Association of High-Sensitivity Cardiac Troponin I Concentration With Cardiac Outcomes in Patients With Suspected Acute Coronary Syndrome

Abstract

Importance: High-sensitivity cardiac troponin I testing is widely used to evaluate patients with suspected acute coronary syndrome. A cardiac troponin concentration of less than 5 ng/L identifies patients at presentation as low risk, but the optimal threshold is uncertain.

Objective: To evaluate the performance of a cardiac troponin I threshold of 5 ng/L at presentation as a risk stratification tool in patients with suspected acute coronary syndrome.

Data sources: Systematic search of MEDLINE, EMBASE, Cochrane, and Web of Science databases from January 1, 2006, to March 18, 2017.

Study selection: Prospective studies measuring high-sensitivity cardiac troponin I concentrations in patients with suspected acute coronary syndrome in which the diagnosis was adjudicated according to the universal definition of myocardial infarction.

Data extraction and synthesis: The systematic review identified 19 cohorts. Individual patient-level data were obtained from the corresponding authors of 17 cohorts, with aggregate data from 2 cohorts. Meta-estimates for primary and secondary outcomes were derived using a binomial-normal random-effects model.

Main outcomes and measures: The primary outcome was myocardial infarction or cardiac death at 30 days. Performance was evaluated in subgroups and across a range of troponin concentrations (2-16 ng/L) using individual patient data.

Results: Of 11 845 articles identified, 104 underwent full-text review, and 19 cohorts from 9 countries were included. Among 22 457 patients included in the meta-analysis (mean age, 62 [SD, 15.5] years; n = 9329 women [41.5%]), the primary outcome occurred in 2786 (12.4%). Cardiac troponin I concentrations were less than 5 ng/L at presentation in 11 012 patients (49%), in whom there were 60 missed index or 30-day events (59 index myocardial infarctions, 1 myocardial infarction at 30 days, and no cardiac deaths at 30 days). This resulted in a negative predictive value of 99.5% (95% CI, 99.3%-99.6%) for the primary outcome. There were no cardiac deaths at 30 days and 7 (0.1%) at 1 year, with a negative predictive value of 99.9% (95% CI, 99.7%-99.9%) for cardiac death.

Conclusions and relevance: Among patients with suspected acute coronary syndrome, a high-sensitivity cardiac troponin I concentration of less than 5 ng/L identified those at low risk of myocardial infarction or cardiac death within 30 days. Further research is needed to understand the clinical utility and cost-effectiveness of this approach to risk stratification.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Chapman has received honoraria from Abbott Diagnostics and AstraZeneca. Dr Cullen has received funding from Abbott Diagnostics, Roche, Alere, Siemens, and Radiometer Pacific for research on diagnostic protocols and from Alere, Boehringer-Ingelheim, Pfizer, AstraZeneca, Abbott Diagnostics, and Radiometer Pacific for speaking and education. Dr Parsonage has received funding from Abbott Diagnostics, Roche, Alere, and Beckmann Coulter for research on diagnostic protocols, honoraria, travel expenses, and consultancy fees from Abbott, AstraZeneca, Hospira, and Sanofi-Aventis; and travel, accommodation, consulting fees, or honoraria from Abbott Laboratories. Dr Metkus performs consulting unrelated to this subject matter for BestDoctors Inc and Oakstone/EBIX and receives royalties for a textbook publication for McGraw-Hill publishing unrelated to this subject matter. Dr Kavsak has received grants, reagents, consultancy, advisory fees, and honoraria from Abbott Laboratories, Abbott Point of Care, Abbott Diagnostics Division Canada, Beckman Coulter, Ortho Clinical Diagnostics, Randox Laboratories, Roche Diagnostics, and Siemens Healthcare Diagnostics. In addition, McMaster University has filed patents with Dr Kavsak listed as an inventor in the acute cardiovascular biomarker field. Dr Anand has received honoraria from Abbott Diagnostics. Dr Carlton has undertaken research under collaborative agreements with Abbott Diagnostics and Randox. Dr Apple has acted as a consultant for Phillips Healthcare Incubator and Metanomics Healthcare, is on the board of directors at HyTest Ltd, has received honoraria from Instrumentation Laboratory and Abbott POC, has been a research principal investigator through the Minneapolis Medical Research Foundation, and has had nonsalaried relationships with Abbott Diagnostics, Roche Diagnostics, Siemens Healthcare, Alere, Ortho-Clinical Diagnostics, Nanomix, Becton Dickinson, and Singulex. Dr Than has accepted travel, accommodation, consulting fees, or honoraria from Abbott Laboratories. Dr Shah has received honoraria from Abbott Diagnostics. Dr Mills has acted as a consultant for Abbott Diagnostics, Beckman-Coulter, Roche, and Singulex. No other disclosures were reported.

Figures

Figure 1.. Flow of the Study Population and Data Analysis

Flow diagram illustrating the systematic database review and screening of articles, level of exclusion, the number of articles included, and the individual patient-level data or aggregate data available for each analysis, based on the PRISMA-IPD guidelines. aArticles identified through a systematic database search: MEDLINE = 2078; EMBASE = 7116; Cochrane = 390; Web of Science = 2261. bAny identical publications were removed, but articles from the same cohorts were retained at this stage. cArticles excluded after full-text review because they evaluated a contemporary cardiac troponin I assay (n = 36), a different high-sensitivity cardiac troponin I assay (n = 14), a high-sensitivity cardiac troponin T assay (n = 5), a different patient population (n = 4), or a different outcome measure (n = 9). dAuthors who did not provide individual patient-level data provided aggregate data for the primary outcome, subgroup analyses, and secondary outcome when available. eSubgroup analyses were prespecified, with the following data available per group: age (n = 18 248), sex (n = 18 248), diagnosis of ischemic heart disease (n = 14 160), time from symptom onset to troponin sample time (n = 13 404), and electrocardiogram (n = 15 887).

Figure 2.. Negative Predictive Value of an hs-cTnI Concentration of Less Than 5 ng/L at Presentation by Cohort for Primary Outcome (Index Myocardial Infarction or Cardiac Death at 30 Days) by Assay Used for Adjudication

Data markers indicate the central estimate of negative predictive value (NPV) (orange markers for cardiac troponin I [cTnI] and black markers for cardiac troponin T [cTnT] assays) with size of the data markers corresponding to the number of patients per cohort (large, >3000 patients; medium, ≥1000 patients; small,

Figure 3.. Negative Predictive Value of an hs-cTnI Concentration of Less Than 5 ng/L at Presentation for Primary Outcome (Index Myocardial Infarction or Cardiac Death at 30 Days) by Prespecified Subgroup

hs-cTnI indicates high-sensitivity cardiac troponin I; NPV, negative predictive value. Data markers indicate the central estimate of NPV with size corresponding to the number of patients per cohort (large, >3000 patients; medium, ≥1000 patients; small, aIschemic heart disease status available in 16 of 19 cohorts. bTime from symptom onset to troponin sample collection available in 15 of 19 cohorts. cElectrocardiogram findings available in 15 of 19 cohorts.

Figure 4.. Optimal Threshold of hs-cTnI at Presentation to Risk-Stratify Patients With Suspected Acute Coronary Syndrome for Myocardial Infarction or Cardiac Death at 30 Days

hs-cTnI indicates high-sensitivity cardiac troponin I; NPV, negative predictive value. In all panels, performance of hs-cTnI thresholds are shown for all patients (dark blue) and when applied to patients with nonischemic electrocardiogram (ECG) findings at presentation (light blue). All estimates of NPV are derived from a binomial-normal random-effects model using individual patient-level data (available in 17 cohorts) for each hs-cTnI threshold (n = 18 601; eTable 5 in the Supplement). A, NPV across a range of hs-cTnI concentrations. Error bars indicate 95% CIs. Horizontal dotted line indicates prespecified target NPV of 99.5% and vertical dotted line indicates hs-cTnI concentration of less than 5 ng/L. B, Cumulative proportion of all patients with suspected acute coronary syndrome classified as low risk. Dotted vertical line indicates proportion of patients with hs-cTnI concentration of less than 5 ng/L. C, Number of false negatives per 1000 patients tested across a range of hs-cTnI thresholds. Electrocardiogram data were not available for 2929 patients (15.7%).