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Opportunities and challenges of clustering, crossing over, and using registry data in the PEPTIC trial
Paul J Young, Sean M Bagshaw, Andrew B Forbes, Alistair D Nichol, Stephen E Wright, Rinaldo Bellomo, Frank van Haren, Edward Litton, Steve A Webb
Crit Care Resusc 2020; 22 (2): 105-109
- Paul J Young 1, 2
- Sean M Bagshaw 3
- Andrew B Forbes 4
- Alistair D Nichol 5, 6, 7
- Stephen E Wright 8
- Rinaldo Bellomo 6, 9, 10
- Frank van Haren 11
- Edward Litton 12
- Steve A Webb 13
- Young PJ, Bagshaw SM, Forbes AB, et al. Effect of stress ulcer prophylaxis with proton pump inhibitors vs histamine-2 receptor blockers on in-hospital mortality among ICU patients receiving invasive mechanical ventilation: the PEPTIC randomized clinical trial. JAMA 2020; 323: 616-26.
- Young PJ, Bagshaw SM, Bellomo R, et al. The implications of the PEPTIC trial for clinical practice. Crit Care Resusc 2020; 22: 4-5.
- Bellomo R, Forbes A, Akram M, et al. Why we must cluster and cross over. Crit Care Resusc 2013; 15: 155-7
- Young PJ, Bagshaw SM, Forbes A, et al. A cluster randomised, crossover, registry-embedded clinical trial of proton pump inhibitors versus histamine-2 receptor blockers for ulcer prophylaxis therapy in the intensive care unit (PEPTIC study): study protocol. Crit Care Resusc 2018; 20: 182-9.
- Arnup SJ, McKenzie JE, Pilcher D, et al. Sample size calculations for cluster randomised crossover trials in Australian and New Zealand intensive care research. Crit Care Resusc 2018; 20: 117-23.
- Ridgeon EE, Bellomo R, Aberegg SK, et al. Effect sizes in ongoing randomized controlled critical care trials. Crit Care 2017; 21: 132.
- Grantham KL, Kasza J, Heritier S, et al. How many times should a cluster randomized crossover trial cross over? Stat Med 2019; 38: 5021-33.
- Sheikh K, Agyepong I, Jhalani M, et al. Learning health systems: an empowering agenda for low-income and middle-income countries. Lancet 2020; 395: 476-7.
- Rice TW, Kripalani S, Lindsell CJ. Proton pump inhibitors vs histamine-2 receptor blockers for stress ulcer prophylaxis in critically ill patients: issues of interpretability in pragmatic trials. JAMA 2020; 323: 611-3.
- Hernán MA, Hernández-Díaz S. Beyond the intention-to-treat in comparative effectiveness research. Clin Trials 2012; 9: 48-55.
- Vincent JL. Improved survival in critically ill patients: are large RCTs more useful than personalized medicine? No. Intensive Care Med 2016; 42: 1778-80.
- Harhay MO, Young PJ, Shankar-Hari M. Could stress ulcer prophylaxis increase mortality in high-acuity patients? Intensive Care Med 2020; doi: 10.1007/s00134-020-05959-x. [Epub ahead of print]
- Aybay C, Imir T, Okur H. The effect of omeprazole on human natural killer cell activity. Gen Pharmacol 1995; 26: 1413-8.
- Capodicasa E, De Bellis F, Pelli MA. Effect of lansoprazole on human leukocyte function. Immunopharmacol Immunotoxicol 1999; 21: 357-77
Novel aspects of the PEPTIC trial designThe PEPTIC trial design incorporated a number of novel aspects that have important implications for the future of ICU research (Table 1). The trial used existing registry data sources predominantly, which greatly reduced the amount of data that needed to be collected from individual patients. This cluster, crossover design 3
Remarkably, the trial afforded similar power to what would have been observed with an individual randomised controlled trial with the same number of participants. This occurred principally because there was little variability in the in-hospital mortality rates of each ICU over time. Such variability is labelled as “between periods within cluster” variability, and is what remains after taking the within-ICU differences between the two interventions — namely, ICU constant factors are cancelled out, and only factors that vary over the two observation periods remain. Minimising this variability is a key component of the power of a cluster crossover design, 5
Relevance to the design of future trialsEven despite these considerations, given the efficient recruitment rates we achieved, the implications of such statistical power for future trials of ubiquitous ICU interventions, such as fluid therapy, oxygen therapy, nutrition and blood pressure targets, are potentially profound. With no observed between-group difference, a 95% confidence interval in a trial similar to PEPTIC would be expected to exclude either an increase or decrease in mortality of one percentage point. Yet, with power to detect absolute mortality differences of 2%, small differences in mortality potentially attributable to idiosyncratic practice variations for ubiquitous therapies are now identifiable. 6
In the PEPTIC trial, while most of the key data were obtained from registries, some data were collected at an individual patient level. Using a combination of registry and individual patient data made it relatively easy to conduct the trial in multiple countries. Using registry data sources greatly reduced costs compared with collecting trial-specific data at an individual patient level. The trial was conducted with less than $500 000 of funding, a cost of under $20 per patient. Such comparatively low cost means that this trial technology might allow future large scale trials to be conducted in low income countries where registries are rapidly developing. 8
Trade-offs inherent in the PEPTIC trial designOne limitation of the PEPTIC trial, which has received attention in trial commentary, 9
Despite the degree of non-adherence to assigned therapy that occurred, there was substantial separation in the exposure to drug classes between treatment groups, and randomisation provides a sound basis for determining that observed differences in outcomes were attributable to these differences in drug exposure. One common criticism of large scale pragmatic trials is that they fail to account for the individual differences in patient characteristics that clinicians might use at the bedside to inform decision making. 11