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.
DESIGN: Double-blind, placebo-controlled, multicenter randomized trial.
SETTING: Tertiary care hospitals.
INTERVENTIONS: Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 μg/[kg min]) or placebo for 24-48 hours.
MEASUREMENTS AND MAIN RESULTS: The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction.
CONCLUSIONS: This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery.
OBJECTIVE: The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Sepsis trial.
DESIGN SETTING AND PARTICIPANTS: The Mega-ROX Sepsis trial is an international randomised clinical trial that will be conducted within an overarching 40,000-patient registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We anticipate that between 10,000 and 13,000 patients with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU will be enrolled in this trial.
MAIN OUTCOME MEASURES: The primary outcome is in-hospital all-cause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of patients discharged home.
RESULTS AND CONCLUSIONS: Mega-ROX Sepsis will compare the effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU. The protocol and a prespecified approach to analyses are reported here to mitigate analysis bias.
METHODS AND ANALYSIS: Hip fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) is a multicentre, international, parallel-group randomised controlled trial (RCT). Patients who suffer a hip fracture are randomly allocated to either accelerated medical assessment and surgical repair with a goal of surgery within 6 hours of diagnosis or standard care where a repair typically occurs 24 to 48 hours after diagnosis. The primary outcome of this substudy is the development of AKI within 7 days of randomisation. We anticipate at least 1998 patients will participate in this substudy.
ETHICS AND DISSEMINATION: We obtained ethics approval for additional serum creatinine recordings in consecutive patients enrolled at 70 participating centres. All patients provide consent before randomisation. We anticipate reporting substudy results by 2021.
TRIAL REGISTRATION NUMBER: NCT02027896; Pre-results.
METHODS AND ANALYSIS: HIP ATTACK is a multicentre, international, parallel group randomised controlled trial (RCT) that will include patients ≥45 years of age and diagnosed with a hip fracture from a low-energy mechanism requiring surgery. Patients are randomised to accelerated medical assessment and surgical repair (goal within 6 h) or standard care. The co-primary outcomes are (1) all-cause mortality and (2) a composite of major perioperative complications (ie, mortality and non-fatal myocardial infarction, pulmonary embolism, pneumonia, sepsis, stroke, and life-threatening and major bleeding) at 90 days after randomisation. All patients will be followed up for a period of 1 year. We will enrol 3000 patients.
ETHICS AND DISSEMINATION: All centres had ethics approval before randomising patients. Written informed consent is required for all patients before randomisation. HIP ATTACK is the first large international trial designed to examine whether accelerated surgery can improve outcomes in patients with a hip fracture. The dissemination plan includes publishing the results in a policy-influencing journal, conference presentations, engagement of influential medical organisations, and providing public awareness through multimedia resources.
TRIAL REGISTRATION NUMBER: NCT02027896; Pre-results.
DESIGN: A systematic review of the literature followed by a consensus-based voting process.
SETTING: A web-based international consensus conference.
PARTICIPANTS: Two hundred fifty-one physicians from 46 countries.
INTERVENTIONS: The authors performed a systematic literature search and identified all randomized controlled trials (RCTs) showing a significant increase in unadjusted landmark mortality among surgical or critically ill patients. The authors reviewed such studies during a meeting by a core group of experts. Studies selected after such review advanced to web-based voting by clinicians in relation to agreement, clinical practice, and willingness to include each intervention in international guidelines.
MEASUREMENTS AND MAIN RESULTS: The authors selected 12 RCTs dealing with 12 interventions increasing mortality: diaspirin-crosslinked hemoglobin (92% of agreement among web voters), overfeeding, nitric oxide synthase inhibitor in septic shock, human growth hormone, thyroxin in acute kidney injury, intravenous salbutamol in acute respiratory distress syndrome, plasma-derived protein C concentrate, aprotinin in high-risk cardiac surgery, cysteine prodrug, hypothermia in meningitis, methylprednisolone in traumatic brain injury, and albumin in traumatic brain injury (72% of agreement). Overall, a high consistency (ranging from 80% to 90%) between agreement and clinical practice was observed.
CONCLUSION: The authors identified 12 clinical interventions showing increased mortality supported by randomized controlled trials with nonconflicting evidence, and wide agreement upon clinicians on a global scale.
METHODS: The authors randomized 10,010 patients with or at risk of atherosclerosis and scheduled for noncardiac surgery in a 1:1:1:1 ratio to clonidine/aspirin, clonidine/aspirin placebo, clonidine placebo/aspirin, or clonidine placebo/aspirin placebo. Patients started taking aspirin or placebo just before surgery; those not previously taking aspirin continued daily for 30 days, and those taking aspirin previously continued for 7 days. Patients were also randomly assigned to receive clonidine or placebo just before surgery, with the study drug continued for 72 h.
RESULTS: Neither aspirin nor clonidine had a significant effect on the primary 1-yr outcome, a composite of death or nonfatal myocardial infarction, with a 1-yr hazard ratio for aspirin of 1.00 (95% CI, 0.89 to 1.12; P = 0.948; 586 patients [11.8%] vs. 589 patients [11.8%]) and a hazard ratio for clonidine of 1.07 (95% CI, 0.96 to 1.20; P = 0.218; 608 patients [12.1%] vs. 567 patients [11.3%]), with effect on death or nonfatal infarction. Reduction in death and nonfatal myocardial infarction from aspirin in patients who previously had percutaneous coronary intervention at 30 days persisted at 1 yr. Specifically, the hazard ratio was 0.58 (95% CI, 0.35 to 0.95) in those with previous percutaneous coronary intervention and 1.03 (95% CI, 0.91to 1.16) in those without (interaction P = 0.033). There was no significant effect of either drug on death, cardiovascular complications, cancer, or chronic incisional pain at 1 yr (all P > 0.1).
CONCLUSIONS: Neither perioperative aspirin nor clonidine have significant long-term effects after noncardiac surgery. Perioperative aspirin in patients with previous percutaneous coronary intervention showed persistent benefit at 1 yr, a plausible sub-group effect.
DESIGN: A post hoc analysis of a randomized trial.
SETTING: Cardiac surgical operating rooms.
PARTICIPANTS: Patients undergoing elective, isolated CABG.
INTERVENTIONS: Patients were randomized to receive a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or total intravenous anesthesia (TIVA). The primary outcome was hemodynamically relevant MI (MI requiring high-dose inotropic support or prolonged intensive care unit stay) occurring within 48 hours from surgery. The secondary outcome was 1-year death due to cardiac causes.
MEASUREMENTS AND MAIN RESULTS: A total of 5,400 patients were enrolled between April 2014 and September 2017 (2,709 patients randomized to the volatile anesthetics group and 2,691 to TIVA). The mean age was 62 ± 8.4 years, and the median baseline ejection fraction was 57% (50-67), without differences between the 2 groups. Patients in the volatile group had a lower incidence of MI with hemodynamic complications both in the per-protocol (14 of 2,530 [0.6%] v 27 of 2,501 [1.1%] in the TIVA group; p = 0.038) and as-treated analyses (16 of 2,708 [0.6%] v 29 of 2,617 [1.1%] in the TIVA group; p = 0.039), but not in the intention-to-treat analysis (17 of 2,663 [0.6%] v 28 of 2,667 [1.0%] in the TIVA group; p = 0.10). Overall, deaths due to cardiac causes were lower in the volatile group (23 of 2,685 [0.9%] v 40 of 2,668 [1.5%] than in the TIVA group; p = 0.03).
CONCLUSIONS: An anesthetic regimen, including volatile agents, may be associated with a lower rate of postoperative MI with hemodynamic complication in patients undergoing CABG. Furthermore, it may reduce long-term cardiac mortality.
METHODS AND RESULTS: The 'COlchicine for the Prevention of Perioperative Atrial Fibrillation' (COP-AF) trial is an international, blinded, randomized trial that compares colchicine to placebo in patients aged at least 55 years and undergoing major noncardiac thoracic surgery with general anesthesia. Exclusion criteria include a history of AF and a contraindication to colchicine (eg, severe renal dysfunction). Oral colchicine at a dose of 0.5 mg or matching placebo is given within 4 hours before surgery. Thereafter, patients receive colchicine 0.5 mg or placebo twice daily for a total of 10 days. The 2 independent co-primary outcomes are clinically important perioperative AF (including atrial flutter) and MINS during 14 days of follow-up. The main safety outcomes are sepsis or infection and non-infectious diarrhea. We aim to enroll 3,200 patients from approximately 40 sites across 11 countries to have at least 80% power for the independent evaluation of the 2 co-primary outcomes. The COP-AF main results are expected in 2023.
CONCLUSIONS: COP-AF is a large randomized and blinded trial designed to determine whether colchicine reduces the risk of perioperative AF or MINS in patients who have major noncardiac thoracic surgery.
DESIGN: Single blinded, international, multicenter randomized controlled trial with 1:1 allocation ratio.
SETTING: Tertiary and University hospitals.
INTERVENTIONS: Patients (n=10,600) undergoing coronary artery bypass graft will be randomized to receive either volatile anesthetic as part of the anesthetic plan, or total intravenous anesthesia.
MEASUREMENTS AND MAIN RESULTS: The primary end point of the study will be one-year mortality (any cause). Secondary endpoints will be 30-day mortality; 30-day death or non-fatal myocardial infarction (composite endpoint); cardiac mortality at 30day and at one year; incidence of hospital re-admission during the one year follow-up period and duration of intensive care unit, and hospital stay. The sample size is based on the hypothesis that volatile anesthetics will reduce 1-year unadjusted mortality from 3% to 2%, using a two-sided alpha error of 0.05, and a power of 0.9.
CONCLUSIONS: The trial will determine whether the simple intervention of adding a volatile anesthetic, an intervention that can be implemented by all anesthesiologists, can improve one-year survival in patients undergoing coronary artery bypass graft surgery.
METHODS: We conducted a pragmatic, multicenter, single-blind, controlled trial at 36 centers in 13 countries. Patients scheduled to undergo elective CABG were randomly assigned to an intraoperative anesthetic regimen that included a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or to total intravenous anesthesia. The primary outcome was death from any cause at 1 year.
RESULTS: A total of 5400 patients were randomly assigned: 2709 to the volatile anesthetics group and 2691 to the total intravenous anesthesia group. On-pump CABG was performed in 64% of patients, with a mean duration of cardiopulmonary bypass of 79 minutes. The two groups were similar with respect to demographic and clinical characteristics at baseline, the duration of cardiopulmonary bypass, and the number of grafts. At the time of the second interim analysis, the data and safety monitoring board advised that the trial should be stopped for futility. No significant difference between the groups with respect to deaths from any cause was seen at 1 year (2.8% in the volatile anesthetics group and 3.0% in the total intravenous anesthesia group; relative risk, 0.94; 95% confidence interval [CI], 0.69 to 1.29; P = 0.71), with data available for 5353 patients (99.1%), or at 30 days (1.4% and 1.3%, respectively; relative risk, 1.11; 95% CI, 0.70 to 1.76), with data available for 5398 patients (99.9%). There were no significant differences between the groups in any of the secondary outcomes or in the incidence of prespecified adverse events, including myocardial infarction.
CONCLUSIONS: Among patients undergoing elective CABG, anesthesia with a volatile agent did not result in significantly fewer deaths at 1 year than total intravenous anesthesia. (Funded by the Italian Ministry of Health; MYRIAD ClinicalTrials.gov number, NCT02105610.).
METHODS: We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex).
RESULTS: Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit.
CONCLUSIONS: The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.).
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.
METHODS: We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025.
RESULTS: A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, -2.6 percentage points; 95% CI, -3.8 to -1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, -1.1 to 1.7; one-sided P = 0.04 for noninferiority).
CONCLUSIONS: Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.).
OBJECTIVE: To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery.
DESIGN: Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723).
SETTING: 110 hospitals in 22 countries.
PATIENTS: 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications.
INTERVENTION: In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80 mm Hg or greater; before and for 2 days after surgery, renin-angiotensin-aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130 mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60 mm Hg or greater; all antihypertensive medications were continued before and after surgery.
MEASUREMENTS: The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment.
RESULTS: The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P = 0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term.
LIMITATION: Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels.
CONCLUSION: In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications.
PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and Research Grant Council of Hong Kong.