We agree with Dr. Raja that more trials of the same type of patients prevalent in this meta-analysis to continue the chase after very small potential differences in death, stroke, or myocardial infarction are likely to be futile. As demonstrated in table 7 of our meta-analysis,1the absolute differences in the outcomes of death, stroke, and myocardial infarction are small (0.2, 0.6, and 0.8%), with narrow confidence intervals. As a result, unrealistic sample sizes would be required to show statistical significant differences, and even if differences were found, the clinical relevance of very small difference might be questioned. Examination of the confidence intervals reveals that clinically relevant differences have been largely ruled out in the patient populations studied. However, this futility in further research should not be considered to extend to other understudied outcomes. Even in this generally younger and lower-risk patient population, there has been inadequate study of the long-term durability of the grafts (i.e. , need for reintervention, myocardial infarction, and survival at 1 yr and beyond). In addition, the need for further study in higher-risk groups should not be understated, because few high-risk patients have been included in randomized trials.1The wide confidence intervals around most endpoints reported at 1–3 yr in our meta-analysis suggest that the difference in off-pump and on-pump surgery may be harmful, no different, or beneficial. Until randomized studies adequately explore this, equipoise will remain. Formal exploration of the expected payoff of further research in this area could be quantified through Bayesian estimation of the “expected value of perfect information.”2This calculation would be laudable to best focus our limited research dollars and time.
We agree that meta-analysis of individual patient data would be valuable to provide further information, especially to determine whether certain patient risk factors at baseline are associated with differences in outcomes with off-pump versus on-pump coronary artery bypass surgery. It is hoped that clinical trial investigators would share their individual patient-level data with meta-analysts attempting the formidable task of individual patient data to maximize the information we can glean from existing randomized trials. Meta-analysts conducting studies of individual patient data would also benefit from further trials of outcomes and patient groups not currently adequately represented in existing randomized trials (long-term outcomes, high-risk subgroups). As suggested by Lau et al. ,3we plan to prospectively update our meta-analysis with the release of each randomized trial of off-pump versus on-pump coronary bypass surgery in the hopes that, over time, further unanswered questions will be addressed.
We thank Landoni et al. for putting further perspective on the very important issue of patients converted from off-pump coronary artery bypass to cardiopulmonary bypass. We agree that the reporting of conversions was far from complete in the randomized trials, and this warrants further investigation, perhaps by contacting the authors. Future investigators should take care to report conversions and appropriately analyze these patients by intention to treat. Most importantly, the reasons for and the outcomes of converted patients should be reported separately so that future systematic reviews can gather sufficient power to analyze the magnitude and breadth of risks of converted patients. Because outcomes were not reported explicitly for converted patients in any of the randomized trials, we performed sensitivity analyses by worst-case scenario for those trials that had reported conversions.1The conclusions were generally robust even during worst-case scenarios, except for the endpoints of mortality, stroke, and myocardial infarction. This is concerning; previous retrospective analyses have suggested that patients converted from off-pump to on-pump surgery have increased risk of mortality and complications compared with nonconverted patients.4Because conversion cannot be predicted at the time of deciding surgery technique but may be more likely in patients who have higher baseline risk, the tantamount question is whether converted patients do worse than they would have had they undergone planned conventional coronary artery bypass surgery from the outset. This underscores the importance of analysis by intention to treat, because the risk of conversion should be attributed to the overall risk of off-pump bypass surgery.
*London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada. firstname.lastname@example.org