Associations of inflammatory biomarkers with morbidity and mortality after noncardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Noncardiac surgery is associated with an inflammatory response. Whether increased inflammation in the perioperative period is associated with subsequent morbidity and mortality is unknown. METHODS: MEDLINE, EMBASE, and CENTRAL were systematically searched from date of inception until May 2023. Longitudinal studies were included if they reported multivariable adjusted associations of biomarkers measured preoperatively and/or within 10 days after surgery with at least one prespecified adverse outcome in noncardiac surgery patients. Data were extracted independently and in duplicate. Risk estimates were pooled using DerSimonian-Laird random-effects models and reported as summary odds ratios (ORs) with 95% CIs. The outcomes were all-cause mortality and major adverse cardiovascular events. RESULTS: Fifty-two studies with a total of 121,849 patients were included. The median follow-up was 56 [IQR, 28-63] months and the average age was 57 (±3) years. Elevated preoperative C-reactive protein (CRP) levels were associated with a higher risk of mortality (OR 1.57, 95% CI 1.29-1.90, I2 = 93%, 28 studies). This association was stronger in non-cancer surgery populations (OR 2.10, 95% CI 1.92-2.31, I2 = 0%, 4 studies) when compared to cancer surgery populations (OR 1.51, 95% CI 1.26-1.81, I2 = 83%, 24 studies) (p for subgroup difference = 0.001). Similarly, higher postoperative CRP levels were associated with all-cause mortality (OR 1.61, 95% CI 1.17-2.20, I2 = 90%, 7 studies). Higher preoperative CRP levels were associated with major cardiovascular events (OR 2.11, 95% CI 1.51-2.94, I2 = 0%, 2 studies). Other preoperatively measured biomarkers associated with all-cause mortality were fibrinogen (OR 1.48, 95% CI 1.05-2.09, I2 = 52%, 5 studies), interleukin-6 (OR 1.17, 95% CI 1.07-1.28, I2 = 27%, 3 studies), and tumour necrosis factor-alpha (OR 1.37, 95% CI 1.16-1.61, I2 = 0%, 2 studies). CONCLUSION AND RELEVANCE: Inflammatory biomarker levels in the perioperative period were associated with all-cause mortality and adverse cardiovascular events in patients undergoing noncardiac surgery.

Perioperative management and outcomes in patients receiving low-dose rivaroxaban and/or aspirin: a subanalysis of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial.

BACKGROUND: No study has investigated the perioperative management and clinical outcomes in patients who are receiving rivaroxaban 2.5 mg twice a day and acetylsalicylic acid (ASA) 81 to 100 mg daily. OBJECTIVE: To assess perioperative management and outcomes in patients who are receiving low-dose rivaroxaban, 2.5 mg twice-daily, and low-dose ASA, 81 to 100 mg daily. To assess perioperative management and outcomes in patients who are receiving low-dose rivaroxaban, 2.5 mg twice-daily, and low-dose ASA, 81 to 100 mg daily. METHODS: Subanalysis of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was performed to assess perioperative management and clinical outcomes in patients with stable coronary or peripheral artery disease who were randomized to receive rivaroxaban 2.5 mg twice a day plus ASA 100 mg daily, rivaroxaban 5 mg twice a day, or ASA 100 mg daily. Patients studied required a surgery/procedure during the trial. The study outcomes, which included myocardial infarction, angina, stroke, acute limb ischemia, bleeding, and death, were assessed according to treatment allocation. RESULTS: There were 2632 patients studied (mean age, 68 years; 80% male) who had a surgery/procedure, comprising percutaneous coronary interventions (∼43%), carotid or other arterial angioplasty (∼15%), pacemaker or internal cardiac defibrillator implantation (∼9%), and coronary artery bypass graft surgery (∼7%). Perioperative study drug management varied, with about one-third of patients not interrupting study drug and the remainder interrupting it between 1 and ≥10 days preprocedure. The incidences of adverse outcomes across treatment groups were 12.7% to 15.3% for myocardial ischemia, 0.8% to 1.2% for stroke, 0.1% to 0.2% for venous thromboembolism, and 3.1% to 4.2% for any bleeding. There was no statistically significant difference in outcome rates across treatment groups. CONCLUSION: In patients in the COMPASS trial who required a surgery/procedure, there was no significant difference in perioperative adverse outcomes whether patients were receiving rivaroxaban 2.5 mg twice a day and ASA 100 mg daily, rivaroxaban 5 mg twice a day, or ASA alone.

Rhythm vs. Rate Control in Patients with Postoperative Atrial Fibrillation after Cardiac Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery; it is associated with morbidity and mortality. We undertook this review to compare the effects of rhythm vs. rate control in this population. METHODS: We searched MEDLINE, Embase and CENTRAL to March 2023. We included randomized trials and observational studies comparing rhythm to rate control in cardiac surgery patients with POAF. We used a random-effects model to meta-analyze data and rated the quality of evidence using GRADE. RESULTS: From 8,110 citations, we identified 8 randomized trials (990 patients). Drug regimens used for rhythm control included amiodarone in four trials, other class III anti-arrhythmics in one trial, class I anti-arrhythmics in four trials and either a class I or III anti-arrhythmic in one trial. Rhythm control compared to rate control did not result in a significant difference in length of stay (mean difference -0.8 days; 95% CI -3.0 to +1.4, I2 = 97%), AF recurrence within 1 week (130 events; risk ratio [RR] 1.1; 95%CI 0.6-1.9, I2 = 54%), AF recurrence up to 1 month (37 events; RR 0.9; 95%CI 0.5-1.8, I2 = 0%), AF recurrence up to 3 months (10 events; RR 1.0; 95%CI 0.3-3.4, I2 = 0%) or mortality (25 events; RR 1.6; 95%CI 0.7-3.5, I2 = 0%). Effect measures from seven observational studies (1428 patients) did not differ appreciably from those in randomized trials. CONCLUSIONS: Although atrial fibrillation is common after cardiac surgery, limited low-quality data guide its management. Limited available evidence suggests no clear advantage to either rhythm or rate control. A large-scale randomized trial is needed to inform this important clinical question.

Lessons from the COVID-19 pandemic and recent developments on the communication of clinical trials, publishing practices, and research integrity: in conversation with Dr. David Moher.

BACKGROUND: The torrent of research during the coronavirus (COVID-19) pandemic has exposed the persistent challenges with reporting trials, open science practices, and scholarship in academia. These real-world examples provide unique learning opportunities for research methodologists and clinical epidemiologists-in-training. Dr. David Moher, a recognized expert on the science of research reporting and one of the founders of the Consolidated Standards of Reporting Trials (CONSORT) statement, was a guest speaker for the 2021 Hooker Distinguished Visiting Professor Lecture series at McMaster University and shared his insights about these issues. MAIN TEXT: This paper covers a discussion on the influence of reporting guidelines on trials and issues with the use of CONSORT as a measure of quality. Dr. Moher also addresses how the overwhelming body of COVID-19 research reflects the "publish or perish" paradigm in academia and why improvement in the reporting of trials requires policy initiatives from research institutions and funding agencies. We also discuss the rise of publication bias and other questionable reporting practices. To combat this, Dr. Moher believes open science and training initiatives led by institutions can foster research integrity, including the trustworthiness of researchers, institutions, and journals, as well as counter threats posed by predatory journals. He highlights how metrics like journal impact factor and quantity of publications also harm research integrity. Dr. Moher also discussed the importance of meta-science, the study of how research is carried out, which can help to evaluate audit and feedback systems and their effect on open science practices. CONCLUSION: Dr. Moher advocates for policy to further improve the reporting of trials and health research. The COVID-19 pandemic has exposed how a lack of open science practices and flawed systems incentivizing researchers to publish can harm research integrity. There is a need for a culture shift in assessing careers and "productivity" in academia, and this requires collaborative top-down and bottom-up approaches.

Tranexamic Acid in Patients Undergoing Noncardiac Surgery.

BACKGROUND: Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. 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.).

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.

Short-term and Long-term Risk of Stroke in Patients With Perioperative Atrial Fibrillation After Cardiac Surgery: Systematic Review and Meta-analysis.

BACKGROUND: Perioperative atrial fibrillation (POAF) after cardiac surgery has been associated with an increased risk of stroke in some studies. However, the exact magnitude of this association during short-term and long-term follow-up remains unclear. METHODS: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) for the time period from database inception to October 2020. We included observational studies with ≥ 100 patients that reported data on short-term or long-term stroke risk in patients with and without POAF after cardiac surgery. Data were pooled using random-effects models. We reported summary risk ratios (RRs) for studies reporting multivariable adjusted results and calculated absolute risk differences (ARDs) with 95% confidence intervals (CIs). RESULTS: A total of 55 studies with 540,209 patients were included. POAF was associated with both an increased relative risk (RR 1.69; 95% CI, 1.41-2.03; I2 = 82%; 9 studies) and absolute risk of short-term stroke (4.5% vs 2.5%; ARD 2.0%; 95% CI, 1.28-2.89). POAF was associated with an increased relative risk (RR 1.20; 95% CI, 1.12-1.29; I2 = 16%; 10 studies) and absolute risk of long-term stroke (1.06 vs 0.88 per 100 patient-years; ARD 0.18 per 100 patient-years; 95% CI, 0.07-0.26). Sensitivity analyses of high-quality studies and studies reporting either ischemic or embolic strokes yielded similar findings. CONCLUSIONS: POAF after cardiac surgery was associated with an increased risk of both short-term and long-term stroke. However, the long-term stroke ARD was small, and whether these patients will benefit from long-term oral anticoagulation therapy is unclear.

CONTEXTE: La fibrillation auriculaire périopératoire (FAPO) après une chirurgie cardiaque a été associée à un risque accru d'accident vasculaire cérébral (AVC) dans certaines études. Cependant, l'ampleur exacte de cette association durant le suivi à court et à long terme reste incertaine. MÉTHODOLOGIE: Nous avons effectué des recherches dans les bases de données PubMed, Embase et CENTRAL (Cochrane Central Register of Controlled Trials) pour la période allant de la création de ces bases à octobre 2020. Nous avons inclus des études d'observation comptant ≥ 100 patients et rapportant des données sur le risque d'AVC à court ou à long terme chez les patients ayant présenté ou non une FAPO après une chirurgie cardiaque. Les données ont été regroupées à l'aide de modèles à effets aléatoires. Nous avons consigné les rapports de risque (RR) sommaires pour les études rapportant des résultats corrigés multivariables et calculé les différences de risque absolu (DRA) avec des intervalles de confiance (IC) à 95 %. RÉSULTATS: Au total, 55 études portant sur 540 209 patients ont été incluses. La FAPO était associée à une augmentation tant du risque relatif (RR : 1,69; IC à 95 % : 1,41 à 2,03; I2 = 82 %; 9 études) que du risque absolu d'AVC à court terme (4,5 % vs 2,5 %; DRA : 2,0 %; IC à 95 % : 1,28 à 2,89). La FAPO était également associée à une augmentation du risque relatif (RR : 1,20; IC à 95 % : 1,12 à 1,29; I2 = 16 %; 10 études) et du risque absolu d'AVC à long terme (1,06 vs 0,88 par 100 années-patients; DRA : 0,18 par 100 années-patients; IC à 95 % : 0,07 à 0,26). Les analyses de sensibilité des études de haute qualité et des études rapportant des AVC ischémiques ou emboliques ont donné des résultats similaires. CONCLUSIONS: La FAPO après une chirurgie cardiaque a été associée à un risque accru d'AVC à court et à long terme. Cependant, comme la différence de risque absolu d'AVC à long terme était faible, la possibilité qu'une anticoagulothérapie orale à long terme soit bénéfique pour ces patients est incertaine.

New-Onset Perioperative Atrial Fibrillation After Coronary Artery Bypass Grafting and Long-Term Risk of Adverse Events: An Analysis From the CORONARY Trial.

Background Perioperative atrial fibrillation (POAF) is common in patients undergoing cardiac surgery. Conflicting evidence exists whether patients with POAF after cardiac surgery have an increased long-term risk of stroke and other adverse events. Methods and Results We prospectively followed for up to 5 years 4624 patients without prior atrial fibrillation who underwent coronary artery bypass grafting in an international study. POAF was defined as atrial fibrillation that occurred during the initial hospitalization for surgery, lasted for ≥5 minutes, and required treatment. Outcomes assessed were a composite of death, nonfatal myocardial infarction or nonfatal stroke, and its individual components. Median age was 67 years, and 778 (16.8%) had an episode of POAF. The incidence of the composite outcome was 6.84 and 4.10 per 100 patient-years in patients with and without POAF, and the incidence of stroke was 0.75 versus 0.45, respectively. The adjusted hazard ratios (aHRs) were 1.36 (95% CI, 1.16-1.59) for the composite outcome; 1.33 (95% CI, 1.10-1.61) for death; 1.58 (95% CI, 1.23-2.02) for myocardial infarction, and 1.27 (95% CI, 0.81-2.00) for stroke. In a landmark analysis excluding events of the initial hospital admission, the aHRs were 1.26 (95% CI, 1.03-1.54) for the composite outcome, 1.28 (95% CI, 1.03-1.59) for death, 1.70 (95% CI, 0.86-3.36) for myocardial infarction, and 1.07 (95% CI, 0.59-1.93) for stroke. At hospital discharge, 10.7% and 1.4% of patients with and without POAF received oral anticoagulation, respectively. Conclusions Patients with POAF after cardiac surgery had an increased long-term risk of adverse outcomes, mainly death and myocardial infarction. The risk of stroke was low and not increased in patients with POAF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00463294.

A sickle cell disease patient with dural venous sinus thrombosis: a case report and literature review.

Dural venous sinus thrombosis (DVST) is a rare disease associated with hypercoagulable states. Patients with sickle cell disease are known to be prothrombotic. We report a case of DVST presenting with anterior neck and facial pain in a 24-year-old female with sickle cell disease, found to have extensive thrombotic disease involving the internal jugular vein. A literature review of DVST in sickle cell disease consisting of 14 case reports was summarized. Headache was a presenting feature in two-thirds of patients. Nine cases were associated with vaso-occlusive crisis (VOC), transfusion, or acute respiratory illness. Most patients were treated with anticoagulation therapy. Over three-quarters either died or suffered from a serious neurological complication, including stroke, seizure, coma, or elevated intracranial pressure. Given its association with life-threatening complications, DVST should be considered when patients with sickle cell disease present with a VOC, especially in the context of headache or neurological deficits.

Compliance With Fecal Calprotectin Testing in Pediatric Patients With Inflammatory Bowel Disease.

Fecal calprotectin (FC) is a highly sensitive biomarker for inflammatory bowel diseases (IBDs). Utilization of this assay has been steadily increasing. Adherence levels for FC have, however, yet to be examined in the pediatric IBD setting. We analyzed 100 consecutive patients diagnosed with IBD between 2014 and 2015 at Texas Children's Hospital. Fifty-six percent of patients were men and median age at diagnosis was 13.7 years. Following diagnosis of IBD, 84 patients had a minimum of 1 FC requested, and 95.2% of these patients completed the test at least once. An average of 2 FCs per patient was ordered each year, and the overall compliance was 76.6%. Patients who completed the initial testing with a minimum of 3 consecutive tests were more likely to remain compliant than those who failed to perform the first lab (P < 0.001). Our findings indicate good compliance with FC testing in pediatric patients with IBD.

Mild neonatal hyperthyrotrophinaemia: 10-year experience suggests the condition is increasingly common but often transient.

OBJECTIVE: To examine a large population of infants with mild neonatal hyperthyrotrophinaemia (MNH) and determine prevalence, clinical characteristics and treatment history. METHODS: Retrospective study of infants with MNH followed at The Hospital for Sick Children between 2000 and 2011. MNH was defined by an abnormal newborn screen followed by thyroid-stimulating hormone (TSH) between 5 and 30 mU/l and normal free T4 (FT4) on confirmatory tests. RESULTS: Mild neonatal hyperthyrotrophinaemia represented 22·3% of patients (103/462; 60 boys, 43 girls) within our clinic. Incidence increased from two of 20 in 2000 to 31 of 74 cases in 2010. Seventy eight percent of patients started L-thyroxine (initial dose: 8·3 ± 2·5 mcg/kg). The treated group had higher confirmatory TSH levels (P = 0·001) and had undergone thyroid scintigraphy more often (P = 0·0001) compared with the nontreated group. Evidence of overtreatment was detected in 45% of thyroid function tests obtained during treatment. Among the treated infants who had reached 3 years of age, 45% (N = 14) underwent a trial-off medication. Compared with those not trialled-off therapy, these infants were less likely to have had dose escalations during treatment (P = 0·001). The trial-off treatment was successful in 50% of cases. In the subset of infants with confirmatory TSH >10 mU/l, trial-off therapy was successful in 40%. None of the assessed variables predicted success of trial-off therapy. CONCLUSIONS: Mild neonatal hyperthyrotrophinaemia is an increasingly common diagnosis. It is more common in males and is often transient, but predictors of success of trial-off therapy were not identified. Further studies are needed to determine optimum L-thyroxine dosing and to determine whether treatment improves neurocognitive outcomes.