Associations of Inflammatory Biomarkers With the Risk of Morbidity and Mortality After Cardiac Surgery: A Systematic Review and Meta-analysis.

BACKGROUND: Although inflammatory biomarkers have been associated with cardiovascular events in nonsurgical settings, these associations have not been systematically addressed in patients undergoing cardiac surgery. This review aimed to evaluate the relationships of inflammatory markers with mortality and adverse cardiovascular events in patients undergoing cardiac surgery. METHODS: Medline, Embase, and Central databases were systematically searched for studies reporting pre- or postoperative levels of inflammatory biomarkers in patients undergoing cardiac surgery. Outcomes of interest were postoperative mortality, nonfatal myocardial infarction, stroke, congestive heart failure, and major adverse cardiovascular events (MACE). Studies reporting multivariable adjusted risk estimates were included. Risk estimates were pooled with the use of random-effects models and reported as summary odds ratios (ORs). RESULTS: Among 14,465 citations identified, 29 studies including 29,401 participants met the eligibility criteria. The average follow-up time after surgery was 31 months. Preoperative C-reactive protein (CRP) levels were associated with an increased risk of all-cause mortality (OR 1.88, 95% CI 1.60-2.20; I2 = 19%; 11 studies) and MACE (OR 1.73, 95% CI 1.34-2.24; I2 = 0%; 3 studies). CRP levels measured on postoperative day 6 (OR 7.4, 95% CI 2.90-18.88, 1 study) and day 10 (OR 11.8, 95% CI 3.50-39.78, 1 study) were associated with a higher risk of all-cause mortality. Less, but overall similar, information was available for other inflammatory biomarkers. CONCLUSIONS: In this large meta-analysis, inflammatory biomarkers measured before or after cardiac surgery were associated with mortality and adverse cardiovascular outcomes in patients undergoing cardiac surgery.

Anticoagulation use in perioperative atrial fibrillation after noncardiac surgery: a systematic review and meta-analysis.

BACKGROUND: Perioperative atrial fibrillation is associated with an increased risk of stroke, myocardial infarction, and death after noncardiac surgery. Anticoagulation therapy is effective for stroke prevention in nonsurgical atrial fibrillation, but its efficacy and safety in perioperative atrial fibrillation are unknown. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from database inception until January 2022. We included studies comparing anticoagulation versus no anticoagulation use in patients with perioperative atrial fibrillation after noncardiac surgery. Our study outcomes included stroke ± systemic embolism, bleeding, mortality, myocardial infarction, and venous thromboembolism. We pooled studies using fixed-effects models. We reported summary risk ratios (RRs) for studies reporting multivariable-adjusted results. RESULTS: Seven observational studies but no randomised trials were included. Of the 27,822 patients, 29.1% were prescribed therapeutic anticoagulation. Anticoagulation use was associated with a lower risk of stroke ± systemic embolism (RR 0.73; 95% CI, 0.62-0.85; I2 = 81%; 3 studies) but a higher risk of bleeding (RR 1.14; 95% CI, 1.04-1.25; 1 study). There was a lower risk of mortality associated with anticoagulation use (RR 0.45; 95% CI, 0.40-0.51; I2 = 80%; 2 studies). There was no difference in the risk of myocardial infarction (RR 2.19; 95% CI, 0.97-4.96; 1 study). The certainty of the evidence was very low across all outcomes. CONCLUSION: Anticoagulation is associated with a reduced risk of stroke and death but an increased risk of bleeding. The quality of the evidence is very poor. Randomised trials are needed to better determine the effects of anticoagulation use in this population.

Rationale and design of the colchicine for the prevention of perioperative atrial fibrillation in patients undergoing major noncardiac thoracic surgery (COP-AF) trial.

BACKGROUND: Perioperative atrial fibrillation (AF) and myocardial injury after noncardiac surgery (MINS) are common complications after noncardiac surgery. Inflammation has been implicated in the pathogenesis of both disorders. The COP-AF trial tests the hypothesis that colchicine reduces the incidence of perioperative AF and MINS in patients undergoing major noncardiac thoracic surgery. 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.

Use of Anticoagulation Therapy in Patients With Perioperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-analysis.

Background: Perioperative atrial fibrillation (POAF) after cardiac surgery is associated with an increased risk of stroke. However, the efficacy and safety of using anticoagulation therapy in this population are unknown. Methods: We performed a systematic review and meta-analysis of studies comparing use of anticoagulation therapy vs no anticoagulation therapy in patients with POAF after cardiac surgery. Outcomes included arterial thromboembolism (ie, stroke ± systemic embolism) and bleeding. Data were pooled using fixed-effects models. We reported summary risk ratios (RRs) for studies with multivariable adjustment and estimated absolute risk differences with 95% confidence intervals (CIs). Results: Nine observational studies met eligibility criteria. No randomized trials were identified. Of the 254,200 POAF patients included, 27.3% received anticoagulation. Six studies reported outcomes after long-term follow-up (median 5.0 years; range 4.2-10.0). The risk of arterial thromboembolism was lower in patients receiving anticoagulation therapy (RR 0.83; 95% CI, 0.69-0.99; I2 = 57%; P = 0.04; 6 studies). The estimated short-term and long-term absolute risk reductions in arterial thromboembolism with use of anticoagulation therapy were 0.8% (95% CI, 0.4-1.4) and 2 events per 1000 person-years (95% CI, 0-4), respectively. The risk of bleeding was higher in patients receiving anticoagulation therapy (RR 3.22; 95% CI, 2.82-3.68; I2 = 98%; P < 0.001; 2 studies). The estimated short-term and long-term absolute risk increases in bleeding with use of anticoagulation therapy were 0.5% (95% CI, 0.4-0.6) and 42 events per 1000 person-years (95% CI, 35-51), respectively. Conclusions: Use of anticoagulation therapy is associated with a small reduction in the risk of arterial thromboembolism, but also an increased risk of bleeding. Randomized controlled trials are needed to address this issue.

Introduction: La fibrillation auriculaire périopératoire (FAPO) après l'intervention chirurgicale au cœur est associée à une augmentation du risque d'accident vasculaire cérébral (AVC). Toutefois, on ne connaît pas l'efficacité et l'innocuité de la l'anticoagulothérapie de cette population. Méthodes: Nous avons réalisé une revue systématique et une méta-analyse d'études qui comparaient l'utilisation de l'anticoagulothérapie vs l'absence d'anticoagulothérapie chez les patients atteints de FAPO après l'intervention chirurgicale au cœur. Les résultats étaient notamment la thromboembolie artérielle (c.-à-d. l'AVC ± l'embolie systémique) et les hémorragies. Nous avons regroupé les données à l'aide de modèles à effets fixes. Nous avons rapporté les risques relatifs (RR) sommaires d'études avec l'ajustement multivarié et l'estimation des différences du risque absolu avec des intervalles de confiance (IC) à 95 %. Résultats: Neuf études observationnelles répondaient aux critères d'admissibilité. Aucun essai à répartition aléatoire n'a été trouvé. Parmi les 254 200 patients atteints de FAPO sélectionnés, 27,3 % avaient reçu une anticoagulation. Six études révélaient des résultats après le suivi à long terme (médiane 5,0 ans ; fourchette 4,2-10,0). Le risque de thromboembolie artérielle était plus faible chez les patients qui avaient reçu une anticoagulothérapie (RR 0,83 ; IC à 95 %, 0,69-0,99 ; I2 = 57 % ; P = 0,04 ; six études). Les estimations de réduction du risque absolu à court terme et à long terme lors de thromboembolie artérielle avec l'utilisation de l'anticoagulothérapie étaient respectivement de 0,8 % (IC à 95 %, 0,4-1,4) et de deux événements par 1000 personnes-années (IC à 95 %, 0-4). Le risque d'hémorragie était plus élevé chez les patients qui avaient reçu une anticoagulothérapie (RR 3,22 ; IC à 95 %, 2,82-3,68 ; I2 = 98 % ; P < 0,001 ; deux études). Les estimations d'augmentation du risque absolu à court terme et à long terme des hémorragies avec l'utilisation de l'anticoagulothérapie étaient respectivement de 0,5 % (IC à 95 %, 0,4-0,6) et de 42 événements par 1000 personnes-années (IC à 95 %, 35-51). Conclusions: L'utilisation de l'anticoagulothérapie est associée à une réduction minime du risque de thromboembolie artérielle, mais aussi à une augmentation du risque d'hémorragie. Des essais cliniques à répartition aléatoire sont nécessaires pour aborder cette question.

Cardiovascular imaging following perioperative myocardial infarction/injury.

Patients developing perioperative myocardial infarction/injury (PMI) have a high mortality. PMI work-up and therapy remain poorly defined. This prospective multicenter study included high-risk patients undergoing major non-cardiac surgery within a systematic PMI screening and clinical response program. The frequency of cardiovascular imaging during PMI work-up and its yield for possible type 1 myocardial infarction (T1MI) was assessed. Automated PMI detection triggered evaluation by the treating physician/cardiologist, who determined selection/timing of cardiovascular imaging. T1M1 was considered with the presence of a new wall motion abnormality within 30 days in transthoracic echocardiography (TTE), a new scar or ischemia within 90 days in myocardial perfusion imaging (MPI), and Ambrose-Type II or complex lesions within 7 days of PMI in coronary angiography (CA). In patients with PMI, 21% (268/1269) underwent at least one cardiac imaging modality. TTE was used in 13% (163/1269), MPI in 3% (37/1269), and CA in 5% (68/1269). Cardiology consultation was associated with higher use of cardiovascular imaging (27% versus 13%). Signs indicative of T1MI were found in 8% of TTE, 46% of MPI, and 63% of CA. Most patients with PMI did not undergo any cardiovascular imaging within their PMI work-up. If performed, MPI and CA showed high yield for signs indicative of T1MI.Trial registration: https://clinicaltrials.gov/ct2/show/NCT02573532 .

The Admit-AF risk score: A clinical risk score for predicting hospital admissions in patients with atrial fibrillation.

AIMS: To develop and externally validate a risk score for all-cause hospital admissions in patients with atrial fibrillation. METHODS AND RESULTS: We used a prospective cohort of 2387 patients with established atrial fibrillation as derivation cohort. Independent risk factors were selected from a broad range of variables using the least absolute shrinkage and selection operator method fit to a Cox model. The risk score was validated in a separate prospective cohort of 1300 atrial fibrillation patients. The incidence of all-cause hospital admission was 19.1 per 100 person-years in the derivation cohort and it was 26.1 per 100 person-years in the validation cohort. The most important predictors for admission were age (75-79 years: adjusted hazard ratio (aHR), 1.34; 95% confidence interval (CI), 1.01-1.78; 80-84 years: aHR, 1.50; 95% CI, 1.11-2.03; ≥85 years: aHR, 1.88; 95% CI, 1.36-2.62), prior pulmonary vein isolation (aHR, 0.72; 95% CI, 0.58-0.88), hypertension (aHR, 1.16; 95% CI, 0.99-1.36), diabetes (aHR, 1.38; 95% CI, 1.17-1.62), coronary heart disease (aHR, 1.17; 95% CI, 1.02-1.36), prior stroke/transient ischaemic attack (aHR, 1.26; 95% CI, 1.18-1.47), heart failure (aHR, 1.19; 95% CI, 1.03-1.39), peripheral artery disease (aHR, 1.35; 95% CI, 1.08-1.67), cancer (aHR, 1.33; 95% CI, 1.12-1.57), renal failure (aHR, 1.17; 95% CI, 0.99-1.37) and previous falls (aHR, 1.40; 95% CI, 1.13-1.74). A risk score with these variables was well calibrated, and achieved a C-index of 0.64 in the derivation and 0.59 in the validation cohort. CONCLUSIONS: Multiple risk factors were associated with hospital admissions in atrial fibrillation patients. This prediction tool selects high-risk patients who may benefit from preventive interventions.

Heart Rate Variability Triangular Index as a Predictor of Cardiovascular Mortality in Patients With Atrial Fibrillation.

Background Impaired heart rate variability (HRV) is associated with increased mortality in sinus rhythm. However, HRV has not been systematically assessed in patients with atrial fibrillation (AF). We hypothesized that parameters of HRV may be predictive of cardiovascular death in patients with AF. Methods and Results From the multicenter prospective Swiss-AF (Swiss Atrial Fibrillation) Cohort Study, we enrolled 1922 patients who were in sinus rhythm or AF. Resting ECG recordings of 5-minute duration were obtained at baseline. Standard parameters of HRV (HRV triangular index, SD of the normal-to-normal intervals, square root of the mean squared differences of successive normal-to-normal intervals and mean heart rate) were calculated. During follow-up, an end point committee adjudicated each cause of death. During a mean follow-up time of 2.6±1.0 years, 143 (7.4%) patients died; 92 deaths were attributable to cardiovascular reasons. In a Cox regression model including multiple covariates (age, sex, body mass index, smoking status, history of diabetes mellitus, history of hypertension, history of stroke/transient ischemic attack, history of myocardial infarction, antiarrhythmic drugs including ß blockers, oral anticoagulation), a decreased HRV index ≤ median (14.29), but not other HRV parameters, was associated with an increase in the risk of cardiovascular death (hazard ratio, 1.7; 95% CI, 1.1-2.6; P=0.01) and all-cause death (hazard ratio, 1.42; 95% CI, 1.02-1.98; P=0.04). Conclusions The HRV index measured in a single 5-minute ECG recording in a cohort of patients with AF is an independent predictor of cardiovascular mortality. HRV analysis in patients with AF might be a valuable tool for further risk stratification to guide patient management. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.

Discontinuation of dual antiplatelet therapy and bleeding in intensive care in patients undergoing urgent coronary artery bypass grafting: a retrospective analysis.

OBJECTIVES: Our goal was to evaluate the impact of the discontinuation times of dual antiplatelet therapy with clopidogrel, prasugrel or ticagrelor on postoperative bleeding rates and the use of blood products in patients undergoing isolated urgent coronary artery bypass grafting (CABG). METHODS: We retrospectively analysed 334 patients with acute coronary syndrome undergoing urgent CABG at the University Hospital Basel. A total of 262 patients continued to take dual antiplatelet therapy during the surgery (72 received clopidogrel; 68, prasugrel; and 122, ticagrelor). They were stratified by the discontinuation time of dual antiplatelet therapy (<24 h, 24-48 h, 48-72 h and >72 h). Seventy-two patients taking acetylsalicylic acid (ASA) as monotherapy served as a comparison group. RESULTS: Median postsurgical bleeding rates were significantly higher with ticagrelor if it was discontinued <24 h [1220 ml, interquartile range (IQR) 978-1520 ml; P < 0.001], 24-48 h (1200 ml, IQR 800-1550 ml; P < 0.001) and 48-72 h (1100 ml, IQR 845-1245 ml; P = 0.036) but not if discontinued >72 h (700 ml, IQR 520-825 ml; P = 0.22) and with prasugrel if discontinued <24 h (1320 ml, IQR 900-1950 ml; P < 0.001) but not if discontinued 24-48 h (1050 ml, IQR 638-1438 ml; P = 0.089) or >72 h (750 ml, IQR 488-1040; P = 0.63) compared to ASA monotherapy (800 ml, IQR 593-1043 ml). The postsurgical use of blood products compared to ASA monotherapy (0, IQR 0-2 units) was significantly higher with ticagrelor and prasugrel if discontinued <24 h (2.5 units, IQR 0-6; P < 0.001 and 2 units, IQR 1-6; P < 0.001, respectively). CONCLUSIONS: Discontinuation of ticagrelor and prasugrel for more than 72 h before urgent CABG was not associated with higher bleeding rates compared to treatment with ASA monotherapy. In contrast, discontinuation for less than 24 h was associated with higher use of blood products. For ticagrelor, this study supports evidence and recent guidelines proposing a shorter discontinuation time of 3 days and raises the question of whether the same could be true for prasugrel.

Fibroblast growth factor 23 and renal function among young and healthy individuals.

BACKGROUND: Fibroblast growth factor 23 (FGF-23), an osteocyte hormone involved in the regulation of phosphate metabolism, is associated with incident and progressive chronic kidney disease. We aimed to assess the association of FGF-23 with renal parameters, vascular function and phosphate metabolism in a large cohort of young and healthy individuals. METHODS: Healthy individuals aged 25-41 years were included in a prospective population-based study. Fasting venous blood and morning urinary samples were used to measure plasma creatinine, cystatin C, endothelin-1, phosphate and plasma FGF-23 as well as urinary creatinine and phosphate. Multivariable regression models were constructed to assess the relationship of FGF-23 with parameters of renal function, endothelin-1 and fractional phosphate excretion. RESULTS: The median age of 2077 participants was 37 years, 46% were males. The mean estimated glomerular filtration rate (eGFR - CKD-EPI creatinine-cystatin C equation) and fractional phosphate excretion were 110 mL/min/1.73 m2 and 8.7%, respectively. After multivariable adjustment, there was a significant inverse relationship of FGF-23 with eGFR (ß per 1 log-unit increase -3.81; 95% CI [-5.42; -2.20]; p<0.0001). Furthermore, we found a linear association between FGF-23 and endothelin-1 (ß per 1 log-unit increase 0.06; [0.01, 0.11]; p=0.01). In addition, we established a significant relationship of FGF-23 with fractional phosphate excretion (ß per 1 log-unit increase 0.62; [0.08, 1.16]; p=0.03). CONCLUSIONS: Increasing plasma FGF-23 levels are strongly associated with decreasing eGFR and increasing urinary phosphate excretion, suggesting an important role of FGF-23 in the regulation of kidney function in young and healthy adults.

Bariatric surgery among patients with heart failure: a systematic review and meta-analysis.

Background: Bariatric surgery reduces cardiovascular risk in obese patients. Heart failure (HF) is associated with an increased perioperative risk following bariatric surgery. This systematic review aimed to assemble the evidence on bariatric surgery in patients with known HF and the potential effect of bariatric surgery on incident HF in obese patients without prevalent HF. Methods: We performed a comprehensive literature search up to 30 September 2017 and included studies comparing bariatric surgery to non-surgical treatment in patients with known presurgical HF. To assess whether bariatric surgery has any effect on incident HF, we also assembled studies looking at new-onset HF among patients without HF prior to surgery. Results: We found five observational studies (0 randomised trials) comparing bariatric surgery with non-surgical treatment in patients with a diagnosis of HF prior to surgery. A review of the available studies (n=676 patients) suggested reduced admission rates for HF exacerbation and increased left ventricular ejection fraction after bariatric surgery. No meta-analysis was possible due to the heterogeneous nature of these studies. Seven studies (one randomised trial) reported data on new-onset HF in obese patients without HF prior to bariatric surgery (n=111 127 patients). When comparing surgical to non-surgical treatment groups, the pooled univariable and multivariable HRs for incident HF were 0.28 (95% CI 0.13 to 0.55) and 0.44 (95% CI 0.36 to 0.55), respectively. Conclusion: In this systematic review, no randomised trial assessed the benefits and risks of bariatric surgery in obese patients with concomitant HF. Available studies do, however, show that surgery might prevent incident HF.

Relationships of kidney injury molecule-1 with renal function and cardiovascular risk factors in the general population.

BACKGROUND: Kidney injury molecule-1 (KIM-1) has been associated with kidney damage in patients with preexisting renal disease. However, little is known about the relationships of KIM-1 with renal function and cardiovascular risk factors in healthy individuals from the general population. METHODS: Healthy individuals aged 25-41years were enrolled in a population-based study. Main exclusion criteria were a BMI >35kg/m2, preexisting kidney disease or established cardiovascular disease. KIM-1 was measured from frozen plasma samples using a high-sensitivity assay. Multivariable linear regression models were constructed to assess the relationships of KIM-1 with renal function and various cardiovascular risk factors. RESULTS: We included 2060 individuals (47% men, median (interquartile range) age: 37 (31-40) years) in this analysis. Median KIM-1 levels were 82.5 (IQR 59.4-112.7) pg/ml. We found no significant relationship of KIM-1 with creatinine (adjusted ß-coefficient (95% confidence interval) 0.0005 (-0.002; 0.003), p=0.61) and cystatin C (-0.02 (-0.21; 0.17), p=0.84). There were significant linear relationships of log-transformed KIM-1 with systolic blood pressure (adjusted ß-coefficient (95% confidence interval) 0.07 (0.04; 0.09), p<0.0001), diastolic blood pressure (0.04 (0.02; 0.07), p=0.001), low-density lipoprotein cholesterol (0.09 (0.06; 0.11), p<0.0001), high-density lipoprotein cholesterol (0.07 (0.05; 0.1), p<0.0001), high-sensitivity C-reactive protein (0.05 (0.03; 0.07), p<0.0001), age (0.09 (0.07; 0.11), p<0.0001), BMI (0.04 (0.01; 0.06), p=0.005) and current smoking (0.12 (0.07; 0.17), p<0.0001). CONCLUSION: Among healthy adults from the general population, plasma levels of KIM-1 were not associated with renal function but were independently related to multiple cardiovascular risk factors.