{"doi":"10.1093/eurjpc/zwae067","title":"Navigating beyond numbers: the clinical context and the role of high-sensitivity troponin on long-term outcomes of patients with suspected acute coronary syndrome","abstract":null,"journal":"European Journal of Preventive Cardiology","year":2024,"id":623926,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1612758,"name":"José Lillo-Moya","orcid":null,"position":1,"is_corresponding":false},{"id":1414892,"name":"Marcelo Llancaqueo","orcid":null,"position":2,"is_corresponding":false},{"id":1612757,"name":"Abraham I J Gajardo","orcid":"0000-0002-6387-3779","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Navigating beyond numbers: the clinical context and the role of high-sensitivity troponin on long-term outcomes of patients with suspected acute coronary syndrome","abstract":"This editorial refers to ‘Serial troponin-I and long-term outcomes in subjects with suspected acute coronary syndrome’, by M. Pareek et al., https://doi.org/10.1093/eurjpc/zwad373. High-sensitivity cardiac troponin (hs-cTn) is critical in the appraisal of patients with suspected acute coronary syndrome (ACS).1 However, for several decades, less reliable biomarkers [such as aspartate transaminase, lactate dehydrogenase, creatine kinase (CK), and CK isoenzyme MB] were used by clinicians attending patients with acute chest pain. Only in the 1990s did cardiac troponins appear on the scene, and only 15 years ago did hs-cTn assays allow the detection of very low concentrations of troponins, with a lower coefficient of variation, high sensitivity, and high specificity for acute myocardial infarction (AMI).2 Nevertheless, hs-cTn is only a tool in clinical decision-making, which should be based on medical history, physical examination, and diagnostic tests. Although diagnostic tools for ACS have improved over time, the basis of the process has not changed, and clinicians should always carefully interpret biomarkers of cardiac injury in the clinical context. Thus, hs-cTn readings should be confronted with the patient’s cardiovascular risk, chest pain characteristics, associated symptoms, findings on physical examination, and electrocardiogram (EKG), among others.1 When one of the authors of this article was in his internal medicine residency, Mr JGG, a 50-year-old patient came to the emergency room with chest pain. He had hypertension, no typical angina, no relevant findings in the physical examination, a normal EKG, and two negative hs-cTn tests. Before going home, he asked about his future health. ‘Keep calm, Mr JGG, you do not have an AMI. Everything should be fine’, said the doctor. However, 1 year later, the same doctor admitted this patient with an AMI, and 6 months after hospital discharge, Mr JGG died. Could we have done anything to prevent this outcome? (1) High-sensitivity troponin and long-term outcomes in suspected or confirmed ACS Cardiac troponins T and I are proteins considered to be specific from the myocardium. Both types of troponins are released by necrotic cardiomyocytes in AMI, and therefore, hs-cTn I and hs-cTn T are used as diagnostics tests in patients with ACS. Despite some similarities, both troponins have different kinetics in AMI: not only peak levels of hs-cTn I are higher than hs-cTn T, but also it decreases faster.3 Also, hs-cTn T results are more susceptible to being affected by haemolysis.4 Nevertheless, guidelines are neutral about the clinical use of both troponins. Recently, Pareek et al.5 published a large-scale study in the European Journal of Preventive Cardiology. The researchers aimed to determine the prognostic implications of hs-cTn I levels in patients with suspected ACS, especially in the long term. The article is pretty similar to a previous study from the same authors regarding hs-cTn T, in terms of aim, the sample of subjects, source of data, and methods in general.6 Nevertheless, the authors argue that the differences between both types of hs-cTn could imply a different prognostic role of hs-cTn I, which should be proved. In the present research,5 by merging different Danish national registries, Pareek et al.’s group constructed a retrospective cohort of 20 609 patients with suspected ACS and 2 hs-cTn I readings taken 1–7 h apart (median 4.6 h between measurements). Patients were classified into four groups based on the combination of both hs-cTn I results (normal or elevated): 72% of patients had two normal results, 23% had two elevated hs-cTn levels, and the other two groups accounted for only 5% of patients. At hospital discharge, most of the patients were considered as not having had a cardiovascular event (72.8% were discharged as ‘observation for suspected myocardial infarction or chest pain’) and only 4.8% of the sample had unstable angina. Acute myocardial infarction diagnosis was made in 22.4% of the total, reaching a higher crude frequency in those with two elevated hs-cTn I readings (AMI in 74.1% of patients) or the first reading normal and the second reading elevated (AMI in 65.6% of patients); strikingly, AMI diagnosis was made in 3.2% of subjects with two normal values. The primary outcome was death by any cause, reported at 0–30 and 31–365 days, standardized by a set of variables. In the longest follow-up, 11.1% of patients with persistently elevated hs-cTn I and 2.65% of those with two normal values died. The authors did not report the outcome in those with AMI, but death at 31–365 days occurred in 9.2% of those with at least one elevated hs-cTn reading and a dynamic change (acute myocardial injury) and in 12.2% of those without a dynamic change (chronic myocardial injury). Also, patient classification by the percentage of change between both hs-cTn readings was not associated with long-term mortality. These real-world data of Pareek et al.5 confirm in a large cohort our understanding regarding the prognostic role of hs-cTn in the long-term outcomes of patients with suspected or confirmed ACS. Also, this research confirms the importance of high-quality observational studies to answer clinically relevant questions not feasible to respond to in a randomized controlled trial. However, there are some issues to consider. The time between the first and the second hs-cTn was longer than that in the current practice, and although the authors standardized risk estimates by time between hs-cTn readings, different times between troponin withdrawal could lead to classifying a patient in different exposure groups. Also, the exclusion of patients with only one hs-cTn I measurement probably implied excluding from the study those patients with a lower risk of AMI (ruled out by rapid protocols) and who have a better short-term and long-term prognosis. Furthermore, limited data about the clinical presentation are provided in the registries to classify patients according to the universal definition of infarction7 or to control for other clinically relevant confounders. On the other hand, the clinical context, together with serial hs-cTn changes, supports the diagnosis and management decisions made by clinicians. Therefore, we do not know whether the reported risk is explained by the clinical diagnosis and management rather than the serial hs-cTn change itself. Additionally, a cluster effect of hospitals could be anticipated, but intra-class correlation is not considered in the analysis of the present study nor in the previous study with hs-cTn T.6 Finally, the possibility of residual confounding remains. Similar results in both researches from Pareek et al.’s5,6 team support the idea that hs-cTn I and hs-cTn T have similar prognostic value in patients with suspected ACS. In fact, there is much evidence that already shows that regardless of the type of hs-cTn, a single hs-cTn measurement has a prognostic role in patients with chest pain or suspected ACS/AMI (Table 1). One important contribution of the present research was calculating absolute standardized risk based on serial hs-cTn measurements and not only relative risks. Similarly, other studies have also shown that patient classification by changes in hs-cTn levels identifies patients at different risks of long-term outcomes, especially when the specific cause or diagnosis is established (Table 1). Even more, in a general population with hs-cTn within normal ranges (below the 99th percentile), the risk of cardiovascular diseases increases with the increment of hs-cTn values.25 (2) The troponin is not only a value … it belongs to a patient Selected studies associating high-sensitive cardiac troponin and long-term outcomes in patients with suspected acute coronary syndrome Data from selected research published in PubMed in the last 5 years (2019–23) are summarized. AMI, acute myocardial infarction; CV, cardiovascular; HR, hazard ratio; hs-cTn, high-sensitivity troponin; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; UAP, unstable angina pectoris. Selected studies associating high-sensitive cardiac troponin and long-term outcomes in patients with suspected acute coronary syndrome Data from selected research published in PubMed in the last 5 years (2019–23) are summarized. AMI, acute myocardial infarction; CV, cardiovascular; HR, hazard ratio; hs-cTn, high-sensitivity troponin; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; UAP, unstable angina pectoris. Nowadays, we know that ∼3 in every 100 patients similar to Mr JGG will die 1 year after hospital discharge with suspected ACS and 2 normal hs-cTn readings. We also know that patients with persistently elevated troponins, regardless of whether chronic or acute injury is present, have the highest risk of death in the long term (11.1%). In both cases, it is necessary to understand the clinical context to interpret the tests in a personalized manner. This implies understanding the underlying pathological process that explains hs-cTn levels in the patient, to make a proper diagnosis and management to prevent adverse health outcomes, although there are no clear guidelines for these cases in the long term. In patients with suspected ACS, hs-cTn is requested to discard myocardial necrosis caused by AMI. However, there are other known mechanisms of cardiac troponin release apart from myocardial necrosis: apoptosis, normal myocyte turnover, increased cellular wall permeability, proteolytic degradation processes, and release from cardiomyocytes by vesicular transport, among others.26 These mechanisms not only explain the blood presence of hs-cTn in many clinical conditions associated with myocardial injury but also could explain high circulating hs-cTn observed in individuals after exercise.26 Thus, hs-cTn values may reflect, at the same time, different acute and/or chronic states that affect the heart of an individual.6 In other words, circulating hs-cTn levels are a consequence of a variety of acute/chronic processes underlying a patient that need a clinical interpretation. Even if two patients with suspected ACS have the same basal hs-cTn values or serial changes, they could have different long-term prognoses if they differ in basal characteristics, clinical presentation, diagnosis, or treatment. Conversely, patients with similar clinical contexts could have different prognoses if they differ in their hs-cTn. However, in any scenario, such as the low-risk scenario of JGG in the first consultation or the high-risk at the second, proper clinical assessment could lead to proper diagnosis and treatment of acute and chronic conditions to prevent adverse long-term outcomes. The study of Pareek et al.5 confirms in a high volume of patients the previous evidence regarding the association of serial hs-cTn levels with long-term outcomes of patients with suspected ACS. This research adds to previous evidence (Table 1) and helps to determine the absolute risk of patients with different trajectories of hs-cTn assessed over a few hours, values that must always be interpreted within the patient’s clinical context. For a better answer to this clinical research question, an observational study with more granular information that emulates a ‘target trial’ could help to better address the true association between hs-cTn and long-term outcomes in patients with suspected ACS27 This work was supported by the Initiation in Research FONDECYT Grant Nº 11241548 (National Agency of Investigation and Development, Government of Chile). 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