Association between self-reported functional capacity and major adverse cardiac events in patients at elevated risk undergoing noncardiac surgery: a prospective diagnostic cohort study.

BACKGROUND: Perioperative cardiovascular guidelines endorse functional capacity estimation, based on 'cut-off' daily activities for risk assessment and climbing two flights of stairs to approximate 4 metabolic equivalents. We assessed the association between self-reported functional capacity and postoperative cardiac events. METHODS: Consecutive patients at elevated cardiovascular risk undergoing in-patient noncardiac surgery were included in this predefined secondary analysis. Self-reported ability to walk up two flights of stairs was extracted from electronic charts. The primary endpoint was a composite of cardiac death and cardiac events at 30 days. Secondary endpoints included the same composite at 1 yr, all-cause mortality, and myocardial injury. RESULTS: Among the 4560 patients, mean (standard deviation) age 73 (SD 8 yr) yr, classified as American Society of Anesthesiologists physical status ≥3 in 61% (n=2786/4560), the 30-day and 1-yr incidences of major adverse cardiac events were 5.7% (258/4560) and 11.2% (509/4560), respectively. Functional capacity less than two flights of stairs was associated with the 30-day composite endpoint (adjusted hazard ratio 1.63, 95% confidence interval [CI] 1.23-2.15) and all other endpoints. The addition of functional capacity information to the revised cardiac risk index (RCRI) significantly improved risk classification (functional capacity plus RCRI vs RCRI: net reclassification improvement [NRI]Events 6.2 [95% CI 3.6-9.9], NRINonevents19.2 [95% CI 18.1-20.0]). CONCLUSIONS: In patients at high cardiovascular risk undergoing noncardiac surgery, self-reported functional capacity less than two flights of stairs was independently associated with major adverse cardiac events and all-cause mortality at 30 days and 1 yr. The addition of self-reported functional capacity to surgical and clinical risk improved risk classification. CLINICAL TRIAL REGISTRATION: INCT 02573532.

Adherence to the European Society of Cardiology/European Society of Anaesthesiology recommendations on preoperative cardiac testing and association with positive results and cardiac events: a cohort study.

BACKGROUND: European Society of Cardiology/European Society of Anaesthesiology (ESC/ESA) guidelines inform cardiac workup before noncardiac surgery based on an algorithm. Our primary hypotheses were that there would be associations between (i) the groups stratified according to the algorithms and major adverse cardiac events (MACE), and (ii) over- and underuse of cardiac testing and MACE. METHODS: This is a secondary analysis of a multicentre prospective cohort. Major adverse cardiac events were a composite of cardiac death, myocardial infarction, acute heart failure, and life-threatening arrhythmia at 30 days. For each cardiac test, pathological findings were defined a priori. We used multivariable logistic regression to measure associations. RESULTS: We registered 359 MACE at 30 days amongst 6976 patients; classification in a higher-risk group using the ESC/ESA algorithm was associated with 30-day MACE; however, discrimination of the ESC/ESA algorithms for 30-day MACE was modest; area under the curve 0.64 (95% confidence interval: 0.61-0.67). After adjustment for sex, age, and ASA physical status, discrimination was 0.72 (0.70-0.75). Overuse or underuse of cardiac tests were not consistently associated with MACE. There was no independent association between test recommendation class and pathological findings (P=0.14 for stress imaging; P=0.35 for transthoracic echocardiography; P=0.52 for coronary angiography). CONCLUSIONS: Discrimination for MACE using the ESC/ESA guidelines algorithms was limited. Overuse or underuse of cardiac tests was not consistently associated with cardiovascular events. The recommendation class of preoperative cardiac tests did not influence their yield. CLINICAL TRIAL REGISTRATION: NCT02573532.

Peri-operative copeptin concentrations and their association with myocardial injury after vascular surgery: A prospective observational cohort study.

BACKGROUND: Copeptin levels in conjunction with cardiac troponin may be used to rule out early myocardial infarction in patients presenting with chest pain. Raised pre-operative copeptin has been shown to be associated with postoperative cardiac events. However, very little is known about the peri-operative time course of copeptin or the feasibility of very early postoperative copeptin measurement to diagnose or rule-out myocardial injury. OBJECTIVES: In this preparatory analysis for a larger trial, we sought to examine the time course of peri-operative copeptin and identify the time at which concentrations returned to pre-operative levels. Second, in an explorative analysis, we sought to examine the association of copeptin in general and at various time points with myocardial injury occurring within the first 48 h. DESIGN: Preparatory analysis of a prospective, observational cohort study. SETTING: Single university centre from February to July 2016. PATIENTS: A total of 30 consecutive adults undergoing vascular surgery. INTERVENTION: Serial peri-operative copeptin measurements. MAIN OUTCOME MEASURE: We measured copeptin concentrations before and immediately after surgery (0 h), then at 2, 4, 6 and 8 h after surgery and on the first and second postoperative day. Postoperative concentrations were compared with pre-operative levels with a Wilcoxon signed-rank test. Second, we explored an association between postoperative copeptin concentrations and myocardial injury by the second postoperative day. Myocardial injury was defined as a 5 ng l increase between pre-operative and postoperative high-sensitivity cardiac troponin T with an absolute peak of at least 20 ng l. RESULTS: Immediate postoperative copeptin concentrations (median [interquartile range]) increased nearly eight-fold from pre-operative values (8.5 [3.6 to 13.8] to 64.75 pmol l [29.6 to 258.7]; P < 0.001). Copeptin concentrations remained elevated until returning to baseline on the second postoperative day. Postoperative copeptin was significantly higher in patients experiencing myocardial injury than in those who did not (P = 0.02). The earliest most promising single time point for diagnosis may be immediately after surgery (0 h). The receiver-operating characteristics curve for immediate postoperative copeptin and myocardial injury by the second postoperative day was 0.743 (95% confidence interval 0.560 to 0.926). CONCLUSION: Copeptin concentrations are greatly increased after vascular surgery and remain so until the 2nd postoperative day. Postoperative copeptin concentrations appear to be higher in patients who go on to exhibit myocardial injury. Immediate postoperative copeptin concentrations show promise for eliminating or identifying those at risk of myocardial injury. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02687776, Mauermann/Lurati Buse.

Postoperative High-Sensitivity Troponin and Its Association With 30-Day and 12-Month, All-Cause Mortality in Patients Undergoing On-Pump Cardiac Surgery.

BACKGROUND: Troponin T is a predictor of cardiac morbidity and mortality after cardiac surgery with most data examining fourth generational troponin T assays. We hypothesize that postoperative high-sensitivity troponin T (hsTnT) measured in increments of the upper limit of the norm independently predicts 30-day all-cause mortality. METHODS: We included consecutive patients undergoing on-pump cardiac surgery from February 2010 to March 2012 in a prospective cohort that measured hsTnT at 0600 of the first and second postoperative day. Our primary end point was 30-day, all-cause mortality. The secondary end point was 12-month, all-cause mortality in patients surviving the first 30 days. We divided hsTnT into 5 predetermined categorizes based on the upper limit of the norm (ULN). We used Cox regression to examine an association of hsTnT independent of the EuroSCORE II at both 30 days as well as at 12 months in patients surviving the first 30 days. We assessed the area under the receiver operating characteristics curve and the net reassignment improvement for examining the benefit of adding of hsTnT to the EuroSCORE II for prognostication and restratification of 30-day, all-cause mortality. RESULTS: We included 1122 of 1155 eligible patients (75% male; mean age 66 ± 11 years). We observed 58 (5.2%) deaths at 30 days and another 35 (3.4%) deaths at 12 months in patients surviving 30 days. HsTnT categorized by ULN exhibited a graded response for the mortality. Furthermore, hsTnT remained an independent predictor of all-cause mortality at 30 days (adjusted hazard ratio 1.019 [1.014-1.024] per 10-fold increase in ULN) as well as at 12 months (adjusted hazard ratio 1.019 [1.007-1.032]) in patients surviving the first 30 days. The addition of hsTnT to the EuroSCORE II significantly increased the area under the receiver operating characteristics curve (area under curve: 0.816 [95% confidence interval, 0.754-0.878] versus area under curve: 0.870 [95% confidence interval, 0.822-0.917], respectively; P = .012). Finally, adding hsTnT to the EuroSCORE II improved restratification by the net reassignment improvement, primarily by improving rule-out of events. CONCLUSIONS: This analysis suggests that, similar to previous assays, higher postoperative concentrations of hsTnT are independently associated with all-cause mortality in patients undergoing on-pump cardiac surgery.

Absolute Postoperative B-Type Natriuretic Peptide Concentrations, but Not Their General Trend, Are Associated With 12-Month, All-Cause Mortality After On-Pump Cardiac Surgery.

BACKGROUND: B-type natriuretic peptide (BNP) is a predictor of mortality after on-pump cardiac surgery. However, previous limited and heterogeneous studies have focused on peak concentrations at 3 to 5 days after surgery and may not offer clinicians much help in early decision-making. After confirming the predictive value of first-postoperative-day BNP in a preliminary analysis, we explored the association between isolated second-postoperative-day BNP concentrations, second-day BNP concentrations in conjunction with first-day BNP concentrations, and the change in BNP (ie, ΔBNP) from the first to the second postoperative day and 12-month, all-cause mortality. METHODS: We included consecutive patients undergoing on-pump cardiac surgery in this observational, secondary analysis of prospectively collected data. We analyzed biomarkers on the first and second postoperative day. ΔBNP was defined as BNP on the second postoperative day minus BNP on the first postoperative day. The primary end point was 12-month, all-cause mortality. The secondary end point was a composite of major adverse cardiac events (MACEs) at 12 months and/or all-cause mortality at 12 months. MACE was defined as nonfatal cardiac arrest, myocardial infarction, and congestive heart failure. The association between BNP and outcomes was examined by receiver operating characteristic curves, as well as univariate and multivariable logistic regression, adjusting for the EuroSCORE II, cross-clamp time, and first-postoperative-day troponin T. RESULTS: We included 1199 patients in the preliminary analysis focused on BNP on postoperative day 1. In the analyses examining BNP variables requiring second-postoperative-day BNP measurement (n = 708), we observed 66 (9.3%) deaths, 48 (6.8%) MACE, and 104 (14.7%) deaths and/or MACE. Both first- and second-postoperative-day BNP were significant independent predictors of all-cause, 12-month mortality per 100 ng/L increase (adjusted odds ratio [aOR], 1.040 [95% confidence interval (CI), 1.019-1.065] and 1.064 [95% CI, 1.031-1.105], respectively). When used in conjunction with one another, first-day BNP was not significant (aOR, 1.021 [95% CI, 0.995-1.048]), while second-day BNP remained significant (aOR, 1.046 [95% CI, 1.008-1.091]). The ΔBNP per 100 ng/L increase was not associated with 12-month, all-cause mortality in the univariable (OR, 0.977 [95% CI, 0.951-1.007]) or multivariable analysis (aOR, 0.989 [95% CI, 0.962-1.021]). CONCLUSIONS: Both absolute concentrations of first- and second-postoperative-day BNP are independent predictors of 12-month, all-cause mortality. When modeled together, second-postoperative-day BNP is more predictive of 12-month, all-cause mortality. Although intuitively appealing, the change in BNP from the first to the second postoperative day is a complex variable and should not routinely be used for prognostication.

Significance of new Q waves and their location in postoperative ECGs after elective on-pump cardiac surgery: An observational cohort study.

BACKGROUND: The clinical significance of new pathological Q waves after on-pump cardiac surgery is uncertain. OBJECTIVES: To determine whether or not either the occurrence per se or the location of new pathological Q waves after on-pump cardiac surgery is associated with 12-month, all-cause mortality and/or major adverse cardiac events (MACEs). DESIGN: Observational cohort study. SETTING: Single university hospital from January 2007 to October 2010. PATIENTS: Consecutive adult patients undergoing elective on-pump cardiac surgery with MACE-free survival until at least the 7th postoperative day and available ECGs both preoperatively and on the 7th postoperative day (n = 1464). We conducted a subgroup analysis in patients undergoing isolated coronary artery bypass grafting (n = 740). MAIN OUTCOME MEASURE: Our primary endpoint was 12-month, all-cause mortality and/or MACE, defined as acute coronary syndrome, cardiac arrest, congestive heart failure or re-vascularisation at 12 months. Using logistic regression, we examined the prognostic value of new pathological Q waves according to the Minnesota ECG Code, adjusting for the EuroSCORE II, cardiopulmonary bypass time and peak postoperative troponin T concentrations. RESULTS: We included 1464 patients (74% men; mean ±â€ŠSD age 66 ±â€Š10 years) and observed 103 (7.0%) all-cause deaths and/or MACEs at 12 months. A total of 236 patients (16.1%) had definite or probable new pathological Q waves according to the Minnesota ECG Code. The occurrence of new pathological Q waves per se was not associated with our primary endpoint [adjusted odds ratio, 0.970 (95% confidence interval, 0.540 to 1.648)]. However, the occurrence of a new pathological Q wave in V1 to V5 (anterior) was a strong independent predictor for poor outcome [adjusted odds ratio, 3.461 (95% confidence interval, 1.501 to 7.242)]. CONCLUSION: The current analysis suggests that for patients undergoing elective on-pump cardiac surgery, only new pathological Q waves in V1 to V5 (anterior) in the 7th postoperative day ECG are associated with 12-month, all-cause mortality and/or MACE. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00468598.

Troponin T and B-type natriuretic peptide after on-pump cardiac surgery: prognostic impact on 12-month mortality and major cardiac events after adjustment for postoperative complications.

BACKGROUND: The independent predictive value of troponin T (TNT) after on-pump cardiac surgery was established in several studies. However, adjustment was limited to preoperative risk factors without considering perioperative complications. Data on the prognostic value of postoperative B-type natriuretic peptide (BNP) are scarce. Our aim was to assess the independent value of TNT and BNP to predict 12-month outcome after cardiac surgery with adjustment for preoperative risk estimates and postoperative complications and to report risk stratification gains when considering the European System for Cardiac Operative Risk Evaluation (EuroSCORE) combined with postoperative biomarkers. METHODS AND RESULTS: This prospective cohort study included consecutive patients undergoing on-pump cardiac surgery between 2007 and 2010. We evaluated postoperative TNT and BNP, the EuroSCORE, and postoperative complications as predictors of adverse events using Cox regression. The primary end point was death or major adverse cardiac events within 1 year after surgery. We calculated the net reclassification index of TNT and BNP in addition to the EuroSCORE. We enrolled 1559 patients, of whom 176 (11.3%) experienced an event. The adjusted hazard ratio of TNT >0.8 µg/L was 2.13 (95% confidence interval, 1.47-3.15) and of BNP >790 ng/L was 2.44 (95% confidence interval, 1.65-3.62). The net reclassification index of the addition of TNT and BNP to the EuroSCORE was 0.276 (95% confidence interval, 0.195-0.348). CONCLUSIONS: Postoperative TNT and BNP are strong predictors of 1-year events after on-pump cardiac surgery independent of preoperative risk factors and postoperative complications. Updating the preoperative EuroSCORE risk with postoperative TNT and BNP after surgery allows for improved prediction of 1-year death or major adverse cardiac events.

Randomized comparison of sevoflurane versus propofol to reduce perioperative myocardial ischemia in patients undergoing noncardiac surgery.

BACKGROUND: Volatile anesthetics provide myocardial preconditioning in coronary surgery patients. We hypothesized that sevoflurane compared with propofol reduces the incidence of myocardial ischemia in patients undergoing major noncardiac surgery. METHODS AND RESULTS: We enrolled 385 patients at cardiovascular risk in 3 centers. Patients were randomized to maintenance of anesthesia with sevoflurane or propofol. We recorded continuous ECG for 48 hours perioperatively, measured troponin T and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) on postoperative days 1 and 2, and evaluated postoperative delirium by the Confusion Assessment Method. At 6 and 12 months, we contacted patients by telephone to assess major adverse cardiac events. The primary end point was a composite of myocardial ischemia detected by continuous ECG and/or troponin elevation. Additional end points were postoperative NT-proBNP concentrations, major adverse cardiac events, and delirium. Patients and outcome assessors were blinded. We tested dichotomous end points by χ(2) test and NT-proBNP by Mann-Whitney test on an intention-to-treat basis. Myocardial ischemia occurred in 75 patients (40.8%) in the sevoflurane and 81 (40.3%) in the propofol group (relative risk, 1.01; 95% confidence interval, 0.78-1.30). NT-proBNP release did not differ across allocation on postoperative day 1 or 2. Within 12 months, 14 patients (7.6%) suffered a major adverse cardiac event after sevoflurane and 17 (8.5%) after propofol (relative risk, 0.90; 95% confidence interval, 0.44-1.83). The incidence of delirium did not differ (11.4% versus 14.4%; P=0.379). CONCLUSIONS: Compared with propofol, sevoflurane did not reduce the incidence of myocardial ischemia in high-risk patients undergoing major noncardiac surgery. The sevoflurane and propofol groups did not differ in postoperative NT-proBNP release, major adverse cardiac events at 1 year, or delirium.

A preliminary report on the prognostic significance of preoperative brain natriuretic peptide and postoperative cardiac troponin in patients undergoing major vascular surgery.

BACKGROUND: Associations between preoperative elevation of brain natriuretic peptide (BNP) or postoperative elevation of cardiac troponins (cTn) with major adverse cardiac events (MACE) after major surgery have been shown previously. In this study, we evaluated the added value of preoperative BNP with postoperative cTn levels for the prediction of MACE in patients undergoing major vascular surgery. METHODS: This is a prospectively prespecified, secondary analysis of data from a cohort of 133 clinically stable patients undergoing major vascular surgery enrolled in a clinical trial evaluating the effectiveness of the sympathetic nervous system-inhibiting drug moxonidine on reducing MACE. Concentrations of BNP and cTn were determined before surgery, and concentrations of cTn were measured immediately after surgery and on postoperative days 1, 2, 3, and 7. The primary end point was the occurrence of MACE (defined as any hospitalization for myocardial revascularization, acute coronary syndrome, acute congestive heart failure, or death by any cause) within 1 yr after surgery. Patients were evaluated for MACE by hospital chart review during hospitalization and by telephone interviews 12 mo after surgery. RESULTS: Within 1 yr after surgery, 19 patients (14%) had a MACE, including 14 patients (11%) who died. After adjustment for age, gender, and the revised cardiac risk index, preoperative BNP elevation > or =50 pg/mL was associated with MACE (adjusted hazard ratio [HR]: 6.5, 95% confidence interval [CI]: 1.4-29.5) regardless of the subsequent cTn I concentrations. The combination of preoperative BNP elevation > or =50 pg/mL and postoperative cTn I elevation > or =2 ng/mL was associated with MACE (adjusted HR: 25.2, 95% CI: 5.0-128.4) and all-cause mortality (adjusted HR: 18.7, 95% CI: 3.1-112.5). The negative predictive value of a normal preoperative BNP value for subsequent adverse events was 0.965 (95% CI: 0.879-0.996). CONCLUSION: These data suggest that measurement of preoperative BNP concentrations in addition to postoperative cTn concentrations provides additive prognostic information for MACE and mortality after major vascular surgery.

Association of Troponin Trends and Cardiac Morbidity and Mortality After On-Pump Cardiac Surgery.

BACKGROUND: Elevated, single-measure, postoperative troponin is associated with adverse events after cardiac surgery. We hypothesized that increases in troponin from the first to the second postoperative day are also associated with all-cause, 12-month mortality and major adverse cardiac events (MACE). METHODS: This observational study included consecutive adults undergoing on-pump cardiac surgery with cardiac arrest. Troponin T was measured on the first and second postoperative day and was classified as "increasing" (>10%), "unchanged" (10% to -10%), or "decreasing" (<-10%). The primary endpoint was all-cause, 12-month mortality. Secondary endpoints were all-cause 12-month mortality or MACE and both outcomes at 30 days. The main analysis was by multivariable Cox regression. RESULTS: Of 1,417 included patients, 99 (7.0%) died and 162 (11.4%) died or suffered MACE at 12 months. A significant interaction (p < 0.001) between first postoperative day troponin and the troponin trend from the first to the second postoperative day on 12-month, all-cause mortality precluded an analysis independent of first postoperative day troponin. Consequently, we stratified patients by their first postoperative day troponin (cutoff, 0.8 µg/L). Increasing troponin was associated with higher mortality in patients with first postoperative day troponin T ≥ 0.8 µg/L (hazard ratio, 1.98; 95% CI, 1.09 to 3.59; p = 0.025). CONCLUSIONS: Troponin changes from the first to the second postoperative day should not be interpreted without consideration of the first postoperative day troponin concentration. For patients with a first postoperative day troponin ≥ 0.8 µg/L, an increase by more than 10% from the first to the second postoperative day was significantly associated with all-cause, 12-month mortality and other adverse events.

Revisiting sample size: are big trials the answer?

The superiority of the evidence generated in randomized controlled trials over observational data is not only conditional to randomization. Randomized controlled trials require proper design and implementation to provide a reliable effect estimate. Adequate random sequence generation, allocation implementation, analyses based on the intention-to-treat principle, and sufficient power are crucial to the quality of a randomized controlled trial. Power, or the probability of the trial to detect a difference when a real difference between treatments exists, strongly depends on sample size. The quality of orthopaedic randomized controlled trials is frequently threatened by a limited sample size. This paper reviews basic concepts and pitfalls in sample-size estimation and focuses on the importance of large trials in the generation of valid evidence.