Stephen A. Hill

Is a pre-operative brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement an independent predictor of adverse cardiovascular outcomes within 30 days of noncardiac surgery? A systematic review and meta-analysis of observational studies.

OBJECTIVES We conducted a systematic review and meta-analysis to determine if pre-operative brain natriuretic peptide (BNP) (i.e., BNP or N-terminal pro-B-type natriuretic peptide [NT-proBNP]) is an independent predictor of 30-day adverse cardiovascular outcomes after noncardiac surgery. BACKGROUND Pre-operative clinical cardiac risk indices have only modest predictive power. BNP predicts adverse cardiovascular outcomes in a variety of nonsurgical settings and may similarly predict these outcomes in the perioperative setting. METHODS We employed 5 search strategies (e.g., searching bibliographic databases), and we included all studies that assessed the independent prognostic value of pre-operative BNP measurement as a predictor of cardiovascular complications after noncardiac surgery. We determined study eligibility and conducted data abstraction independently and in duplicate. We calculated a pooled odds ratio using a random effects model. RESULTS Nine studies met eligibility criteria, and included a total of 3,281 patients, among whom 314 experienced 1 or more perioperative cardiovascular complications. The average proportion of patients with elevated BNP was 24.8% (95% confidence interval [CI]: 20.1 to 30.4%; I(2) = 89%). All studies showed a statistically significant association between an elevated pre-operative BNP level and various cardiovascular outcomes (e.g., a composite of cardiac death and nonfatal myocardial infarction; atrial fibrillation). Data pooled from 7 studies demonstrated an odds ratio (OR) of 19.3 (95% CI: 8.5 to 43.7; I(2) = 58%). The pre-operative BNP measurement was an independent predictor of perioperative cardiovascular events among studies that only considered the outcomes of death, cardiovascular death, or myocardial infarction (OR: 44.2, 95% CI: 7.6 to 257.0, I(2) = 51.6%), and those that included other outcomes (OR: 14.7, 95% CI: 5.7 to 38.2, I(2) = 62.2%); the p value for interaction was 0.28. CONCLUSIONS These results suggest that an elevated pre-operative BNP or NT-proBNP measurement is a powerful, independent predictor of cardiovascular events in the first 30 days after noncardiac surgery.

Capability of ischemia-modified albumin to predict serious cardiac outcomes in the short term among patients with potential acute coronary syndrome

Background: Ischemia-modified albumin (IMA) has been suggested as a marker of cardiac ischemia. Little, however, is known about its capacity to predict short-term serious cardiac outcomes (death, myocardial infarction, congestive heart failure, serious arrhythmia, or refractory ischemic cardiac pain) in patients arriving at the emergency department with symptoms that may indicate cardiac ischemia. Methods: We screened 546 patients over a 4-week period, of whom 189 fulfilled our entry criteria by presenting to an emergency department with potential cardiac-ischemia symptoms within 6 hours after chest pain, seeing an emergency physician who chose to order a troponin I test, and having no serious cardiac outcome before the troponin result became available. We followed the study patients for 72 hours to determine if any experienced a serious cardiac outcome. We calculated the likelihood ratios (LRs) of IMA findings predicting serious cardiac outcomes that could not be diagnosed at presentation with current techniques. Results: Of the 189 patients, 24 had a serious cardiac outcome within 72 hours after their arrival at the emergency department. The likelihood ratios for IMA measurement within 6 hours after chest pain predicting a serious cardiac outcome within the next 72 hours were 1.35 (95% confidence interval [CI] 0.315–5.79) for IMA ≤ 80 U/mL and 0.98 (95% CI 0.86– 1.11) for IMA > 80 U/mL. Conclusions: These data suggest that in patients presenting with chest pain who have not yet experienced a serious cardiac event, IMA is a poor predictor of serious cardiac outcomes in the short term.

High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: A prospective cohort study☆

OBJECTIVES To determine the proportion of noncardiac surgery patients exceeding the published 99th percentile or change criteria with the high sensitivity Troponin T (hs-TnT) assay. DESIGN AND METHODS We measured hs-TnT preoperatively and postoperatively on days 1, 2 and 3 in 325 adults. RESULTS Postoperatively 45% (95% CI: 39-50%) of patients had hs-TnT≥14ng/L and 22% (95% CI:17-26%) had an elevation (≥14ng/L) and change (>85%) in hs-TnT. CONCLUSION Further research is needed to inform the optimal hs-TnT threshold and change in this setting.

Utility of Urine Myoglobin for the Prediction of Acute Renal Failure in Patients with Suspected Rhabdomyolysis: A Systematic Review

BACKGROUND Urine myoglobin continues to be used as a marker of rhabdomyolysis, particularly to assess risk of developing acute renal failure and evaluate treatment success. We sought to determine the predictive validity of urine myoglobin (uMb) for acute renal failure (ARF) in patients with suspected rhabdomyolysis. METHODS We performed a broad systemic review of the literature from January 1980 to December 2006 using the search terms myoglobin

Monthly intra-individual variation in lipids over a 1-year period in 22 normal subjects

AND (renal OR ARF OR kidney). Only primary studies published in English where uMb measurement was related to ARF were included. RESULTS Of 1602 studies screened, 52 met all selection criteria. The studies covered a wide spectrum of etiologies for rhabdomyolysis, dissimilar diagnostic criteria for ARF and rhabdomyolysis, and various methods of uMb measurement and were mostly case series (n = 32). There was poor reporting on the uMb method, and 17 studies failed to provide any information about the method. The reporting of clinical criteria for ARF with respect to timing, description, performance, and interpretation also lacked adequate detail for replication. Eight studies (total 295 patients) had data for 2-by-2 tables. Sensitivity of the uMb test was 100% in 5 of the 8 studies, specificity varied widely (15% to 88%), and CIs around these measures were high. Pooling of data was not possible because of study heterogeneity. CONCLUSIONS There is inadequate evidence evaluating the use of uMb as a predictor of ARF in patients with suspected rhabdomyolysis.

Acceptable Analytical Variation May Exceed High-Sensitivity Cardiac Troponin I Cutoffs in Early Rule-Out and Rule-In Acute Myocardial Infarction Algorithms.

OBJECTIVES Previous reports on biological variation in lipids differ widely in the time interval between sampling, the number of samples analyzed per patient and the total study period. The present investigation was carried out to determine monthly intra-individual variation in lipids over 1 year and to establish whether there was a consistent change in lipid values over the summer months. The importance of taking this variation into consideration during the assessment of risk of coronary heart disease (CHD) was also examined. DESIGN AND METHODS Cholesterol, triglycerides, HDL, apo A1, and apo B were measured at monthly intervals for 12 months in 22 healthy, free-living volunteers (11 females, 11 males) by standardized methods. RESULTS When compared to analytical variation, biological variation was the dominant component of the intra-individual changes observed during the 1-year study period. As expected, triglycerides showed the greatest biological variation; the ratio of biological/analytical variation was 33.1. Much smaller ratios were observed for the other lipids measured in this study with values ranging from 4.2 to 6.8. Different subjects attained their maximum and minimum values in virtually every month of the year. There were significant reductions in cholesterol, HDL, LDL, and apo A1 in the summer months while triglycerides showed a non-significant increase and apo B a non-significant decrease during this period. CONCLUSIONS All the analytes showed considerable intra-individual variation. It is, therefore, important to measure lipids sequentially over several weeks to arrive at an average value for risk stratification for CHD.

Mutations in cholesteryl ester transfer protein and hepatic lipase in a North American population

To the Editor: In patients presenting to the emergency department (ED)1 with symptoms suggestive of acute coronary syndrome (ACS), clinical studies and guidelines have proposed earlier cardiac troponin sampling protocols and, specifically for high-sensitivity cardiac troponin, at 3, 2, or 1 h, depending on the algorithm and high-sensitivity cardiac troponin assay (1). Because of this shorter time interval between high-sensitivity cardiac troponin measurements, there will be smaller changes in concentration (δ) for risk classification. This raises the possibility that the analytical variation of the assay at the low concentration range may possibly exceed the δ for ruling in patients using these shortened algorithms (2). In addition, biological variation should be considered in the evaluation of change, since the frequency of an absolute reference change value ≥2 ng/L in 1 ED study population was observed in nearly half of all patients without ACS (3). The Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE) and 2-Hour Accelerated Diagnostic Protocol to Assess Patients with Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker (ADAPT) study investigators have developed a 2-h protocol for a clinically available (outside US) high-sensitivity cardiac troponin I (hs-cTnI) assay (Abbott Architect) (1). The results show approximately 60% of the patients being ruled out and 15% ruled in (1). However, questions remain around the contribution of analytical and biological variation to the applied cutoffs and deltas. We also questioned whether these …

A systematic review of BNP and NT-proBNP in the management of heart failure: overview and methods

OBJECTIVE To examine a North American population sample with increased HDL cholesterol for mutations in the genes coding for cholesteryl ester transfer protein (CETP) and hepatic lipase (HL). DESIGN AND METHODS Seventy individuals with increased HDL cholesterol at the time of initial presentation to the Lipid Clinic (males > 1.7 mmol/L, females > 1.8 mmol/L) were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP) analysis for known mutations in CETP intron 14 and exon 15 and HL exons 6 and 8. RESULTS CETP intron 14 mutation frequency 0.7%, CETP exon 15 A1503G 0%, HL exon 6 C873T 2.1%, HL exon 8 C1221T 0%. An unusual mutation in CETP exon 15 G1533A was found at a frequency of 3.5%. The sequence of this mutation was determined to be a G to A change at bp 1533 resulting in a predicted amino acid change of arginine to glutamine at position 451. CONCLUSIONS Known mutations in CETP were much less prevalent in this North American population than in the Japanese populations that have been previously reported. HL mutations, described previously in only 6 families worldwide, appear to be more prevalent than previously recognized. CETP G1533A, reported only once previously is prevalent in this population at a surprisingly high frequency. The functional significance of this mutation is unknown.

Performance of BNP and NT-proBNP for diagnosis of heart failure in primary care patients: a systematic review

B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels are increased in persons with heart failure (HF); low levels of these peptides rule out HF. We systematically reviewed the literature to assess the use of BNP and NT-proBNP in the diagnosis, prognosis, and treatment for HF. We also examined the biological variation of these peptides in persons with and without HF. We searched Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language studies published between January 1989 and June 2012. Supplemental searches involved the gray literature and the reference lists of included studies. Trained reviewers used standardized forms to screen articles for inclusion in the review and to extract data from included papers. We examined the risk of bias with QUADAS-2 for diagnosis studies, the Hayden criteria for prognosis studies, and the Jadad scale for treatment studies. We assessed the strength of evidence in four domains (risk of bias, consistency, directness, and precision) for the diagnosis and treatment studies. Results were reported as narrative syntheses. Additional meta-analyses were conducted for the diagnosis studies. Three hundred ten articles passed through screening and were included in the review. One hundred four articles applied to diagnostic accuracy, 190 papers pertained to prognosis, and nine articles addressed BNP- or NT-proBNP-guided treatment. Each individual paper in this series reports, summarizes, and discusses the evidence regarding diagnosis, prognosis, or treatment.

Ninety-Minute vs 3-h Performance of High-Sensitivity Cardiac Troponin Assays for Predicting Hospitalization for Acute Coronary Syndrome

National and international guidelines have been published recommending the use of natriuretic peptides as an aid to the diagnosis of heart failure (HF) in acute settings; however, few specific recommendations exist for governing the use of these peptides in primary care populations. To summarize the available data relevant to the diagnosis of HF in primary care patient population, we systematically reviewed the literature to identify original articles that investigated the diagnostic accuracy of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) in primary care settings. The search yielded 25,864 articles in total: 12 investigating BNP and 20 investigating NT-proBNP were relevant to our objective and included in the review. QUADAS-2 and GRADE were used to assess the quality of the included articles. Diagnostic data were pooled based on three cutpoints: lowest and optimal, as chosen by study authors, and manufacturers’ suggested. The effect of various determinants (e.g., age, gender, BMI, and renal function) on diagnostic performance was also investigated. Pooled sensitivity and specificity of BNP and NT-proBNP using the lowest [0.85 (sensitivity) and 0.54 (specificity)], optimal (0.80 and 0.61), and manufacturers’ (0.74 and 0.67) cutpoints showed good performance for diagnosing HF. Similar performance was seen for NT-proBNP: lowest (0.90 and 0.50), optimal (0.86 and 0.58), and manufacturers’ (0.82 and 0.58) cutpoints. Overall, we rated the strength of evidence as high because further studies will be unlikely to change the estimates diagnostic performance.