk adjustment but both groups were found to be comparable before surgery

78. OPCAB Surgery: Conclusions to Date Coronary surgery off-pump is performed in hundreds of centers across the world. The evidence is structured in > 1000 peer- reviewed articles.

79. OPCAB Surgery: Conclusions to Date The selection of the patients is related to the experience of the center and to the degree of process re-engineering that has taken place. Coronary surgery off-pump reduces, after adjustment for variability in risk, early mortality and some major morbidity events: neurocognitive dysfunction, stroke and renal failure.

80. OPCAB Surgery: Conclusions to Date Off-pump coronary surgery allows and mandates a rigorous re-engineering of the surgical production process. Only then can there also be an improvement of the economic performance. Coronary surgery off-pump is here to stay.