Aspirin and clonidine in non-cardiac surgery: acute kidney injury substudy protocol of the Perioperative Ischaemic Evaluation (POISE) 2 randomised controlled trial

Abstract

IntroductionPerioperative Ischaemic Evaluation-2 (POISE-2) is an international 2×2 factorial randomised controlled trial of low-dose aspirin versus placebo and low-dose clonidine versus placebo in patients who undergo non-cardiac surgery. Perioperative aspirin (and possibly clonidine) may reduce the risk of postoperative acute kidney injury (AKI).Methods and analysisAfter receipt of grant funding, serial postoperative serum creatinine measurements began to be recorded in consecutive patients enrolled at substudy participating centres. With respect to the study schedule, the last of over 6500 substudy patients from 82 centres in 21 countries were randomised in December 2013. The authors will use logistic regression to estimate the adjusted OR of AKI following surgery (compared with the preoperative serum creatinine value, a postoperative increase ≥26.5 μmol/L in the 2 days following surgery or an increase of ≥50% in the 7 days following surgery) comparing each intervention to placebo, and will report the adjusted relative risk reduction. Alternate definitions of AKI will also be considered, as will the outcome of AKI in subgroups defined by the presence of preoperative chronic kidney disease and preoperative chronic aspirin use. At the time of randomisation, a subpopulation agreed to a single measurement of serum creatinine between 3 and 12 months after surgery, and the authors will examine intervention effects on this outcome.Ethics and disseminationThe authors were competitively awarded a grant from the Canadian Institutes of Health Research for this POISE-2 AKI substudy. Ethics approval was obtained for additional kidney data collection in consecutive patients enrolled at participating centres, which first began for patients enrolled after January 2011. In patients who provided consent, the remaining longer term serum creatinine data will be collected throughout 2014. The results of this study will be reported no later than 2015.Clinical Trial Registration NumberNCT01082874.

Perioperative Aspirin and Clonidine and Risk of Acute Kidney Injury

“…The prespecified protocol and analysis plan for this POISE-2 acute kidney injury substudy was published. 25 We justify minor deviations from the published protocol and the current report in eTable 3 in the Supplement. Regional ethics boards approved the kidney data collection in centers that agreed to study participation, and all patients provided written informed consent.…”

“…POISE-2 used an efficient kidney data collection schedule as done in other large multicenter randomized trials. 43 A key limitation of our protocol (as previously reported 25 ) is our reliance on the serum creatinine concentration collected during routine care as the sole measure of kidney function. It would have been preferable to have multiple baseline measures of serum creatinine and other assessments of kidney function, and additional follow-up measures during the perioperative period.…”

“…The secondary outcomes were the stage of acute kidney injury as defined in recent guidelines and our prespecified protocol. 25,27 The 2 separate outcomes of severe acute kidney injury were receipt of dialysis within 30 days of surgery and stage 3 acute kidney injury. The following criteria were used to define stage 3 acute kidney injury: (1) a postoperative percentage increase in serum creatinine concentration of 200% or greater from the preoperative concentration within 7 days of surgery, (2) an increase in postoperative serum creatinine concentration of at least 0.3 mg/dL or greater (≥26.5 μmol/L) to an absolute value of 4.0 mg/dL or greater (≥353.6 μmol/L) within 7 days of surgery, or (3) receipt of dialysis within 30 days of surgery.…”

“…Results in the aspirin trial were assessed in following 2 predefined subgroups (through use of an interaction term in each model as described elsewhere 25 ): (1) the presence or absence of preoperative chronic kidney disease as defined by a prerandomization estimated GFR category of 60 mL/min per 1.73 m 2 or less (we hypothesized a greater RR reduction in patients with preoperative chronic kidney disease 33 ), and (2) the presence or absence of a history of long-term aspirin use prior to randomization (we anticipated a greater RR reduction in patients with a history of long-term aspirin use given the potential for greater susceptibility to thrombosis after aspirin discontinuation 34 ). Results in the clonidine trial were assessed in the following predefined subgroup: the presence or absence of preoperative chronic kidney disease, with no prespecified hypothesis.…”

“…We conducted 4 other prespecified analyses. 25 First, we assessed adherence to the study drugs. Second, we assessed the possibility of differential ascertainment of acute kidney injury between our study groups.…”