Risk assessment for major adverse cardiovascular events after noncardiac surgery using self-reported functional capacity: international prospective cohort study.

BACKGROUND: Guidelines endorse self-reported functional capacity for preoperative cardiovascular assessment, although evidence for its predictive value is inconsistent. We hypothesised that self-reported effort tolerance improves prediction of major adverse cardiovascular events (MACEs) after noncardiac surgery. METHODS: This is an international prospective cohort study (June 2017 to April 2020) in patients undergoing elective noncardiac surgery at elevated cardiovascular risk. Exposures were (i) questionnaire-estimated effort tolerance in metabolic equivalents (METs), (ii) number of floors climbed without resting, (iii) self-perceived cardiopulmonary fitness compared with peers, and (iv) level of regularly performed physical activity. The primary endpoint was in-hospital MACE consisting of cardiovascular mortality, non-fatal cardiac arrest, acute myocardial infarction, stroke, and congestive heart failure requiring transfer to a higher unit of care or resulting in a prolongation of stay on ICU/intermediate care (≥24 h). Mixed-effects logistic regression models were calculated. RESULTS: In this study, 274 (1.8%) of 15 406 patients experienced MACE. Loss of follow-up was 2%. All self-reported functional capacity measures were independently associated with MACE but did not improve discrimination (area under the curve of receiver operating characteristic [ROC AUC]) over an internal clinical risk model (ROC AUCbaseline 0.74 [0.71-0.77], ROC AUCbaseline+4METs 0.74 [0.71-0.77], ROC AUCbaseline+floors climbed 0.75 [0.71-0.78], AUCbaseline+fitnessvspeers 0.74 [0.71-0.77], and AUCbaseline+physical activity 0.75 [0.72-0.78]). CONCLUSIONS: Assessment of self-reported functional capacity expressed in METs or using the other measures assessed here did not improve prognostic accuracy compared with clinical risk factors. Caution is needed in the use of self-reported functional capacity to guide clinical decisions resulting from risk assessment in patients undergoing noncardiac surgery. CLINICAL TRIAL REGISTRATION: NCT03016936.

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.

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.

Cardiac Biomarkers for the Prediction and Detection of Adverse Cardiac Events After Noncardiac Surgery: A Narrative Review.

Yearly, more than 200 million people worldwide undergo noncardiac surgery, of whom about 5% will develop cardiovascular complications. Prevention, early recognition, and prompt treatment of these adverse cardiovascular events is therefore an important concern in perioperative medicine. The present narrative review aims to provide an overview and critical analysis of the currently available evidence on the role of biomarkers in perioperative cardiac risk assessment and monitoring of perioperative cardiac events before and after noncardiac surgery.

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.

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.

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.

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.

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.

Predicting the occurrence of major adverse cardiac events within 30 days of a vascular surgery: an empirical comparison of the minimum p value method and ROC curve approach using individual patient data meta-analysis.

We aimed to compare the minimum p value method and the area under the receiver operating characteristics (ROC) curve approach to categorize continuous biomarkers for the prediction of postoperative 30-day major adverse cardiac events in noncardiac vascular surgery patients. Individual-patient data from six cohorts reporting B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NTproBNP) were obtained. These biomarkers were dichotomized using the minimum p value method and compared with previously reported ROC curve-derived thresholds using logistic regression analysis. A final prediction model was developed, internally validated, and assessed for its sensitivity to clustering effects. Finally, a preoperative risk score system was proposed. Thresholds identified by the minimum p value method and ROC curve approach were 115.57 pg/ml (p < 0.001) and 116 pg/ml for BNP, and 241.7 pg/ml (p = 0.001) and 277.5 pg/ml for NTproBNP, respectively. The minimum p value thresholds were slightly stronger predictors based on our logistic regression analysis. The final model included a composite predictor of the minimum p value method's BNP and NTproBNP thresholds [odds ratio (OR) = 8.5, p < 0.001], surgery type (OR = 2.5, p = 0.002), and diabetes (OR = 2.1, p = 0.015). Preoperative risks using the scoring system ranged from 2 to 49 %. The minimum p value method and ROC curve approach identify similar optimal thresholds. We propose to replace the revised cardiac risk index with our risk score system for individual-specific preoperative risk stratification after noncardiac nonvascular surgery.

N-terminal pro-B-type Natriuretic Peptides' Prognostic Utility Is Overestimated in Meta-analyses Using Study-specific Optimal Diagnostic Thresholds.

BACKGROUND: N-terminal fragment B-type natriuretic peptide (NT-proBNP) prognostic utility is commonly determined post hoc by identifying a single optimal discrimination threshold tailored to the individual study population. The authors aimed to determine how using these study-specific post hoc thresholds impacts meta-analysis results. METHODS: The authors conducted a systematic review of studies reporting the ability of preoperative NT-proBNP measurements to predict the composite outcome of all-cause mortality and nonfatal myocardial infarction at 30 days after noncardiac surgery. Individual patient-level data NT-proBNP thresholds were determined using two different methodologies. First, a single combined NT-proBNP threshold was determined for the entire cohort of patients, and a meta-analysis conducted using this single threshold. Second, study-specific thresholds were determined for each individual study, with meta-analysis being conducted using these study-specific thresholds. RESULTS: The authors obtained individual patient data from 14 studies (n = 2,196). Using a single NT-proBNP cohort threshold, the odds ratio (OR) associated with an increased NT-proBNP measurement was 3.43 (95% CI, 2.08 to 5.64). Using individual study-specific thresholds, the OR associated with an increased NT-proBNP measurement was 6.45 (95% CI, 3.98 to 10.46). In smaller studies (<100 patients) a single cohort threshold was associated with an OR of 5.4 (95% CI, 2.27 to 12.84) as compared with an OR of 14.38 (95% CI, 6.08 to 34.01) for study-specific thresholds. CONCLUSIONS: Post hoc identification of study-specific prognostic biomarker thresholds artificially maximizes biomarker predictive power, resulting in an amplification or overestimation during meta-analysis of these results. This effect is accentuated in small studies.

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.

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.

The predictive value of preoperative natriuretic peptide concentrations in adults undergoing surgery: a systematic review and meta-analysis.

BACKGROUND: Several studies have evaluated preoperative B-type natriuretic peptides (NPs) for predicting mortality after surgery; however, the number of deaths in each study was small, limiting the power of these studies. We conducted a systematic review and meta-analysis of studies addressing preoperative NP levels to predict mortality after cardiac and noncardiac surgery. METHODS: We searched MEDLINE and EMBASE using the terms "natriuretic peptides," "surgery or surgical procedures," and a validated combination of prognostic and diagnostic terms. Two investigators independently assessed studies for eligibility and extracted data. The end points were all-cause mortality at ≥6 months and at ≤90 days. We used a bivariate model to derive measures of prognostic accuracy and their heterogeneity. We calculated the pooled positive predictive value (PPV) and negative predictive value (NPV) by Bayesian Markov chain Monte Carlo methods. RESULTS: Of the 1558 retrieved articles, 23 studies satisfied the predefined eligibility criteria. After cardiac surgery, the diagnostic odds ratio of NP was 4.11 (95% confidence interval, 2.22-7.60) for ≥6-month mortality, the PPV 0.17 (95% Bayesian confidence interval, 0.07-0.36), and the NPV 0.96 (0.90-0.98). After noncardiac surgery, the diagnostic odds ratio of NP was 4.97 (3.06-8.07) for ≥6-month mortality. The corresponding PPV was 0.24 (0.14-0.38) and the NPV 0.94 (0.88-0.97). Results were similar for ≤90-day mortality. CONCLUSIONS: Preoperative NP concentrations were associated with mortality after cardiac and noncardiac surgery. NP had high NPVs for both types of surgery suggesting that preoperative NP concentrations may be helpful in preoperative risk stratification.

The prognostic value of troponin release after adult cardiac surgery - a meta-analysis.

To assess the accuracy of increased troponin (Tn) concentrations for the prediction of mid-term (> or = 12 months) mortality after coronary artery bypass graft (CABG) and valve surgery, we performed a systematic review identifying all studies reporting on the association between postoperative troponin release and mortality after cardiac surgery. Studies were identified through 30 April 2008 by electronic searches of the MEDLINE, EMBASE and BIOSIS databases. Two reviewers independently selected studies, assessed methodological quality and extracted the data. We primarily considered mid-term (> or = 12 months) and secondarily short-term (< or = 30 days) all-cause mortality. A bivariate random-effects model was used to study determinants and to pool measures of prognostic accuracy of Tn. Seventeen studies fulfilled the inclusion criteria with a total of 237 mid-term deaths in 5189 patients and 296 short-term deaths in 9703 patients. The diagnostic odds ratio of increased Tn concentrations was 5.46 (95% confidence interval (CI) 2.0-14.6) for mid-term mortality and 6.57 (95% CI 4.3-10.1) for short-term mortality after adult cardiac surgery. Alternatively expressed, for troponin elevation, the sensitivity was 0.45 (0.26-0.67) and the specificity 0.87 (0.73-0.90) to predict mid-term mortality. The sensitivity was 0.59 (0.48-0.69) and the specificity 0.82 (0.72-0.89) for short-term mortality. Between-study variability was high. In conclusion, this meta-analysis provides evidence for an association between postoperative Tn release with mid- and short-term all-cause mortality after adult cardiac surgery. However, differences in populations, timing of Tn testing, Tn subunit and Tn assays make definitive conclusions about effect size and cut-off values difficult.

12-month outcome after cardiac surgery: prediction by troponin T in combination with the European system for cardiac operative risk evaluation.

BACKGROUND: The prognostic value of troponin T for midterm outcome in cardiac surgery is insufficiently known. We aimed to assess the value of troponin T to predict 12-month outcome after cardiac surgery, as a single predictor and in combination with the European system for cardiac operative risk evaluation (EuroSCORE). METHODS: This cohort study included consecutive patients undergoing on-pump cardiac surgery between January 2005 and December 2006. We evaluated postoperative troponin T (TNT) on days 1 and 2 and the EuroSCORE as predictor variables. The primary composite endpoint was all-cause mortality or any major adverse cardiac event (MACE) at 12 months. Logistic regression was used to study the prognostic effect of TNT in a univariate analysis and after adjustment for EuroSCORE. The area under the receiver-operator curve (AUC) was calculated to report the discriminatory performance of the models. RESULTS: Seven hundred forty-one patients were available for analysis. Within 12 months after surgery, 92 (12.4%) patients had a MACE, 48 (6.5%) of whom died. A multivariate model of continuous TNT and the continuous logistic EuroSCORE showed a significant independent association between TNT and the composite endpoint (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.02 to 1.04 per 0.1 microg/L increase in TNT). The AUC for the prediction of the composite endpoint of the model combining TNT and the EuroSCORE was 0.72; when based on EuroSCORE alone it was 0.64 (p < 0.0001). CONCLUSIONS: Postoperative TNT increase (per 0.1 microg/L) is a strong independent predictor of 12-month outcome after on-pump cardiac surgery. Updating the preoperative EuroSCORE risk with postoperative TNT allows for better prediction of 12-month MACE and all-cause mortality.

Impact of the American College of Cardiology/American Heart Association guidelines for interpretability of continuous electrocardiography on the association of silent ischemia with troponin release after major noncardiac surgery.

INTRODUCTION: Preexisting electrocardiographic abnormalities may limit accuracy of continuous electrocardiography (cECG) for ischemia determination. The American College of Cardiology/American Heart Association published criteria for the exclusion of unsuitable cECG curves from ST-segment interpretation. These criteria consider medication and 12-lead ECG findings (medication- and 12-lead ECG-based criteria) and cECG lead characteristics (cECG-based criteria). METHODS: We recorded cECG in 300 patients undergoing major noncardiac surgery. We determined postoperative troponin and 12-month outcome. We compared the associations of cECG-detected ischemia with troponin and 12-month outcome with and without adherence to the criteria. RESULTS: Adherence to the medication- and 12-lead ECG-based criteria enhanced the association between troponin and perioperative ischemia in CM5 (odds ratio, 3.74; 95% confidence interval, 1.88-7.44) and 7.03 (2.67-18.49), respectively; P = .049). Similarly, the association between ischemia in CM5 and 12-month outcome tended to increase (P = .081). CONCLUSIONS: Applying the guideline criteria for the interpretation of cECG enhanced cECG diagnostic value in surgical patients.