Karen Schulz

Cardiac troponin changes to distinguish type 1 and type 2 myocardial infarction and 180-day mortality risk

Aims: To determine the ability of serial cardiac troponin (cTnI) changes (delta) to distinguish type 1 and type 2 myocardial infarction (MI) (excluding all ST-segment elevation MIs (STEMIs)) and describe the diagnostic accuracy and 180-day mortality in MI versus no-MI patients. Methods and results: Serial cTnIs were measured in 1112 consecutive patients without STEMI and within 6h of presentation to a United States emergency department: 856 (77%) with no MI, 66 (6%) type 1 MI, and 190 (17%) type 2 MI. Of the 0 to 3h and 0 to 6h absolute and relative cTnI changes, only the distribution of absolute change from 0 to 6h was significantly different between type 1 and type 2 MI: median (interquartile range) 311 (1430) ng/l vs. 80 (330) ng/l, p=0.03. Neither the absolute concentration change nor the absolute percent change from either 0 h to 3h (areas under the curves (AUCs) 0.57 and 0.54 respectively) or 0 h to 6h (AUCs 0.60 and 0.51) improved on the performance of the individual cTnI results at 3h (AUC 0.60) or 6h (AUC 0.62), respectively. After adjusting for age, and histories of heart failure and renal insufficiency, those with type 2 MI (hazard ratio 2.9, 95% confidence interval (CI) 1.4–5.9, p=0.004) and those with no index MI and cTnImax0–6h > 34 ng/l (2.5, CI 1.1–6.0, p=0.04) had increased risk of death within 180 days compared with those with no MI and cTnImax 0–6h ≤ 34 ng/l. Conclusion: Delta cTnI did not aid in distinguishing type 1 MI from the more common type 2 MI. Patients diagnosed with type 2 MIs, which represented more than half of all index MIs, had increased risk of death after discharge.

Diagnosis of Type 1 and Type 2 Myocardial Infarction Using a High-Sensitivity Cardiac Troponin I Assay with Sex-Specific 99th Percentiles Based on the Third Universal Definition of Myocardial Infarction Classification System

BACKGROUND The frequency and characteristics of myocardial infarction (MI) subtypes per the Third Universal Definition of MI (TUDMI) classification system using high-sensitivity (hs) cardiac troponin assays with sex-specific cutoffs is not well known. We sought to describe the diagnostic characteristics of type 1 (T1MI) and type 2 (T2MI) MI using an hs-cardiac troponin I (hs-cTnI) assay with sex-specific cutoffs. METHODS A total of 310 consecutive patients with serial cTnI measurements obtained on clinical indication were studied with contemporary and hs-cTnI assays. Ninety-ninth percentile sex-specific upper reference limits (URLs) for the hs-cTnI assay were 16 ng/L for females and 34 ng/L for males. The TUDMI consensus recommendations were used to define and adjudicate MI based on each URL. RESULTS A total of 127 (41%) patients had at least 1 hs-cTnI exceeding the sex-specific 99th percentiles, whereas 183 (59%) had hs-cTnI within the reference interval. Females had more myocardial injury related to supply/demand ischemia than males (39% vs 18%, P = 0.01), whereas males had more multifactorial or indeterminate injury (52% vs 33%, P = 0.05). By hs-cTnI, there were 32 (10%) acute MIs, among which 10 (3%) were T1MI and 22 (7%) were T2MI. T2MI represented 69% (22 out of 32) of all acute MIs, whereas T1MI represented 31% (10 out of 32). Ninety-five patients (31%) had an increased hs-cTnI above the 99th percentile but did not meet criteria for acute MI. The most common triggers for T2MI were tachyarrhythmias, hypotension/shock, and hypertension. By contemporary cTnI, more MIs (14 T1MI and 29 T2MI) were diagnosed. By contemporary cTnI, there were 43 MIs, 14 T1MI, and 29 T2MI. CONCLUSIONS Fewer MI diagnoses were found with the hs-cTnI assay, contrary to the commonly accepted idea that hs-cTnI will lead to excessive false-positive diagnoses.

Spinal manipulative therapy and exercise for seniors with chronic neck pain

BACKGROUND CONTEXT Neck pain, common among the elderly population, has considerable implications on health and quality of life. Evidence supports the use of spinal manipulative therapy (SMT) and exercise to treat neck pain; however, no studies to date have evaluated the effectiveness of these therapies specifically in seniors. PURPOSE To assess the relative effectiveness of SMT and supervised rehabilitative exercise, both in combination with and compared to home exercise (HE) alone for neck pain in individuals ages 65 years or older. STUDY DESIGN/SETTING Randomized clinical trial. PATIENT SAMPLE Individuals 65 years of age or older with a primary complaint of mechanical neck pain, rated ≥3 (0-10) for 12 weeks or longer in duration. OUTCOME MEASURES Patient self-report outcomes were collected at baseline and 4, 12, 26, and 52 weeks after randomization. The primary outcome was pain, measured by an 11-box numerical rating scale. Secondary outcomes included disability (Neck Disability Index), general health status (Medical Outcomes Study Short Form-36), satisfaction (7-point scale), improvement (9-point scale), and medication use (days per week). METHODS This study was funded by the US Department of Health and Human Services, Health Resources and Services Administration. Linear mixed model analyses were used for comparisons at individual time points and for short- and long-term analyses. Blinded evaluations of objective outcomes were performed at baseline and 12 weeks. Adverse event data were collected at each treatment visit. RESULTS A total of 241 participants were randomized, with 95% reporting primary outcome data at all time points. After 12 weeks of treatment, the SMT with home exercise group demonstrated a 10% greater decrease in pain compared with the HE-alone group, and 5% change over supervised plus home exercise. A decrease in pain favoring supervised plus HE over HE alone did not reach statistical significance. Compared with the HE group, both combination groups reported greater improvement at week 12 and more satisfaction at all time points. Multivariate longitudinal analysis incorporating primary and secondary patient-rated outcomes showed that the SMT with HE group was superior to the HE-alone group in both the short- and long-term. No serious adverse events were observed as a result of the study treatments. CONCLUSIONS SMT with HE resulted in greater pain reduction after 12 weeks of treatment compared with both supervised plus HE and HE alone. Supervised exercise sessions added little benefit to the HE-alone program.

Myeloperoxidase Improves Risk Stratification in Patients with Ischemia and Normal Cardiac Troponin I Concentrations

BACKGROUND We assessed the ability of myeloperoxidase (MPO) to identify the risk for major adverse cardiac events (MACE) in patients who present with ischemic symptoms suggestive of acute coronary syndrome and have a normal cardiac troponin I (cTnI) value. METHODS We used Siemens (n = 400) and Abbott (n = 350) assays to measure MPO and cTnI in plasma samples from 400 patients. Event rates (myocardial infarction, cardiac death, percutaneous coronary intervention, coronary artery bypass grafting) were estimated by the Kaplan-Meier method and compared with the log-rank statistic. RESULTS At the 30-day follow-up, the adjusted hazard ratios for MACE were 3.9 (P < 0.001) for increased cTnI and 2.7 (P = 0.006) for increased MPO for the Siemens assays and were 5.5 (P < 0.001) for increased cTnI and 2.9 (P = 0.001) for increased MPO for the Abbott assays. Similar findings were observed with 6 months of follow-up. Patients who initially had a normal cTnI value and an increased Siemens MPO value demonstrated a higher rate of MACE at 30 days than those in whom both values were normal (16.1% vs 3.6%, P = 0.002) and 6 months (18.1% vs 5.0%, P = 0.002). Similarly, patients who had an increased Abbott MPO result demonstrated a higher MACE rate at 30 days (12.3% vs 3.9%, P = 0.03) and at 6 months (16.2% vs 5.1%, P = 0.01) than those with normal values. CONCLUSIONS A combination of MPO and cTnI allowed the identification of a greater proportion of patients at risk for MACE than the use of cTnI alone. Increased MPO values remained predictive of future cardiac events even when the cTnI value was normal.

Incidence of Undetectable, Measurable, and Increased Cardiac Troponin I Concentrations Above the 99th Percentile Using a High-Sensitivity vs a Contemporary Assay in Patients Presenting to the Emergency Department

INTRODUCTION We compared the incidence of undetectable [below the limit of detection (LoD)], measurable (LoD to 99th percentile), and increased cardiac troponin I (cTnI) concentrations above the 99th percentile between Abbott high-sensitivity cTnI (hs-cTnI) and contemporary cTnI assays in a US emergency department population. METHODS Patients (n = 2100) presenting to the emergency department who had serial cTnI (0, 3, 6, 9 h) measurements ordered on clinical indication were enrolled. Contemporary cTnI [Abbott Architect used clinically; 99th percentile: 0.030 μg/L (30 ng/L)] and hs-cTnI [Abbott investigational; sex-specific 99th percentiles: female (F) 16 ng/L, male (M) 34 ng/L] assays simultaneously measured fresh EDTA plasma. RESULTS The hs-cTnI assay measured fewer undetectable cTnI concentrations compared to the contemporary cTnI assay across baseline (F: 31% vs 47%, M: 22% vs 40%) and serial (F: 21% vs 46%; M: 19% vs 54%) measurements. Conversely, the proportion of measurable cTnI concentrations was higher using hs-cTnI compared to contemporary cTnI assay across both baseline (F: 46% vs 31%; M: 60% vs 33%) and serial (F: 48% vs 28%; M: 83% vs 40%) measurements. The overall proportion of patients with increased cTnI concentrations above the 99th percentile was not significantly different between the contemporary (31%) and hs-cTnI (26%) assays (P = 0.09). CONCLUSIONS In patients presenting to the emergency department, the use of the Abbott hs-cTnI assay provides clinicians with more numeric cTnI concentrations. This occurs via a shift from results below the LoD to those between the LoD and the 99th percentile and does not increase in the number of cTnI concentrations above the 99th percentile.

Diagnostic Performance of High Sensitivity Compared with Contemporary Cardiac Troponin I for the Diagnosis of Acute Myocardial Infarction

BACKGROUND We examined the diagnostic performance of high-sensitivity cardiac troponin I (hs-cTnI) vs contemporary cTnI with use of the 99th percentile alone and with a normal electrocardiogram (ECG) to rule out acute myocardial infarction (MI) and serial changes (deltas) to rule in MI. METHODS We included consecutive patients presenting to a US emergency department with serial cTnI onclinical indication. Diagnostic performance for acute MI, including MI subtypes, and 30-day outcomes were examined. RESULTS Among 1631 patients, MI was diagnosed in 12.9% using the contemporary cTnI assay and in 10.4% using the hs-cTnI assay. For ruling out MI, contemporary cTnI ≤99th percentile at 0, 3, and 6 h and a normal ECG had a negative predictive value (NPV) of 99.5% (95% CI, 98.6-100) and a sensitivity of 99.1% (95% CI, 97.4-100) for diagnostic and safety outcomes. Serial hs-cTnI measurements ≤99th percentile at 0 and 3 h and a normal ECG had an NPV and sensitivity of 100% (95% CI, 100-100) for diagnostic and safety outcomes. For ruling in MI, contemporary cTnI measurements had specificities of 84.4% (95% CI, 82.5-86.3) at presentation and 78.7% (95% CI, 75.4-82.0) with serial testing at 0, 3, and 6 h, improving to 89.2% (95% CI, 87.1-91.3) by using serial cTnI changes (delta, 0 and 6 h) >150%. hs-cTnI had specificities of 86.9% (95% CI, 85.1-88.6) at presentation and 85.7% (95% CI, 83.5-87.9) with serial testing at 0 and 3 h, improving to 89.3% (95% CI, 87.3-91.2) using a delta hs-cTnI (0 and 3 h) >5 ng/L. CONCLUSIONS hs-cTnI and contemporary cTnI assays are excellent in ruling out MI following recommendations predicated on serial testing and the 99th percentile with a normal ECG. For ruling in MI, deltas improve the specificity. ClinicalTrials.gov Identifier: NCT02060760.

Sex-specific 99th percentiles derived from the AACC Universal Sample Bank for the Roche Gen 5 cTnT assay: Comorbidities and statistical methods influence derivation of reference limits

OBJECTIVES Our purpose was to determine a) overall and sex-specific 99th percentile upper reference limits (URL) and b) influences of statistical methods and comorbidities on the URLs. METHODS Heparin plasma from 838 normal subjects (423 men, 415 women) were obtained from the AACC (Universal Sample Bank). The cobas e602 measured cTnT (Roche Gen 5 assay); limit of detection (LoD), 3ng/L. Hemoglobin A1c (URL 6.5%), NT-proBNP (URL 125ng/L) and eGFR (60mL/min/1.73m2) were measured, along with identification of statin use, to better define normality. 99th percentile URLs were determined by the non-parametric (NP), Harrell-Davis Estimator (HDE) and Robust (R) methods. RESULTS 355 men and 339 women remained after exclusions. Overall<50% of subjects had measureable concentrations ≥ LoD: 45.6% no exclusion, 43.5% after exclusion; compared to men: 68.1% no exclusion, 65.1% post exclusion; women: 22.7% no exclusion, 20.9% post exclusion. The statistical method used influenced URLs as follows: pre/post exclusion overall, NP 16/16ng/L, HDE 17/17ng/L, R not available; men NP 18/16ng/L, HDE 21/19ng/L, R 16/11ng/L; women NP 13/10ng/L, HDE 14/14ng/L, R not available. CONCLUSIONS We demonstrated that a) the Gen 5 cTnT assay does not meet the IFCC guideline for high-sensitivity assays, b) surrogate biomarkers significantly lowers the URLs and c) statistical methods used impact URLs. Our data suggest lower sex-specific cTnT 99th percentiles than reported in the FDA approved package insert. We emphasize the importance of detailing the criteria used to include and exclude subjects for defining a healthy population and the statistical method used to calculate 99th percentiles and identify outliers.

Discordance between ICD-Coded Myocardial Infarction and Diagnosis according to the Universal Definition of Myocardial Infarction

BACKGROUND International Classification of Diseases (ICD) coding is the standard diagnostic tool for healthcare management. At present, type 2 myocardial infarction (T2MI) classification by the Universal Definition of Myocardial Infarction (MI) remains ignored in the ICD system. We determined the concordance for the diagnosis of MI using ICD-9 coding vs the Universal Definition. METHODS Cardiac troponin I (cTnI) was measured by both contemporary (cTnI) and high-sensitivity (hs-cTnI) assays in 1927 consecutive emergency department (ED) patients [Use of TROPonin In Acute coronary syndromes (UTROPIA) cohort] who had cTnI ordered on clinical indication. All patients were adjudicated using both contemporary and hs-cTnI assays. The Kappa index and McNemar test were used to assess concordance between ICD-9 code 410 and type 1 MI (T1MI) and type 2 MI (T2MI). RESULTS Among the 249 adjudicated MIs using the contemporary cTnI, only 69 (28%) were ICD-coded MIs. Of 180 patients not ICD coded as MI, 34 (19%) were T1MI and 146 (81%) were T2MI. For the ICD-coded MIs, 79% were T1MI and 21% were T2MI. A fair Kappa index, 0.386, and a McNemar difference of 0.0892 (P < 0.001) were found. Among the 207 adjudicated MIs using the hs-cTnI assay, 67 (32%) were ICD coded as MI. Of the 140 patients not ICD coded as MI, 27 (19%) were T1MI and 113 (81%) were T2MI. For the ICD-coded MIs, 85% were T1MI and 15% T2MI. A moderate Kappa index, 0.439, and a McNemar difference of 0.0674 (P < 0.001) were found. CONCLUSIONS ICD-9-coded MIs captured only a small proportion of adjudicated MIs, primarily from not coding T2MI. Our findings emphasize the need for an ICD code for T2MI.

ROLE OF DELTA CARDIAC TROPONIN I TO DISTINGUISH BETWEEN TYPE I NSTEMI AND TYPE II MYOCARDIAL INFARCTION

Numerous pathologies aside from ACS are associated with an increased cardiac troponin (cTn). We hypothesized that delta cTn would be useful for improving diagnostic accuracy and distinguishing outcomes of spontaneous MI (type 1) versus MI secondary to supply/demand imbalance (type 2). We

Renal Dysfunction Influences the Diagnostic and Prognostic Performance of High-Sensitivity Cardiac Troponin I

Measures of cardiac troponin (cTn) may have lower specificity for myocardial infarction in patients with CKD. We examined the diagnostic accuracy of baseline and serial high-sensitivity cTnI (hs-cTnI) measurements for myocardial infarction and 30- and 180-day mortality according to renal function. hs-cTnI was measured (Abbott assay) using sex-specific 99th percentiles (women, 16 ng/L; men, 34 ng/L) in 1555 adults presenting to the emergency department with symptoms suggesting ischemia (NCT02060760). Myocardial infarction was adjudicated along universal definition classification. Renal function did not significantly affect sensitivity or negative predictive values. Specificity decreased with impaired renal function from 93%-95% with normal function (eGFR≥90 ml/min per 1.73 m2; n=722) to 57%-61% with severely impaired renal function (eGFR<30 ml/min per 1.73 m2; n=81) and 40%-41% on dialysis (n=78). Positive predictive values decreased with decreasing renal function from 51%-57% with normal function to 27%-42% with severely impaired function and 15%-32% on dialysis. Receiver operating characteristic curve areas trended lower at baseline and 3 hours with renal impairment. Mortality increased significantly with increasing hs-cTnI tertile (1.3%, 6.0%, and 10.4%, respectively). Patients with hs-cTnI concentration exceeding concentrations in the 99th percentiles had a mortality rate (11.7%) significantly higher than that of patients with concentrations between 99th percentile concentrations and limit of detection (6.2%) or below limit of detection (1.1%). Renal dysfunction and dialysis reduced the rule-in performance but not the rule-out performance of hs-cTnI for myocardial infarction, and mortality increased in patients with higher hs-cTnI concentrations and any level of renal dysfunction.