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

Introduction: Perioperative 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 analysis: After 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 dissemination: The 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.Amit X Garg ... Tom Painter ... et al. on behalf of the POISE-2 Investigator

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3) : a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Altres ajuts: Canadian Institutes of Health Research (CIHR, FDN-143302); General Research Fund (14104419), Research Grant Council, Hong Kong SAR, China; National Health and Medical Research Council, Funding Schemes (NHMRC Project Grant 1162362), Australia; McMaster University Department of Medicine Career Research Award and a Physicians' Services Incorporated (PSI) Foundation Mid-Career Clinical Research Award.Background: For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods: The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion: Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. Trial registration: ClinicalTrials.gov NCT03505723. Registered on 23 April 2018

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Background For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. Trial registration ClinicalTrials.gov NCT03505723. Registered on 23 April 2018

Neuraxial block and postoperative epidural analgesia:Effects on outcomes in the POISE-2 trial

Background: We assessed associations between intraoperative neuraxial block and postoperative epidural analgesia, and a composite primary outcome of death or non-fatalmyocardial infarction, at 30 days post-randomization in POISE-2 Trial subjects. Methods: 10 010 high-risk noncardiac surgical patients were randomized aspirin or placebo and clonidine or placebo. Neuraxial block was defined as intraoperative spinal anaesthesia, or thoracic or lumbar epidural anaesthesia. Postoperative epidural analgesia was defined as postoperative epidural local anaesthetic and/or opioid administration. We used logistic regression with weighting using estimated propensity scores. Results: Neuraxial block was not associated with the primary outcome [7.5% vs 6.5%; odds ratio (OR), 0.89; 95% CI (confidence interval), 0.73-1.08; P=0.24], death (1.0% vs 1.4%; OR, 0.84; 95% CI, 0.53-1.35; P=0.48), myocardial infarction (6.9% vs 5.5%; OR, 0.91; 95% CI, 0.74-1.12; P=0.36) or stroke (0.3% vs 0.4%; OR, 1.05; 95% CI, 0.44-2.49; P=0.91). Neuraxial block was associated with less clinically important hypotension (39% vs 46%; OR, 0.90; 95% CI, 0.81-1.00; P=0.04). Postoperative epidural analgesia was not associated with the primary outcome (11.8% vs 6.2%; OR, 1.48; 95% CI, 0.89-2.48; P=0.13), death (1.3% vs 0.8%; OR, 0.84; 95% CI, 0.35-1.99; P=0.68], myocardial infarction (11.0% vs 5.7%; OR, 1.53; 95% CI, 0.90-2.61; P=0.11], stroke (0.4% vs 0.4%; OR, 0.65; 95% CI, 0.18-2.32; P=0.50] or clinically important hypotension (63% vs 36%; OR, 1.40; 95% CI, 0.95-2.09; P=0.09). Conclusions: Neuraxial block and postoperative epidural analgesia were not associated with adverse cardiovascular outcomes among POISE-2 subjects

Perioperative aspirin and clonidine and risk of acute kidney injury: a randomized clinical trial

Original Investigation ResearchIMPORTANCE: Acute kidney injury, a common complication of surgery, is associated with poor outcomes and high health care costs. Some studies suggest aspirin or clonidine administered during the perioperative period reduces the risk of acute kidney injury; however, these effects are uncertain and each intervention has the potential for harm. OBJECTIVE: To determine whether aspirin compared with placebo, and clonidine compared with placebo, alters the risk of perioperative acute kidney injury. DESIGN, SETTING, AND PARTICIPANTS: A 2 × 2 factorial randomized, blinded, clinical trial of 6905 patients undergoing noncardiac surgery from 88 centers in 22 countries with consecutive patients enrolled between January 2011 and December 2013. INTERVENTIONS: Patients were assigned to take aspirin (200 mg) or placebo 2 to 4 hours before surgery and then aspirin (100 mg) or placebo daily up to 30 days after surgery, and were assigned to take oral clonidine (0.2 mg) or placebo 2 to 4 hours before surgery, and then a transdermal clonidine patch (which provided clonidine at 0.2 mg/d) or placebo patch that remained until 72 hours after surgery. MAIN OUTCOMES AND MEASURES: Acute kidney injury was primarily defined as an increase in serum creatinine concentration from the preoperative concentration by either an increase of 0.3 mg/dL or greater (≥26.5 μmol/L) within 48 hours of surgery or an increase of 50% or greater within 7 days of surgery. RESULTS: Aspirin (n = 3443) vs placebo (n = 3462) did not alter the risk of acute kidney injury (13.4% vs 12.3%, respectively; adjusted relative risk, 1.10; 95% CI, 0.96-1.25). Clonidine (n = 3453) vs placebo (n = 3452) did not alter the risk of acute kidney injury (13.0% vs 12.7%, respectively; adjusted relative risk, 1.03; 95% CI, 0.90-1.18). Aspirin increased the risk of major bleeding. In a post hoc analysis, major bleeding was associated with a greater risk of subsequent acute kidney injury (23.3% when bleeding was present vs 12.3% when bleeding was absent; adjusted hazard ratio, 2.20; 95% CI, 1.72-2.83). Similarly, clonidine increased the risk of clinically important hypotension. In a post hoc analysis, clinically important hypotension was associated with a greater risk of subsequent acute kidney injury (14.3% when hypotension was present vs 11.8% when hypotension was absent; adjusted hazard ratio, 1.34; 95% CI, 1.14-1.58). CONCLUSIONS AND RELEVANCE: Among patients undergoing major noncardiac surgery, neither aspirin nor clonidine administered perioperatively reduced the risk of acute kidney injury. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01082874.Amit X. Garg ... Thomas Painter ... et al. for the POISE-2 Investigator