Clinical Features and Outcomes of Emergency Department Patients With High-Sensitivity Cardiac Troponin I Concentrations Within Sex-Specific Reference Intervals
2019; Lippincott Williams & Wilkins; Volume: 139; Issue: 14 Linguagem: Inglês
10.1161/circulationaha.118.038284
ISSN1524-4539
AutoresYader Sandoval, Stephen W. Smith, Anne Sexter, Ian L. Gunsolus, Karen Schulz, Fred S. Apple,
Tópico(s)Atrial Fibrillation Management and Outcomes
ResumoHomeCirculationVol. 139, No. 14Clinical Features and Outcomes of Emergency Department Patients With High-Sensitivity Cardiac Troponin I Concentrations Within Sex-Specific Reference Intervals Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBClinical Features and Outcomes of Emergency Department Patients With High-Sensitivity Cardiac Troponin I Concentrations Within Sex-Specific Reference Intervals Yader Sandoval, MD, Stephen W. Smith, MD, Anne Sexter, MPH, Ian L. Gunsolus, PhD, Karen Schulz, DC and Fred S. Apple, PhD Yader SandovalYader Sandoval Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (Y.S.). , Stephen W. SmithStephen W. Smith Department of Emergency Medicine (S.W.S.), Hennepin County Medical Center and University of Minnesota, Minneapolis , Anne SexterAnne Sexter Chronic Disease Research Group (A.S.), Hennepin Healthcare Research Institute, Minneapolis, MN. , Ian L. GunsolusIan L. Gunsolus Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee (I.L.G.). , Karen SchulzKaren Schulz Cardiac Biomarkers Trials Laboratory (F.S.A., K.S.), Hennepin Healthcare Research Institute, Minneapolis, MN. and Fred S. AppleFred S. Apple Fred S. Apple, PhD, Hennepin County Medical Center, Clinical Laboratories P4, 701 Park Ave, Minneapolis, MN 55415. Email E-mail Address: [email protected] Department of Laboratory Medicine and Pathology (F.S.A.), Hennepin County Medical Center and University of Minnesota, Minneapolis Cardiac Biomarkers Trials Laboratory (F.S.A., K.S.), Hennepin Healthcare Research Institute, Minneapolis, MN. Originally published1 Apr 2019https://doi.org/10.1161/CIRCULATIONAHA.118.038284Circulation. 2019;139:1753–1755Clinical implications of measurable cardiac troponin (cTn) within the reference interval in emergency department patients remain uncertain. Using high-sensitivity (hs) cTnI, our goals were 3-fold. First, we examined clinical features of patients with hs-cTnI within sex-specific reference intervals. Second, we examined the prognostic impact of hs-cTnI within sex-specific reference intervals using baseline and serial measurements. Third, using hs-cTnI reference change values (RCVs; biological variation), we determined the prognostic impact of serial changes within sex-specific intervals.After obtaining institutional review board approval and confirmation of patient disclosure agreement for specimen use (residual waste specimens), we studied emergency department patients with serial cTnI (UTROPIA [Use of Abbott High Sensitivity Troponin I Assay in Acute Coronary Syndromes], clinicaltrials.gov unique identifier NCT02060760). Design and primary results have been reported.1 This is a post hoc analysis focused on patients with serial hs-cTnI less than or equal to the sex-specific 99th percentile upper-reference limits (URLs) in whom myocardial injury and infarction were excluded.2 The limit of detection (LoD) of the hs-cTnI assay (Abbott) is 1.9 ng/L, and 99th percentile URLs are 16 ng/L for women and 34 ng/L for men. RCVs of 69% and −41% were used to interpret data produced by serial testing within the sex-specific reference ranges.3 Multivariable proportional hazards models (assumptions checked) with adjustment for age, sex, baseline hs-cTnI, diabetes mellitus, ischemic heart disease, hypertension, dyslipidemia, and congestive heart failure were constructed.A total of 1216 patients (58±15 years old, 41% women) met inclusion criteria. Compared with patients with baseline undetectable ( 3-fold higher risk of major adverse cardiac events (MACE; postdischarge death, myocardial infarction, unstable angina, revascularization, or congestive heart failure) at 180 days (1.6% [7/440] versus 9.0% [70/776], P<0.0001; adjusted hazard ratio [HR], 3.2; 95% CI, 1.4–7.3; P=0.005), predominantly because of more deaths (n=41) and congestive heart failure (n=19) among those with measurable hs-cTnI. At 30 days, 0.5% (2/440) with baseline hs-cTnI less than the LoD had MACE, whereas 3.0% (23/776) with measurable hs-cTnI had MACE, including 13 deaths.Both men and women with baseline measurable hs-cTnI had worse outcomes at 180 days than did those with undetectable concentrations (Figure, A and B). After adjustment, differences remained in men (adjusted HR, 4.3; 95% CI, 1.3–14.3; P=0.016) but not women (adjusted HR, 2.2; 95% CI, 0.7–6.9; P=0.19). No differences in MACE rates between men and women were observed in those with undetectable (1.4% versus 1.8%; P=1.0) or measurable (9.3% versus 8.6%; P=0.7) hs-cTnI at presentation. An additional model that examined hs-cTnI as a continuous variable demonstrated that baseline hs-cTnI (HR, 1.05; 95% CI, 1.02–1.08; P<0.002), age (HR, 1.03; 95% CI, 1.01–1.04; P=0.002), and congestive heart failure (HR, 4.1; 95% CI, 2.5–7.0; P=0.002) predicted 180-day MACE. Predicted probabilities of MACE according to baseline hs-cTnI (continuous) by sex are shown in the Figure (C and D).Download figureDownload PowerPointFigure. Prognostic implications of high-sensitivity cardiac troponin I concentrations within sex-specific reference intervals. MACE-free survival (unadjusted Kaplan–Meier curves) among men (A) and women (B) in patients with high-sensitivity cardiac troponin I less than the LoD (undetectable) and LoD to less than or equal to 99th percentile URL (measurable); and predicted probabilities (unadjusted) of 180-day MACE in relationship to baseline high-sensitivity cardiac troponin I concentrations as a continuous variable in relationship to 180-day MACE for men (C) and women (D). LoD indicates limit of detection; and MACE, major adverse cardiac event.Patients with serial hs-cTnI within sex-specific reference intervals had a MACE rate of 9.4% (70/744) compared with 1.0% (2/196) in those with serial hs-cTnI less than the LoD (P<0.0001). Using serial sampling at 0 and 3 hours (n=768), no difference was observed in 180-day MACE (4.6% versus 6.9%, P=0.2) between those with changes greater than the RCV (n=217) and less than or equal to the RCV (n=551).Our study has several important findings. First, we demonstrated that among patients presenting to the emergency department in whom acute myocardial injury and infarction have been ruled out, measurable hs-cTnI concentrations within the sex-specific reference interval have important prognostic implications, with the higher the cTn, the higher the probability of MACE at 180 days. After section 510(k) clearance of several hs-cTn assays by the US Food and Drug Administration for clinical use, patients with measurable hs-cTnI within the reference interval will be increasingly recognized. Those with undetectable hs-cTnI may be at low risk not only because of their low concentrations but also because hs-cTnI less than the LoD identifies a much younger group of patients, in whom comorbidities are less likely. Our findings complement studies using contemporary and other hs-cTnI and hs-cTnT assays.4,5 Second, despite concerns that the presence of significant changes within the reference range might identify higher-risk patients, our findings suggest that patients with concentration changes within the reference interval exceeding the RCVs of the assay do not have an increased risk for MACE. Finally, concerns exist that sex-specific URLs could be inappropriate because of underdiagnosis in men. Our findings indicate this is not the case and support the use of sex-specific URLs, as shown by the absence of a difference in MACE rates between men and women with measurable hs-cTnI. Study limitations exist, with analyses limited by the number of events, particularly for women, in whom the reference range is narrower, and larger studies are needed to validate our findings.In conclusion, measurable hs-cTnI concentrations less than or equal to sex-specific URLs have important prognostic implications. Our findings underscore the importance of recognizing cTn as a continuous variable, with the higher the cTn, the higher the probability of MACE. We caution against the clinical use of the terms normal or negative among such patients.Sources of FundingThe UTROPIA study (NCT02060760) is funded in part through a grant from Abbott Diagnostics, which had no role in the design and conduction of the study (including data collection, management, analysis, and interpretation of the data and preparation, review, or approval of the final manuscript); investigator-initiated study (F.S.A. principal investigator; nonsalaried), and the Hennepin Healthcare Research Institute.DisclosuresDr Sandoval has served on an advisory board for Abbott Diagnostics. Dr Gunsolus has received an honorarium from Abbott Diagnostics (speaker at a meeting). Dr Apple has served on the board of directors for HyTest Ltd; as a consultant for LumiraDx, on an advisory board for Siemens Healthcare (received an honorarium for being a speaker at a meeting), as an unsalaried research principal investigator through Hennepin Healthcare Research Institute (formerly Minneapolis Medical Research Foundation) for Abbott Diagnostics, Abbott Point of Care, Roche Diagnostics, Siemens Healthcare, Quidel/Alere, Ortho Clinical Diagnostics, and Beckman Coulter, and as associate editor for Clinical Chemistry. The other authors report no conflicts.Footnoteshttps://www.ahajournals.org/journal/circData and study materials will not be made available to other researchers. Study information is available in other peer-reviewed publications from UTROPIA and on the registered trial site (clinicaltrials.gov: NCT02060760).Fred S. Apple, PhD, Hennepin County Medical Center, Clinical Laboratories P4, 701 Park Ave, Minneapolis, MN 55415. Email [email protected]eduReferences1. 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Mills N and Omland T (2019) Cardiac Troponin to Guide the Use of Noninvasive Testing in Patients Ruled Out for Myocardial Infarction, Circulation, 139:14, (1655-1657), Online publication date: 2-Apr-2019. April 2, 2019Vol 139, Issue 14 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.038284PMID: 30933618 Originally publishedApril 1, 2019 Keywordsrisk assessmentbiomarkerstroponinPDF download Advertisement SubjectsBiomarkersDiagnostic TestingMortality/SurvivalPrognosis
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