Anand, Atul

Lowry, Matthew

Mills, Nicholas L

English

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RESPONSE TO LETTERResponse to Letter Regarding Article, “Influence of age on the diagnosis of myocardial infarction”Matthew TH Lowry MD1, Nicholas L Mills MD PhD1,2, Atul Anand MD PhD1on behalf of the High-STEACS Investigators1 BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK2 Usher Institute, University of Edinburgh, Edinburgh, UKCorresponding author:Dr Atul AnandBHF Centre for Cardiovascular ScienceUniversity of EdinburghEdinburgh EH16 4SAUnited Kingdom Telephone: +44 131 242 6515Fax: +44 131 242 6379Email: atul.anand@ed.ac.uk  Disclosures:  NLM reports research grants awarded to the University of Edinburgh from Abbott Diagnostics and Siemens Healthineers outside the submitted work, and honoraria from Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics and LumiraDx. All other authors have no interests to declare.Text:  		631		References: 	7	We wish to thank Chen et al. and Gibson et al. for their thoughtful appraisal of our recent article, in which we evaluated the impact of age on the diagnostic performance of high sensitivity cardiac troponin for myocardial infarction.1 Chen et al. highlight the importance of considering renal function when interpreting elevated cardiac troponin concentrations in older persons. Two in every five patients with suspected myocardial infarction and renal impairment have cardiac troponin concentrations above the 99th centile upper reference limit.2 This is thought to reflect underlying coronary or structural heart disease rather than impaired renal clearance.3 We agree the relationship between age and declining renal function is likely to partly explain the lower specificity of cardiac troponin in older persons. In the same study population, we have previously demonstrated the lower specificity of an elevated cardiac troponin in patients with renal impairment compared to those without (70.9% [67.5 to 74.2] versus 92.1% [91.2 to 93.0]).2 The authors’ observations support our primary conclusion that age-specific thresholds are unlikely to improve the diagnostic accuracy of myocardial infarction in older populations, as such blunt transformations do not capture the complexity of the relationship between troponin, aging and the development of comorbidities including renal disease.  Gibson et al. highlight that there is more to a diagnosis of myocardial infarction than raised cardiac troponin concentrations. We fully agree. Indeed, we adjudicated the diagnosis in 48,282 consecutive patients based on all clinical information, investigations, and serial high-sensitivity cardiac troponin measurements to provide confidence in the distinction of myocardial infarction from injury.1 We would highlight that in patients with suspected acute coronary syndrome the use of a presentation cardiac troponin concentration to identify patients at high or low probability of myocardial infarction, facilitating early rule-out or rule-in, is an established and internationally recognised component of diagnostic pathways. However, the authors’ substantive point is important. They highlight one of the major methodological challenges in conducting research to evaluate the performance of new cardiac troponin thresholds: the current 99th centile is fundamental to the definition and clinical diagnosis of myocardial infarction. We have previously demonstrated the clinical utility of using lower cardiac troponin concentrations to risk stratify patients and enable myocardial infarction to be ruled out at presentation4, and of sex-specific thresholds to reduce disparities in the diagnosis amongst women.5 In both of these scenarios, we are harnessing the improved sensitivity of cardiac troponin to provide additional information to clinicians and have safely implemented these findings into practice.6 In contrast, a prospective study of higher cardiac troponin thresholds for older persons, will inevitably reduce sensitivity in search of higher specificity, and risk missing the diagnosis of myocardial infarction and other forms of myocardial injury.Even if a suitable alternative gold standard was available to make such a prospective diagnostic study feasible, we would question whether the determination and implementation of age-specific thresholds would be desirable or practical. The development of subclinical heart disease and comorbidities are not senescent processes across the population, with marked heterogeneity seen between older adults of the same age.7 The simplistic approach of defining different thresholds for older people based on age alone would fail to capture this complexity as highlighted by the failure of age-adjusted thresholds to demonstrate parity of diagnosis between older age groups in our study.1 This risks missing opportunities to identify older persons with subclinical heart disease who may benefit from treatment. The introduction of sex-specific thresholds improved the identification of myocardial infarction in women.5 Age-specific thresholds risk achieving the opposite for older patients. We suggest that rather than crudely adjusting binary cardiac troponin thresholds, clinicians should use serial testing as part of a holistic assessment in older patients to establish the diagnosis of myocardial infarction, and recognise the prognostic information conferred by chronic myocardial injury, to avoid disadvantaging older patients.   FundingMTHL is supported by a Clinical Research Training Fellowship from the Medical Research Council (MR/W000598/1). NLM is supported by a Chair Award (CH/F/21/90010), Programme Grant (RG/20/10/34966) and a Research Excellent Award (RE/18/5/34216) from the British Heart Foundation.References 1.	Lowry MTH, Doudesis D, Wereski R, Kimenai DM, Tuck C, Ferry AV, Bularga A, Taggart C, Lee KK, Chapman AR, Shah ASV, Newby DE, Mills NL and Anand A. Influence of Age on the Diagnosis of Myocardial Infarction. Circulation. 2022;146:1135-1148.2.	Miller-Hodges E, Anand A, Shah ASV, Chapman AR, Gallacher P, Lee KK, Farrah T, Halbesma N, Blackmur JP, Newby DE, Mills NL and Dhaun N. High-Sensitivity Cardiac Troponin and the Risk Stratification of Patients With Renal Impairment Presenting With Suspected Acute Coronary Syndrome. Circulation. 2018;137:425-435.3.	Apple FS, Murakami MM, Pearce LA and Herzog CA. Predictive Value of Cardiac Troponin I and T for Subsequent Death in End-Stage Renal Disease. Circulation. 2002;106:2941-2945.4.	Shah AS, Anand A, Sandoval Y, Lee KK, Smith SW, Adamson PD, Chapman AR, Langdon T, Sandeman D, Vaswani A, Strachan FE, Ferry A, Stirzaker AG, Reid A, Gray AJ, Collinson PO, McAllister DA, Apple FS, Newby DE and Mills NL. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet. 2015;386:2481-8.5.	Shah AS, Griffiths M, Lee KK, McAllister DA, Hunter AL, Ferry AV, Cruikshank A, Reid A, Stoddart M, Strachan F, Walker S, Collinson PO, Apple FS, Gray AJ, Fox KA, Newby DE and Mills NL. High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study. Bmj. 2015;350:g7873.6.	Anand A, Lee KK, Chapman AR, Ferry AV, Adamson PD, Strachan FE, Berry C, Findlay I, Cruikshank A, Reid A, Collinson PO, Apple FS, McAllister DA, Maguire D, Fox KAA, Newby DE, Tuck C, Harkess R, Keerie C, Weir CJ, Parker RA, Gray A, Shah ASV and Mills NL. High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial. Circulation. 2021;143:2214-2224.7.	Bergström G, Persson M, Adiels M, Björnson E, Bonander C, Ahlström H, Alfredsson J, Angerås O, Berglund G, Blomberg A, Brandberg J, Börjesson M, Cederlund K, Faire Ud, Duvernoy O, Ekblom Ö, Engström G, Engvall JE, Fagman E, Eriksson M, Erlinge D, Fagerberg B, Flinck A, Gonçalves I, Hagström E, Hjelmgren O, Lind L, Lindberg E, Lindqvist P, Ljungberg J, Magnusson M, Mannila M, Markstad H, Mohammad MA, Nystrom FH, Ostenfeld E, Persson A, Rosengren A, Sandström A, Själander A, Sköld MC, Sundström J, Swahn E, Söderberg S, Torén K, Östgren CJ and Jernberg T. Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population. Circulation. 2021;144:916-929.Disclosures statementNLM reports research grants awarded to the University of Edinburgh from Abbott Diagnostics and Siemens Healthineers outside the submitted work, and honoraria from Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics and LumiraDx. All other authors have no conflicts of interest to declare.1

Response to Letter Regarding Article, “Influence of age on the diagnosis of myocardial infarction”

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Response to Letter Regarding Article, “Influence of age on the diagnosis of myocardial infarction”

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