Marcucci et al. Trials (2022) 23:101 https://doi.org/10.1186/s13063-021-05992-1 STUDY PROTOCOL Open Access 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 Maura Marcucci1,2,3* , Thomas W. Painter4,5, David Conen2,3, Kate Leslie6,7, Vladimir V. Lomivorotov8,9, Daniel Sessler10, Matthew T. V. Chan11, Flavia K. Borges1,2,3, Maria J. Martínez Zapata12, C. Y. Wang13, Denis Xavier14, Sandra N. Ofori1,3, Giovanni Landoni15,16, Sergey Efremov17, Ydo V. Kleinlugtenbelt18, Wojciech Szczeklik19, Denis Schmartz20, Amit X. Garg3,21, Timothy G. Short22,23, Maria Wittmann24, Christian S. Meyhoff25, Mohammed Amir26, David Torres27,28, Ameen Patel2, Emmanuelle Duceppe3,29, Kurtz Ruetzler10, Joel L. Parlow30, Vikas Tandon2, Michael K. Wang1,2,3, Edith Fleischmann31, Carisi A. Polanczyk32,33, Raja Jayaram34, Sergey V. Astrakov35,36, Mangala Rao14, Tomas VanHelder37, William K. K. Wu11, Chao Chia Cheong13, Sabry Ayad38, Marat Abubakirov39, Mikhail Kirov40, Keyur Bhatt41, Miriam de Nadal42, Valery Likhvantsev43,44, Pilar Paniagua Iglesisas45, Hector J. Aguado46, Michael McGillion3,47, Andre Lamy3,48, Richard P. Whitlock3,48, Pavel Roshanov49, David Stillo3, Ingrid Copland3, Jessica Vincent3, Kumar Balasubramanian3, Shrikant I. Bangdiwala1,3, Bruce Biccard50, Andrea Kurz10,51, Sadeesh Srinathan52, Shirley Petit3, John Eikelboom2,3, Toby Richards53, Peter L. Gross2, Pascal Alfonsi54, Gordon Guyatt1,2, Emily Belley-Cote2,3, Jessica Spence1,3,37, William McIntyre2,3, Salim Yusuf2,3 and P. J. Devereaux1,2,3 Abstract 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. * Correspondence: marcum2@mcmaster.ca 1 Department of Health Research Methods, Evidence, and Impact, McMaster University, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada 2 Department of Medicine, McMaster University, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada Full list of author information is available at the end of the article © The Author(s). 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Marcucci et al. Trials (2022) 23:101 Page 2 of 12 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. Keywords: Noncardiac surgery, Tranexamic acid, Perioperative bleeding, Perioperative hypotension, Cardiovascular complications, Randomized controlled trial Introduction prothrombotic setting such as noncardiac surgery, if Perioperative bleeding in noncardiac surgery is frequent TXA prevents bleeding, it may reduce cardiovascular and is associated with a poor prognosis. In the Vascular complications. The existing studies of TXA in noncar- events In noncardiac Surgery patIents cOhort evaluatioN diac surgery were too small—and often selected a low- (VISION) study—a large, international, prospective co- risk population—to definitely establish its cardiovascular hort study that included a representative sample of safety [19]. We conducted a pilot study in 100 patients, 40,000 adults ≥ 45 years of age undergoing noncardiac with or at risk of cardiovascular disease, undergoing surger y[1, 2]—major bleeding was the complication noncardiac surgery at two sites in Hamilton, ON, with the highest attributable risk for mortality at 30 days, Canada [20]. Patients were randomized to receive TXA accounting for 17% of the deaths [3]. Perioperative or matching placebo, as an intravenous bolus of 1 g at bleeding is also independently associated with cardiovas- the beginning and at the end of surgery. We demon- cular complications including myocardial injury and in- strated the feasibility of recruiting such a patient popula- farction, stroke, and acute kidney injury [4–7]. tion and of administering the study drug [20]. Tranexamic acid (TXA) is an antifibrinolytic agent Perioperative hypertension has been associated with that has been shown to safely prevent clinically import- cardiovascular complications after noncardiac surgery ant bleeding in large randomized controlled trials [21–24]. Perioperative hypotension occurs most fre- (RCTs) in various settings, including acute trauma [8], quently in the operating room, but it is also common obstetrics [9], and cardiac surgery [10]. However, a re- during the first two days after surgery; moreover, on cent large RCT that evaluated TXA in patients with surgical wards, hypotension lasts longer than in the in- acute gastrointestinal bleeding reported an increased risk tensely monitored operating room [25, 26]. Preoperative, of venous thromboembolism with TXA versus placebo intraoperative, and postoperative hypotension are inde- (48 [0.8%] of 5952 patients versus 26 [0.4%] of 5977 pa- pendently associated with an increased risk of all-cause tients; relative risk [RR], 1.85; 95% confidence interval mortality and cardiovascular complications at 30 days [CI], 1.15–2.98) [11]. The risk-benefit profile of TXA in after noncardiac surgery [25–31]. Two RCTs suggested those undergoing noncardiac surgery is unknown. Sev- benefits of higher or individualized perioperative blood eral small RCTs in orthopedic surgery have suggested pressure (BP) targets [32, 33]; however, these trials were that TXA reduces blood loss and transfusions [12–16]. relatively small with few events [32, 33]. A few small RCTs have been conducted in other types Usual perioperative care is commonly consistent with of noncardiac surgery [17, 18]. Although there is con- a hypertension-avoidance strategy, that is most patients cern that TXA may increase thrombotic events in a continue their antihypertensive medications throughout Marcucci et al. Trials (2022) 23:101 Page 3 of 12 the perioperative period and low intraoperative mean ar- Table 1 Inclusion criteria terial pressures (MAPs) are commonly accepted [25]. Patients must fulfill ≥ 1 of the following criteria: Observational studies and small RCTs suggest that with- 1. NT-proBNP ≥ 200 ng/L; holding antihypertensive medications, and in particular 2. History of coronary artery disease; angiotensin converting enzyme inhibitors (ACEIs) or 3. History of peripheral arterial disease; angiotensin receptor blockers (ARBs), may reduce peri- operative hypotension and cardiovascular complications 4. History of stroke; [25, 34–36]. There is, however, no definitive evidence 5. Undergoing major vascular surgery; OR from adequately powered RCTs to inform whether a 6. Any 3 of 9 risk criteria hypotension-avoidance or hypertension-avoidance strat- A. Undergoing major surgery; B. History of congestive heart failure; egy is superior. C. History of a transient ischemic attack; We designed the third PeriOperative ISchemic Evalu- D. Diabetes and currently taking an oral hypoglycemic agent or ation (POISE-3) Trial to address the following questions insulin; E. Age ≥ 70 years; in patients with or at risk of cardiovascular disease who F. History of hypertension; are undergoing noncardiac surgery: (1) is TXA superior G. Serum creatinine > 175 μmol/L (> 2.0 mg/dl); to placebo for the occurrence of life-threatening, major, H. History of smoking within 2 years of surgery; or I. Undergoing emergent/urgent surgery. and critical organ bleeding, and non-inferior to placebo NT-proBNP N-terminal pro–B-type natriuretic peptide for the occurrence of major arterial and venous throm- botic events, within 30 days after surgery? and (2) among patients also chronically taking an antihypertensive drug, Patient recruitment is a perioperative hypotension-avoidance strategy super- In the majority of centers, study personnel screen the ior to a hypertension-avoidance strategy on the 30-day patient list in the preoperative assessment clinic to iden- risk of a major cardiovascular event? tify eligible patients. Multiple strategies are then applied in order to capture additional patients who do not Methods Table 2 Exclusion criteria Trial design A. Patients are not eligible for POISE-3 trial if any of the following criteria POISE-3 is an international RCT of 10,000 adults at risk is present: of bleeding and cardiovascular complications who are 1. Patients undergoing cardiac surgery undergoing noncardiac surgery. Patients are randomized 2. Patients undergoing cranial neurosurgery to receive intraoperative TXA or placebo. Using a 2 × 2 3. Planned use of systemic TXA during surgery 4. Low-risk surgical procedure (based on individual physician’s partial factorial design, patients taking ≥ 1 antihyperten- judgment) sive medication are also randomized to a hypotension- 5. Hypersensitivity or known allergy to TXA avoidance or a hypertension-avoidance strategy. The 6. Creatinine clearance < 30 mL/min (Cockcroft-Gault equation) or on chronic dialysis trial is registered at clinicaltrials.gov (NCT03505723). 7. History of seizure disorder The Standard Protocol Items: Recommendations for 8. Patients with recent (< 3 months) stroke, myocardial infarction, acute Interventional Trials (SPIRIT) checklist for our paper arterial thrombosis, or venous thromboembolism 9. Patients with fibrinolytic condition following consumption is provided as Additional file 1. coagulopathy 10. Patients with subarachnoid hemorrhage within the past 30 days 11. Women of childbearing potential who are not taking effective Trial population contraception, pregnant or breast-feeding We include patients who meet the following criteria: (1) 12. Previously enrolled in POISE-3 Trial undergoing noncardiac surgery; (2) ≥ 45 years of age; (3) B. Patients are not eligible for the BP management factorial trial if any of expected to stay in hospital at least one night after sur- the following criteria is present: gery; (4) meeting ≥ 1 of 6 cardiovascular and bleeding 1. Patients with advanced congestive heart failure (New York Heart risk criteria (Table 1); and (5) providing written in- Association functional class III or IV or left ventricular ejection fraction ≤ 30%) formed consent. Detailed inclusion criteria including 2. Patients with untreated brain aneurysm definitions are provided in the Additional File 2. Table 2 3. Patients with previous history of hypertensive related cerebral describes the exclusion criteria. hemorrhage 4. Patients undergoing surgery for pheochromocytoma or history of Patients are eligible for the BP management factorial if untreated pheochromocytoma they are treated chronically (i.e., at least 30 days in the 6 5. Patients who are hemodynamically unstable or requiring weeks preceding randomization) with at least one anti- vasopressors or inotropic support before undergoing surgery 6. Patients with thyrotoxicosis (i.e., severe hyperthyroidism) requiring hypertensive medication of any class. Table 2 lists the perioperative beta-blocker therapy additional exclusion criteria for the BP management POISE PeriOperative ISchemic Evaluation, TXA tranexamic acid, BP factorial. blood pressure Marcucci et al. Trials (2022) 23:101 Page 4 of 12 attend the preoperative assessment clinic, including a 1:1 ratio. Patients eligible for the BP management fac- screening patients on the daily surgical list, patients on torial are also randomized to the hypotension-avoidance surgical wards and intensive care units, and patients in or hypertension-avoidance strategy, with a 1:1 ratio. the preoperative holding area. At each center, the ser- Patients, health care providers, data collectors, outcome vices of anesthesia, surgery, and medicine are requested assessors and adjudicators, and investigators are all to contact the study personnel regarding all surgical ad- blinded to the TXA or placebo allocation. Outcome asses- missions through the emergency department and ward sors and adjudicators are blinded to the treatment alloca- patients requiring surgery. Study personnel approach all tion for the comparison of BP management strategies. eligible patients to obtain informed consent before We do not anticipate any requirement for unblinding surgery. of TXA treatment allocation; however, telephonic access (primary number and secondary back-up number) to a Randomization and blinding 24/7 central emergency unblinding system is provided to Figure 1 shows the trial flow chart. Study personnel allow the blind to be broken when deemed absolutely randomize patients before surgery via a central 24-h necessary. Any unblinding will be recorded. Interactive Web Randomization System. The randomization process uses block randomization strati- Trial interventions fied by center, with block size varying randomly, and the Tranexamic acid or placebo study personnel do not know the block sizes. Patients Patients receive two intravenous doses of either 1 g are randomized to receive TXA or placebo according to of TXA or matching placebo (i.e., equivalent volume Fig. 1 The POISE-3 trial flow chart Marcucci et al. Trials (2022) 23:101 Page 5 of 12 of 0.9% normal saline), as a bolus or 10-min infu- before the operation on the day of surgery, and during sion. The first dose is given at the beginning of sur- the first 2 days after surgery, the patient’s chronic antihy- gery (i.e., within 20 min preceding the anticipated pertensive therapy is managed based on a study algo- skin incision), and the second at the end of surgery rithm, described in Fig. 2. Patients in this group are not (i.e., at wound closure). Additional File 3 provides given any ACEI, ARB, or renin inhibitor. Intraopera- the rationale for the choice of the TXA dosing regi- tively, the anesthesiologists are encouraged to target a men in this study. MAP of ≥ 80 mmHg from the time of anesthetic induc- TXA and 0.9% normal saline are sourced locally. Cen- tion until the end of surgery. Methods to achieve the in- ters use any approved marketed version of TXA 100 mg/ traoperative MAP target (e.g., fluids, vasopressors, mL solution. The study drugs are prepared either by a inotropes) are left to the discretion of the attending pharmacist or another designated qualified personnel, anesthesiologist. who are not involved in any other study activities. In order to ensure blinding, individuals preparing study drugs at each participating center sign an agreement in- Hypertension-avoidance BP management strategy dicating they will maintain the confidentiality of (control) In the hypertension-avoidance group, on the randomization assignments. morning of surgery before the operation, patients receive all the antihypertensive medications that they take Perioperative BP management strategies chronically. The attending anesthesiologists are encour- 9pt?>The BP strategies occur during three periods (i.e., aged to target a MAP ≥ 60 mmHg from the time of preoperative, intraoperative, and postoperative), with anesthetic induction until the end of surgery. Patients the postoperative phase involving the first 2 days after resume taking their antihypertensive medications imme- the day of surgery. Whenever possible, patients identi- diately after surgery. A POISE-3 iOS App has been de- fied as eligible for the BP management partial factorial veloped and made available to participating sites to are advised in advance not to take their antihypertensive support the implementation of the BP management fac- medications on the morning of surgery or the night be- torial (Additional File 4). fore surgery and to bring their antihypertensive medica- The Project Office reviews data on each center’s ad- tions to the hospital. In the preoperative and herence to the interventions and provides feedback to postoperative phase, patients’ vital signs are measured centers to maximize center adherence. There are no spe- as per routine practice. Intraoperatively, sites are ad- cial criteria for discontinuing or modifying allocated in- vised to monitor the MAP at least every 15 min. terventions for a given trial participant. Hypotension-avoidance BP management strategy (intervention) In the hypotension-avoidance group, Fig. 2 Algorithm for management of the patient antihypertensive medications in the hypotension avoidance strategy arm. SBP, systolic blood pressure; ACEi, angiotensin-converting-enzyme inhibitors; ARB, angiotensin II receptor blockers; HR, heart rate; CCB, calcium channel blockers; BP, blood pressure Marcucci et al. Trials (2022) 23:101 Page 6 of 12 Trial outcomes and who will oversee the adjudication of the following TXA trial outcomes: death (vascular versus non-vascular), MINS, The primary efficacy outcome is a composite of life- myocardial infarction, cardiac arrest, stroke, peripheral threatening, major, and critical organ bleeding at 30 days arterial thrombosis, symptomatic pulmonary embolism, after randomization. The primary safety outcome is a symptomatic proximal deep vein thrombosis, bleeding, composite of myocardial injury after noncardiac surgery acute congestive heart failure, new clinically important (MINS) [2], non-hemorrhagic stroke, peripheral arterial atrial fibrillation, acute kidney injury, infection/sepsis, thrombosis, and symptomatic proximal venous and seizure. thromboembolism at 30 days after randomization. The secondary outcomes at 30 days after Follow-up randomization are as follows: (1) bleeding independently The participant timeline based on the SPIRIT diagram is associated with mortality after noncardiac surgery provided as Fig. 3. Study personnel follow patients (BIMS) [37]; (2) life-threatening bleeding; (3) major throughout their time in hospital evaluating the patients bleeding; (4) critical organ bleeding; (5) MINS; (63) and reviewing their medical records and recording any MINS not fulfilling the universal definition of myocar- outcomes. For patients enrolled in the BP management dial infarction [38]; (7) myocardial infarction; and (8) the factorial, study personnel ensure patients receive their composite of vascular death, bleeding (i.e., non-fatal life- antihypertensive medication as per the trial arm they threatening, major, or critical organ), MINS, stroke, per- were randomized to, up to postoperative day 2 inclu- ipheral arterial thrombosis, and symptomatic proximal sively. Study personnel contact all patients by telephone venous thromboembolism (i.e. a net risk-benefit at 30 days and at 1 year after randomization to assess the outcome). occurrence of clinically relevant events that might meet any study outcome or serious adverse event definitions BP management trial and to administer the disability questionnaire. In case The primary outcome is a composite of vascular death the administration of the study interventions deviates and non-fatal MINS, stroke, and cardiac arrest at 30 days from the protocol, study personnel continue to collect after randomization. data on study outcomes at 30 days and at 1 year after The secondary outcomes at 30 days after randomization, unless the participants explicitly state randomization are as follows: (1) MINS; (2) MINS not that they do not want to be followed. If this happens, fulfilling the universal definition of myocardial infarction study personnel request to collect data on the patient [38]; (3) myocardial infarction; (4) stroke; (5) vascular through their healthcare provider. If the patient refuses mortality; and (6) all-cause mortality. this, no further data is collected on the patient. Tertiary outcomes at 30 days and 1 year are listed in the Additional File 5. All outcome definitions are listed Data management in the Additional File 6. The Event Adjudication Com- Study personnel at the participating sites record data on mittee consists of clinicians with expertise in periopera- case report forms (CRFs) and submit the CRFs through tive outcomes who are blinded to treatment allocation a secure web-based computerized database (i.e., Fig. 3 SPIRIT figure: participant timeline. Superscript lowercase letter “a” indicates the following: in most centers randomization occurs on the day of surgery prior to the procedure, and always within 24 h before the planned surgery. Superscript lowercase letter “b” indicates the following: in the table, days + 1, + 2, and + 3 refer to days + 1, + 2, and + 3 with respect to the day of surgery. Since randomization most often occurs on the day of surgery prior to the procedure, if surgery is not delayed or canceled, days + 1, + 2, and + 3 after randomization do correspond to postoperative days 1–3 Marcucci et al. Trials (2022) 23:101 Page 7 of 12 iDataFax). Patients are identified using a unique numeric Taking into account information from the POISE-2 code and all patient data are anonymized to ensure pa- trial [5], we expect a placebo event rate for the TXA pri- tient confidentiality. Data validity checks are pro- mary efficacy outcome of at least 7%. With a similar pla- grammed in the database and are monitored by data cebo event rate, a sample size of 10,000 patients will give management assistants from the Project Office through us ≥ 95% power to show a relative hazard reduction of multi-level data validation of CRFs. at least 30% (i.e., HR 0.70) with TXA compared to pla- cebo in the composite of life-threatening, major and crit- ical organ bleeding (based on Cox’s proportional hazard Statistical considerations model, with type I error of 0.05, two-sided test). The Sample size trial will still have 90% power to detect a relative hazard The hypothesis of non-inferiority of TXA on thrombotic reduction of at least 25% (i.e., HR 0.75). events compared with placebo is the one requiring the We expect that at least 80% of patients will be on largest sample size. Table 3 shows the related sample chronic antihypertensive therapy. We conservatively esti- size calculations. We expect the placebo event rate for mated that at least 65% of the patients in the TXA com- the composite of arterial and venous thrombotic events ponent of the trial would be eligible for the BP to range between 10 and 12% (after accounting for the management factorial. A sample of 6500 patients will partial factorial design). We set up the non-inferiority provide 95% power to test the hypothesis that the margin on a hazard ratio (HR) with TXA compared with hypotension-avoidance strategy will reduce the occur- placebo of 1.125, which, given the expected placebo rence of the composite of vascular death and nonfatal event rates, correspond to an absolute increase between MINS, stroke, and cardiac arrest with an HR of 0.75 and 1.18 and 1.39%. The relative 12.5% hazard increase as an expected control event rate of 11.0% (based on Cox’s non-inferiority margin was chosen to be half the 25% proportional hazard model, type I error of 0.05, two- relative hazard reduction used to establish the superior- sided test). The same sample size will still provide > 80% ity of either aspirin or clonidine compared with placebo power to detect a HR of 0.80. in POISE-2 [5, 26]. Although we designed POISE-3 to establish if TXA is non-inferior to placebo, it is possible Data analysis that TXA might in fact have a small beneficial effect on For the TXA primary efficacy outcome, we will analyze postoperative cardiovascular events due to the decreased patients in the treatment group to which they are allo- bleeding. We quantified this small beneficial effect to cated, according to the intention-to-treat principle. We correspond to a true HR of 0.9 (Table 3). Based on these will conservatively test the non-inferiority safety hypoth- assumptions, a sample size of 10,000 patients will allow esis in the per-protocol population [39]; a sensitivity us to test our non-inferiority hypothesis, with a power of intention-to-treat analysis will be secondarily performed. ≥ 90% (Table 3). The analyses of the primary outcome in the BP Table 3 Sample size calculation for non-inferiority safety hypothesis of tranexamic acid vs. placebo Placebo event rate NI margin, absolute risk difference TXA vs. placebob Power Sample sizec 0.90 8,868 a 10% 1.18% 0.95 10,963 0.97 12,441 0.90 8,078 11%a 1.29% 0.95 9,990 0.97 11,340 0.90 7,390 a 12% 1.39% 0.95 9,136 0.97 10,367 NI non-inferiority margin, TXA tranexamic acid a The estimates are based on the event rates observed in the POISE-2 trial (aspirin-placebo group) [5] and in a simulated subpopulation of the VISION cohort [1, 2] matching the POISE-3 inclusion criteria b These are the NI margins expressed as absolute risk differences, corresponding to a NI margin expressed as hazard ratio of 1.125, when the placebo event rate is 10%, 11%, or 12% c These sample sizes are obtained from non-inferiority test for two survival curves using Cox’s proportional hazard model, with a hazard ratio of 1.125 as non- inferiority margin, and a hazard ratio of 0.9 as actual hazard ratio (one-sided test, alpha of 0.025) Marcucci et al. Trials (2022) 23:101 Page 8 of 12 management factorial will follow the intention-to-treat ng/L. We expect the hypotension-avoidance strategy will principle. Patients lost to follow-up will be censored at have a greater beneficial effect in patients on chronic the time of their last follow-up. We will develop and ACEI/ARB therapy, taking ≥ 2 chronic antihypertensive finalize a statistical analysis plan before any investigator medications, with a lower preoperative SBP, and higher is unblinded. preoperative NT-proBNP values. For each subgroup analysis, we will undertake a Cox Main analysis proportional hazards model assessing each primary out- For the analyses on each primary outcome, we will use come incorporating a subgroup interaction term to pro- Cox proportional hazards models with stratification ac- vide the basis for evaluating subgroup effects. We will cording to the randomization in the partial factorial. We consider the possibility that a subgroup effect is present will assess model assumptions including the propor- if the interaction term of treatment and subgroup is sta- tional hazard assumption. We will present the time-to- tistically significant at a p-value < 0.05. We will also con- the first occurrence of one of the components of the pri- sider other credibility criteria to judge the reliability of a mary outcomes using the Kaplan-Meier estimator. subgroup effect [40, 41]. For the effect of TXA on the primary safety outcome, we will calculate the HR and the corresponding upper Interim analyses bound of the one-sided 97.5% CI. We will declare the POISE-3 interim analyses are described in the Additional non-inferiority of TXA compared with placebo if the File 7. upper bound falls below 1.125. For the effect of TXA compared with placebo on the Oversight and monitoring primary efficacy outcome, and the effect of the Trial organization hypotension-avoidance strategy compared with the The Population Health Research Institute (PHRI; hypertension-avoidance strategy on the primary out- Hamilton General Hospital Campus, David Braley Car- come, we will calculate the HRs, corresponding 95% CIs diac, Vascular and Stroke Research Institute, 237 Barton and associated p-values. We will infer statistical signifi- Street East, Hamilton, Ontario, Canada L8L 2X2) is the cance if the computed 2-sided p-value is < 0.05. A simi- sponsor and coordinating center for this trial and is re- lar approach will be adopted for the secondary and sponsible for the central randomization, trial database, tertiary outcomes. data consistency checks, data analyses, and coordination We anticipate that the effect of TXA and of the of participating centers worldwide. Additional File 8 de- hypotension-avoidance strategy will act independently, scribes the trial organizational structure and the plan for but we will evaluate the possibility of synergism or an- the oversight of the trial conduct. Additional File 10 tagonism between the two interventions by formally lists POISE-3 investigators across centres and the com- testing for differences among the strata. position of the study committees. Subgroup analyses Adverse event reporting For the primary efficacy and safety outcomes in the In POISE-3 trial, we collect data on serious adverse TXA factorial, we will evaluate the following subgroups: events (SAEs) and suspected unexpected serious adverse orthopedic versus non-orthopedic surgery; preoperative reactions (SUSARs); however, we do not collect data on hemoglobin < 120 g/L versus ≥ 120 g/L; preoperative es- adverse events that are not serious. We defined an SAE timated glomerular filtration rate (eGFR) < 45, 45– < 60, as any untoward medical occurrence that at any dose is and ≥ 60 ml min−1 1.73 m2; and preoperative N-terminal life-threatening, or requires inpatient hospitalization or pro–B-type natriuretic peptide (NT-proBNP) < 200, prolongation of existing hospitalization, or results in per- 200– < 1500, and ≥ 1500 ng/L. We expect TXA to have sistent or significant disability/incapacity, or is a con- greater benefit and safety in patients having orthopedic genital anomaly/birth defect, or is a medically important surgery, with a preoperative hemoglobin < 120 g/L, a event. We defined SUSARs as events that meet the fol- lower preoperative eGFR, and higher preoperative NT- lowing criteria: (1) suspected to be causally associated proBNP values. with TXA; (2) unexpected if the nature, severity, or out- For the primary outcome in the BP management fac- come of the reaction(s) is not consistent with the refer- torial, we will evaluate the following subgroups: chronic ence information (i.e., product monograph for TXA); (3) ACEI/ARB therapy versus no chronic ACEI/ARB ther- serious (as defined above for an SAE); and (4) not a trial apy; number of chronic antihypertensive medications (1 efficacy outcome. versus ≥ 2); preoperative systolic blood pressure (SBP) < Efficacy and safety outcomes will be recorded separ- 130, 130–159, 160–180, and > 180 mmHg; and pre- ately and not as SAEs, except if, because of the course or operative NT-proBNP < 200, 200– < 1500, and ≥ 1500 severity or any other feature of such events, the Marcucci et al. Trials (2022) 23:101 Page 9 of 12 investigator, according to his/her best medical judgment, Trial progress considers these events as exceptional in this medical This paper is based on the most recent version of the condition. Hospitalizations, which were planned before study protocol (i.e., v7.0, 2021-07-22). The first patient inclusion in the study (e.g., elective or scheduled surgery was randomized on June 27, 2018. The DMC undertook or other interventions), will not be regarded as SAEs. the planned interim analyses and recommended con- This pertains also to hospitalizations which are part of tinuation of the trial. This study protocol was submitted the normal treatment or monitoring of the studied dis- when recruitment in the study was completed but before ease or another disease present before inclusion in the completion of last patient/last visit. A few protocol study (e.g., patient returning to the hospital for chemo- amendments have been implemented during the course therapy) and which did not result in a worsening of the of the trial with the most recent version of the protocol disease. here reported being formally finalized close to the end of All SAEs need to be reported within 24 h of knowledge the recruitment. There was consensus among the of the event to the Project Office. For such events, re- POISE-3 investigators to publish the study protocol be- search personnel will complete an SAE CRF in the data- fore closure of the study database but only in its defini- base. The Project Office will then inform regulatory tive version, i.e., the one that will inform the report of authorities in a timely manner, as necessary, according the study results. Recruitment has involved 106 centers to the applicable regulations. across 22 countries. The Data Monitoring Committee (DMC) will provide oversight of patients’ safety throughout the trial by Abbreviations ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin-receptor reviewing unblinded aggregate data (including all re- blocker; BIMS: Bleeding independently associated with mortality after ported study outcome events and SAEs) by treatment noncardiac surgery; BP: Blood pressure; DMC: Data Monitoring Committee; group at regular intervals throughout the duration of the eGFR: Estimated glomerular filtration rate; MINS: Myocardial injury after noncardiac surgery; PHRI: Population Health Research Institute; trial and as defined in the DMC Charter. POISE: Perioperative Ischemic Evaluation Study; RCT: Randomized controlled trial; SAE: Serious adverse event; SBP: Systolic blood pressure; Dissemination SUSAR: Suspected unexpected serious adverse reactions; TXA: Tranexamic acid; VISION: Vascular events In noncardiac Surgery patIents cOhort Our dissemination plan includes the following: presenta- evaluatioN tion at national and international conferences, publica- tions in peer reviewed high-impact journals, and posts on the “Reducing Global Perioperative Risk” Resource Supplementary Information The online version contains supplementary material available at https://doi. Centre (http://perioperative-risk.amjmed.com/), a multi- org/10.1186/s13063-021-05992-1. media global-scale platform we developed with Elsevier (Canadian Institutes of Health Research funded), linked Additional file 1. POISE-3 SPIRIT checklist. to Elsevier’s global online readership. Additional file 2. POISE-3 detailed inclusion criteria including definitions. Discussion Additional file 3. Rationale for POISE-3 study dosing regimen of tranex- amic acid. Over 200 million adults annually undergo major noncar- Additional file 4. POISE-3 App for the blood pressure management diac surgery and millions will suffer a major cardiovas- factorial. cular complication. Bleeding in the perioperative setting Additional file 5. POISE-3 tertiary outcomes. can lead to immediate death or trigger a cascade of Additional file 6. POISE-3 outcome definitions. events associated with major complications. TXA has Additional file 7. POISE-3 interim analyses. the potential to prevent perioperative bleeding but a trial Additional file 8. POISE-3 organizational structure and oversight of trial is needed to demonstrate such a benefit and to establish conduct. safety. Additional file 9. POISE-3 informed consent form template (English). The effects of noncardiac surgery and anesthesia on Additional file 10. List of investigators and committees. patient hemodynamics (e.g., blood pressure) can play a fundamental role in the pathophysiology of perioperative Acknowledgements cardiovascular complications. Whether a hypotension- Not applicable. avoidance or a hypertension-avoidance BP management strategy in the perioperative setting will prevent major Authors’ contributions PJD, MM, TP, KL, and DS participated in the conceptualization of the study cardiovascular complications is another fundamental and led its design and protocol development. PJD and MM wrote the first question that requires an answer. draft of the manuscript. All authors contributed to the design and POISE-3 will answer two crucial management ques- implementation of the protocol. All authors provided critical revisions to the manuscript before approving the final version. All named authors adhere to tions and influence future perioperative practices around the authorship guidelines of Trials. All authors have agreed to publication. All the world. authors read and approved the final manuscript. Marcucci et al. Trials (2022) 23:101 Page 10 of 12 Funding the submitted work; and TR is a regular speaker at national and international The study is supported by the following grants: Canadian Institutes of Health conferences on anemia, blood transfusion, wound healing and vascular dis- Research (CIHR) Foundation Grant awarded to PJD (FDN-143302), Canada; eases for which he has received expenses for travel, accommodation and General Research Fund 14104419, Research Grant Council, Hong Kong SAR, sundries. TR has worked with several agencies promoting meetings or China; and National Health and Medical Research Council, Funding Schemes, healthcare. TR is a director of The Iron Clinic Ltd and director of Veincare NHMRC Project Grant 1162362, Australia. MM holds a McMaster University London Ltd & Veincare WA also TR is the Vascular lead for 18-week wait Ltd. Department of Medicine Career Research Award and a Physicians' Services All the other co-authors report no conflict of interest. Incorporated (PSI) Foundation Mid-Career Clinical Research Award to support her research work in perioperative medicine. FKB holds a McMaster Univer- Author details 1 sity Department of Medicine Career Research Award to support her research Department of Health Research Methods, Evidence, and Impact, McMaster work in perioperative medicine. University, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada. 2 Department of Medicine, McMaster University, 237 Barton Street East, Availability of data and materials Hamilton, ON L8L 2X2, Canada. 3Population Health Research Institute, The PHRI is the sponsor of this trial. The PHRI believes the dissemination of Hamilton, ON, Canada. 4Discipline of Acute Care Medicine, University of clinical research results is vital and sharing of data is important. PHRI Adelaide, Adelaide, South Australia, Australia. 5Department of Anaesthesia, prioritizes access to data analyses to researchers who have worked on the Royal Adelaide Hospital, Adelaide, South Australia, Australia. 6Department of trial for a significant duration, have played substantial roles, and have Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, participated in raising the funds to conduct the trial. PHRI balances the Australia. 7Department of Critical Care Medicine, Melbourne Medical School, length of the research study, and the intellectual and financial investments University of Melbourne, Melbourne, Australia. 8Department of that made it possible with the need to allow wider access to the data Anesthesiology and Intensive Care, E. Meshalkin National Medical Research collected. Data will be disclosed only upon request and approval of the Center, Novosibirsk, Russia. 9Department of Anesthesiology and Intensive proposed use of the data by a Review Committee. Data will be available to Care, Novosibirsk State University, Novosibirsk, Russia. 10Department of the journal for evaluation of reported analyses. Data requests from other Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, non-POISE-3 investigators will not be considered until 5 years after the close Ohio, USA. 11The Chinese University of Hong Kong, Hong Kong, China. 12 out of the trial. Iberoamerican Cochrane Centre-Public Health and Clinical Epidemiology Service, IIB Sant Pau, CIBER de Epidemiología y Salud Pública (CIBERESP), Declarations Barcelona, Spain. 13Department of Anaesthesiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. 14St. John’s Medical College, Ethics approval and consent to participate Bangalore, India. 15Department of Anesthesia and Intensive Care, IRCCS San This trial is conducted in compliance with the protocol, the Declaration of Raffaele Scientific Institute, Milan, Italy. 16School of Medicine, Vita-Salute San Helsinki, the International Consensus on Harmonization - Good Clinical Raffaele University, Milan, Italy. 17Saint Petersburg State University Hospital, Practice (ICH-GCP), and all applicable laws and regulations of the countries in Saint Petersburg, Russia. 18Department of Orthopedic and Trauma Surgery, which the study is performed. Before sites start recruiting patients, the local Deventer Ziekenhuis, Deventer, the Netherlands. 19Jagiellonian University investigators must have written and dated approval/favorable opinion from Medical College, Center for Intensive Care and Perioperative Medicine, the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for Krakow, Poland. 20CHU Brugmann, Université libre de Bruxelles, Brussels, the protocol, consent form (Additional File 9), subject recruitment materials/ Belgium. 21Department of Medicine, Epidemiology and Biostatistics, Western process and, where applicable, approval by the participating countries University, London, ON, Canada. 22Auckland City Hospital, Auckland, New Competent Authority (CA) in accordance with local laws and regulations. Zealand. 23University of Auckland, School of Health Sciences, Auckland, New Amendments to the protocol also require IRB/IEC and/or CA approval, where Zealand. 24Department of Anesthesiology, University Hospital, Bonn, applicable. All data are stored on a central encrypted, high-security computer Germany. 25Department of Anaesthesia and Intensive Care, Bispebjerg and system and kept strictly confidential. There is no anticipated harm and com- Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark. 26 pensation for participants who suffer harm from trial participation. There is Shifa International Hospital (STMU), Islamabad, Pakistan. 27Clinica Santa no plan for provision of any post-trial care. This trial does not involve collect- Maria, Santiago, Chile. 28Universidad de Los Andes, Santiago, Chile. 29 ing biological specimens for storage. Department of Medicine, Universite de Montreal, Montreal, QC, Canada. 30 Department of Anesthesiology and Perioperative Medicine, Kingston General Hospital and Queen’s University, Kingston, ON, Canada. Consent for publication 31 Department of Anesthesia, General Intensive Care and Pain Management, Not applicable. Medical University of Vienna, Vienna, Austria. 32Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 33Cardiology Department, Hospital de Competing interests Clínicas de Porto Alegre, Porto Alegre, Brazil. 34Nuffield Department of ED acknowledges Investigator initiated research grants from Roche Anaesthetics, Clinical Neurosciences, University of Oxford, Oxford, UK. 35City Diagnostics, Abbott Laboratories and Boehringer Ingelheim; lecture fee and hospital No. 25, Novosibirsk, Russia. 36Department of Anesthesiology, honoraria for participation in advisory board meeting by Roche Diagnostics; Novosibirsk State University, Novosibirsk, Russia. 37Department of Anesthesia, support by a Fonds de Recherche en Sante du Quebec salary award. MJM-Z McMaster University, Hamilton, ON, Canada. 38Case Western Reserve is supported by a Miguel Servet II research contract from the ISCIII (CP1120/ University, Anesthesiology Institute, Cleveland Clinic - Fairview Hospital, 00023), Spain. CSM: has co-founded a start-up company, WARD247 ApS, with Cleveland, OH, USA. 39Meshalkin National Medical Research Center, the aim of pursuing the regulatory and commercial activities of the WARD- Novosibirsk, Russia. 40Department of Anesthesiology and Intensive Care project, an Innovation Fund Denmark funded research project on wireless Medicine, Northern State Medical University, Arkhangelsk, Russia. 41SIDS vital signs. CSM also reports direct and indirect research funding to his de- Hospital & Research Centre, Surat, India. 42Anesthesiology and Intensive Care partment from Ferring Pharmaceuticals, Merck, Sharp & Dohme Corp. and Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain. 43V. Boehringer Ingelheim outside the submitted work as well as lecture fees Negovskiy Reanimatology Research Institute, Moscow, Russia. 44M. from Radiometer. DT received speaker honorarium from 3 M and Pfizer. EB-C Vladimirskiy Moscow Regional Clinical and Research Institute, Moscow, received grants from Bayer, Roche, and BMS-Pfizer. AP acknowledges to have Russia. 45Department of Anaesthesia and Pain Management Santa Creu i provided expertise and have been speaker for Laboratory Edwards, 3 M, and Sant Pau University Hospital, Barcelona, Spain. 46Trauma & Orthopaedic MSD laboratories; to have been speaker for Pfizer. AXG is supported by the surgery department, Hospital Clínico Universitario, Valladolid, Spain. 47School Dr. Adam Linton Chair in Kidney Health Analytics. PLG has received speaker of Nursing, McMaster University, Hamilton, ON, Canada. 48Department of fees from Bayer, Bristol-Myers-Squibb, Pfizer, Leo Pharma and Valeo. TR re- Surgery, McMaster University, Hamilton, ON, Canada. 49Department of ports grants from UK, NIHR HTA; grants from Australian, NHMRC; grants, per- Medicine, London Health Sciences Centre, London, ON, Canada. sonal fees and non-financial support from Pharmocosmos; grants, personal 50 Department of Anaesthesia and Perioperative Medicine, Groote Schuur fees and non-financial support from Vifor Pharma; grants from UK, NIHR EME; Hospital and University of Cape Town, Cape Town, South Africa. grants from Australian MRFF; grants from Western Australia FHRF; grants and 51 Department of General Anaesthesiology, Emergency- and Intensive Care personal fees from Pfizer Australia; personal fees from BioAge Labs, outside Marcucci et al. Trials (2022) 23:101 Page 11 of 12 Medicine, Medical University Graz, Graz, Austria. 52Department of Surgery, A meta-analysis of 34 randomized controlled trials. Eur J Orthop Surg University of Manitoba, Winnipeg, Manitoba, Canada. 53Faculty of Health and Traumatol. 2015;25(3):525–41. https://doi.org/10.1007/s00590-014-1568-z. Medical Sciences, University of Western Australia, Perth, Australia. 16. Li ZJ, Fu X, Xing D, Zhang HF, Zang JC, Ma XL. Is tranexamic acid effective 54 Department of Anesthesiology, GH Paris Saint Joseph, Paris, France. and safe in spinal surgery? A meta-analysis of randomized controlled trials. Eur Spine J. 2013;22(9):1950–7. https://doi.org/10.1007/s00586-013-2774-9. Received: 24 September 2021 Accepted: 29 December 2021 17. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ. 2012;344:e3054. https://doi.org/10.1136/bmj.e3054. 18. Koh A, Adiamah A, Gomez D, Sanyal S. Safety and efficacy of tranexamic References acid in minimizing perioperative bleeding in extrahepatic abdominal 1. Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) surgery: meta-analysis. BJS Open. 2021;5(2):1-9. https://doi.org/10.1093/ Study Investigators, Devereaux PJ, Chan MT, et al. Association between bjsopen/zrab004. postoperative troponin levels and 30-day mortality among patients 19. Taeuber I, Weibel S, Herrmann E, Neef V, Schlesinger T, Kranke P, et al. undergoing noncardiac surgery. JAMA. 2012;307(21):2295–304. https://doi. Association of intravenous tranexamic acid with thromboembolic events org/10.1001/jama.2012.5502. and mortality: a systematic review, meta-analysis, and meta-regression. 2. Writing Committee for the VISION Study Investigators, Devereaux PJ, Biccard JAMA Surg. 2021;156(6):e210884. https://doi.org/10.1001/jamasurg.2021. BM, et al. Association of postoperative high-sensitivity troponin levels with 0884. myocardial injury and 30-day mortality among patients undergoing 20. Marcucci M, Duceppe E, Le Manach Y, et al. Tranexamic acid and noncardiac surgery. JAMA. 2017;317(16):1642–51. https://doi.org/10.1001/ja rosuvastatin in patients at risk of cardiovascular events after noncardiac ma.2017.4360. surgery: a pilot of the POISE-3 randomized controlled trial. Pilot Feasibility 3. Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) Stud. 2020;6(1):104. https://doi.org/10.1186/s40814-020-00643-9. Study Investigators. Association between complications and death within 21. Charlson ME, MacKenzie CR, Gold JP, Ales KL, Topkins M, Shires GT. 30 days after noncardiac surgery. CMAJ. 2019;191(30):E830–E7. https://doi. Intraoperative blood pressure. What patterns identify patients at risk for org/10.1503/cmaj.190221. postoperative complications. Ann Surg. 1990;212(5):567–80. https://doi.org/1 4. Devereaux PJ, Xavier D, Pogue J, Guyatt G, Sigamani A, Garutti I, et al. 0.1097/00000658-199011000-00003. Characteristics and short-term prognosis of perioperative myocardial 22. Howell SJ, Hemming AE, Allman KG, Glover L, Sear JW, Foex P. Predictors of infarction in patients undergoing noncardiac surgery: a cohort study. Ann postoperative myocardial ischaemia. The role of intercurrent arterial Intern Med. 2011;154(8):523–8. https://doi.org/10.7326/0003-4819-154-8-2 hypertension and other cardiovascular risk factors. Anaesthesia. 1997;52(2): 01104190-00003. 107–11. https://doi.org/10.1111/j.1365-2044.1997.29-az029.x. 5. Devereaux PJ, Mrkobrada M, Sessler DI, Leslie K, Alonso-Coello P, Kurz A, 23. Reich DL, Bennett-Guerrero E, Bodian CA, Hossain S, Winfree W, Krol M. et al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. Intraoperative tachycardia and hypertension are independently associated 2014;370(16):1494–503. https://doi.org/10.1056/NEJMoa1401105. with adverse outcome in noncardiac surgery of long duration. Anesth 6. Kamel H, Johnston SC, Kirkham JC, Turner CG, Kizer JR, Devereux RB, et al. Analg. 2002;95(2):273–7. https://doi.org/10.1213/00000539-200208000-00003. Association between major perioperative hemorrhage and stroke or Q-wave 24. Abbott TEF, Pearse RM, Archbold RA, Ahmad T, Niebrzegowska E, Wragg A, myocardial infarction. Circulation. 2012;126(2):207–12. https://doi.org/10.11 et al. A prospective international multicentre cohort study of intraoperative 61/CIRCULATIONAHA.112.094326. heart rate and systolic blood pressure and myocardial injury after 7. Garg AX, Kurz A, Sessler DI, Cuerden M, Robinson A, Mrkobrada M, et al. noncardiac surgery: results of the VISION study. Anesth Analg. 2018;126(6): Perioperative aspirin and clonidine and risk of acute kidney injury: a 1936–45. https://doi.org/10.1213/ANE.0000000000002560. randomized clinical trial. JAMA. 2014;312(21):2254–64. https://doi.org/10.1 25. Roshanov PS, Rochwerg B, Patel A, Salehian O, Duceppe E, Belley-Côté EP, 001/jama.2014.15284. et al. Withholding versus continuing angiotensin-converting enzyme 8. CRASH-2 trial Collaborators, Shakur H, Roberts I, et al. Effects of tranexamic inhibitors or angiotensin ii receptor blockers before noncardiac surgery: an acid on death, vascular occlusive events, and blood transfusion in trauma analysis of the Vascular events In noncardiac Surgery patIents cOhort patients with significant haemorrhage (CRASH-2): a randomised, placebo- evaluatioN prospective cohort. Anesthesiology. 2017;126(1):16–27. https:// controlled trial. Lancet. 2010;376(9734):23–32. https://doi.org/10.1016/S0140- doi.org/10.1097/ALN.0000000000001404. 6736(10)60835-5. 26. Devereaux PJ, Sessler DI, Leslie K, Kurz A, Mrkobrada M, Alonso-Coello P, 9. WOMAN Trial Collaborators. Effect of early tranexamic acid administration et al. Clonidine in patients undergoing noncardiac surgery. N Engl J Med. on mortality, hysterectomy, and other morbidities in women with post- 2014;370(16):1504–13. https://doi.org/10.1056/NEJMoa1401106. partum haemorrhage (WOMAN): an international, randomised, double-blind, 27. Group PS, Devereaux PJ, Yang H, et al. Effects of extended-release placebo-controlled trial. Lancet. 2017;389(10084):2105–16. https://doi.org/1 metoprolol succinate in patients undergoing non-cardiac surgery (POISE 0.1016/S0140-6736(17)30638-4. trial): a randomised controlled trial. Lancet. 2008;371(9627):1839–47. https:// 10. Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, et al. doi.org/10.1016/S0140-6736(08)60601-7. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J 28. Venkatesan S, Myles PR, Manning HJ, Mozid AM, Andersson C, Jørgensen Med. 2017;376(2):136–48. https://doi.org/10.1056/NEJMoa1606424. ME, et al. Cohort study of preoperative blood pressure and risk of 30-day 11. HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of mortality after elective non-cardiac surgery. Br J Anaesth. 2017;119(1):174. tranexamic acid on death and thromboembolic events in patients with https://doi.org/10.1093/bja/aex223. acute gastrointestinal bleeding (HALT-IT): an international randomised, 29. Walsh M, Devereaux PJ, Garg AX, Kurz A, Turan A, Rodseth RN, et al. double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927–36. Relationship between intraoperative mean arterial pressure and clinical https://doi.org/10.1016/S0140-6736(20)30848-5. outcomes after noncardiac surgery: toward an empirical definition of 12. Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use hypotension. Anesthesiology. 2013;119(3):507–15. https://doi.org/10.1097/A of antifibrinolytic therapy to reduce transfusion in patients undergoing LN.0b013e3182a10e26. orthopedic surgery: a systematic review of randomized trials. Thromb Res. 30. Salmasi V, Maheshwari K, Yang D, Mascha EJ, Singh A, Sessler DI, et al. 2009;123(5):687–96. https://doi.org/10.1016/j.thromres.2008.09.015. Relationship between intraoperative hypotension, defined by either reduction 13. Sukeik M, Alshryda S, Haddad FS, Mason JM. Systematic review and meta- from baseline or absolute thresholds, and acute kidney and myocardial injury analysis of the use of tranexamic acid in total hip replacement. J Bone Joint after noncardiac surgery: a retrospective cohort analysis. Anesthesiology. 2017; Surg Br. 2011;93(1):39–46. https://doi.org/10.1302/0301-620X.93B1.24984. 126(1):47–65. https://doi.org/10.1097/ALN.0000000000001432. 14. Zhang H, Chen J, Chen F, Que W. The effect of tranexamic acid on blood 31. Mascha EJ, Yang D, Weiss S, Sessler DI. Intraoperative mean arterial pressure loss and use of blood products in total knee arthroplasty: a meta-analysis. variability and 30-day mortality in patients having noncardiac surgery. Knee Surg Sports Traumatol Arthrosc. 2012;20(9):1742–52. https://doi.org/1 Anesthesiology. 2015;123(1):79–91. https://doi.org/10.1097/ALN. 0.1007/s00167-011-1754-z. 0000000000000686. 15. Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P. Is tranexamic acid 32. Futier E, Lefrant JY, Guinot PG, Godet T, Lorne E, Cuvillon P, et al. Effect of clinically effective and safe to prevent blood loss in total knee arthroplasty? individualized vs standard blood pressure management strategies on Marcucci et al. Trials (2022) 23:101 Page 12 of 12 postoperative organ dysfunction among high-risk patients undergoing major surgery: a randomized clinical trial. JAMA. 2017;318(14):1346–57. https://doi.org/10.1001/jama.2017.14172. 33. Wu X, Jiang Z, Ying J, Han Y, Chen Z. Optimal blood pressure decreases acute kidney injury after gastrointestinal surgery in elderly hypertensive patients: a randomized study: optimal blood pressure reduces acute kidney injury. J Clin Anesth. 2017;43:77–83. https://doi.org/10.1016/j.jclinane.2017.09. 004. 34. Bertrand M, Godet G, Meersschaert K, Brun L, Salcedo E, Coriat P. Should the angiotensin II antagonists be discontinued before surgery. Anesth Analg. 2001;92(1):26–30. https://doi.org/10.1097/00000539-200101000-00006. 35. Coriat P, Richer C, Douraki T, Gomez C, Hendricks K, Giudicelli JF, et al. Influence of chronic angiotensin-converting enzyme inhibition on anesthetic induction. Anesthesiology. 1994;81(2):299–307. https://doi.org/1 0.1097/00000542-199408000-00006. 36. Schirmer U, Schurmann W. Preoperative administration of angiotensin- converting enzyme inhibitors. Anaesthesist. 2007;56(6):557–61. https://doi. org/10.1007/s00101-007-1177-x. 37. Roshanov PS, Eikelboom JW, Sessler DI, Kearon C, Guyatt GH, Crowther M, et al. Bleeding Independently associated with Mortality after noncardiac Surgery (BIMS): an international prospective cohort study establishing diagnostic criteria and prognostic importance. Br J Anaesth. 2021;126(1): 163–71. https://doi.org/10.1016/j.bja.2020.06.051. 38. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth universal definition of myocardial infarction (2018). J Am Coll Cardiol. 2018;72(18):2231–64. https://doi.org/10.1016/j.jacc.2018.08.1038. 39. Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG, Group C. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 2012;308(24):2594–604. https://doi. org/10.1001/jama.2012.87802. 40. Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ. 2010; 340:c117. https://doi.org/10.1136/bmj.c117. 41. Schandelmaier S, Briel M, Varadhan R, Schmid CH, Devasenapathy N, Hayward RA, et al. Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses. CMAJ. 2020;192(32):E901–E6. https://doi.org/10.1503/ cmaj.200077. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.