LETTER
Why Not Use a High-sensitivity Troponin Assay as an End Point in Clinical Trials? To the Editor: Cardiac troponins T and I are specific markers of cardiomyocytes. The main clinical use of these assays is to diagnose acute coronary syndrome, and they are considered the gold standard for this procedure. Cardiac troponin T was introduced into clinical laboratory practice in 1989 and cardiac troponin I was introduced in 1992. Since their introduction, laboratory assays have improved. The analytical sensitivity of these assays permits the detection of small heart lesions.1 Any insult to cardiomyocytes liberates troponins into the blood. Many disorders and even treatments increase troponins: pulmonary emboli, septicemias, cardiac insufficiency, pericarditis, endocarditis, heart catheterism, surgery, and many others.2 Troponin levels and the time at which increased levels are detected depend on the underlying pathology and its severity. Other confounding factors are biological variation and kidney function because of its role in filtration and excretion.3 With sensitivity assays, we can measure troponin levels in normal individuals, and it is possible to define population values for normal populations, taking into account sex, age, and other parameters.4 Many papers show that higher levels of troponin have a clear correlation with cardiovascular mortality, independent of the underlying pathology. The same is true for the prognosis of mortality during surgery (cardiac and noncardiac), as well as after angioplasty, acute coronary syndrome, sepsis, cardiac lesions from drugs, and other clinical episodes.5-9 More sensitive assays show this correlation even with low values, and it is possible to classify patients beginning with 1.2 pg/mL. Clinical trials attempt to test the effects of new procedures or drugs, as well as to determine their safety. The classic observed end points are late-stage: death, myocardial infarction, and cerebrovascular accident. Alternative endpoint measurements that are less severe or irreversible are Funding: None. Conflict of Interest: CESF and CNF have no conflict of interest. FAHF reports receiving lecture fees, and consulting fees from AstraZeneca and Merck in the last 36 months. Authorship: All authors had access to the data and a role in writing the manuscript.
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved.
early clinical and laboratory assessments, and both should be used to correlate with the later end points.10 With this information, could we use troponin levels as alternate markers for mortality? This could be performed during drug evaluation with anti-inflammatory nonhormonal agents, hunger inhibitors, antihypertensive medications, and chemotherapeutic agents; during comparative surgical procedures, such as myocardial revascularization vs endovascular stents; or during different physical activities. Carlos Eduardo dos Santos Ferreira, MD, MBA, PhDa,b Carolina Nunes França, PhDb,c Francisco Antonio Helfenstein Fonseca, MD, PhDb a
Hospital Israelita Albert Einstein São Paulo, Brazil b Federal University of São Paulo Brazil c University of Santo Amaro São Paulo, Brazil
http://dx.doi.org/10.1016/j.amjmed.2014.10.050
References 1. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 2012;126(16):2020-2035. 2. Hochholzer W, Buettner HJ, Trenk D, et al. New definition of myocardial infarction: impact on long-term mortality. Am J Med. 2008;121(5):399-405. 3. Wu AH, Lu QA, Todd J, et al. Short- and long-term biological variation in cardiac troponin I measured with a high-sensitivity assay: implication for clinical practice. Clin Chem. 2009;55(1):52-58. 4. Apple FS, Simpson PA, Murakami MM. Defining the serum 99th percentile in a normal reference population measured by a high sensitivity cardiac troponin I assay. Clin Biochem. 2010;43(12):1034-1036. 5. Mills NL, Churchhouse AM, Lee KK, et al. Implementation of a sensitive troponin I assay and risk of recurrent myocardial infarction and death in patients with suspected acute coronary syndrome. JAMA. 2011;305(12):1210-1216. 6. Lansky AJ, Stone GW. Periprocedural myocardial infarction: prevalence, prognosis, and prevention. Circ Cardiovasc Interv. 2010;3(6):602-610. 7. Cavallini C, Verdecchia P, Savonitto S, et al. Prognostic value of isolated troponin I elevation after percutaneous coronary intervention. Circ Cardiovasc Interv. 2010;3(5):431-435. 8. Bessiere F, Khenifer S, Dubourg J, et al. Prognostic value of troponins in sepsis: a meta-analysis. Intensive Care Med. 2013;39(7):1181-1189. 9. Ewer MS, Ewer SM. Troponin I provides insight into cardiotoxicity and the anthracycline-trastuzumab interaction. J Clin Oncol. 2010;28(25):3901-3904. 10. DeGruttola VG, Clax P, DeMets DL, et al. Considerations in the evaluation of surrogate endpoints in clinical trials (summary of a National Institutes of Health Workshop). Control Clin Trials. 2001;22(5):485-502.
Why Not Use a High-sensitivity Troponin Assay as an End Point in Clinical Trials? To the Editor: Cardiac troponins T and I are specific markers of cardiomyocytes. The main clinical use of these assays is to diagnose acute coronary syndrome, and they are considered the gold standard for this procedure. Cardiac troponin T was introduced into clinical laboratory practice in 1989 and cardiac troponin I was introduced in 1992. Since their introduction, laboratory assays have improved. The analytical sensitivity of these assays permits the detection of small heart lesions.1 Any insult to cardiomyocytes liberates troponins into the blood. Many disorders and even treatments increase troponins: pulmonary emboli, septicemias, cardiac insufficiency, pericarditis, endocarditis, heart catheterism, surgery, and many others.2 Troponin levels and the time at which increased levels are detected depend on the underlying pathology and its severity. Other confounding factors are biological variation and kidney function because of its role in filtration and excretion.3 With sensitivity assays, we can measure troponin levels in normal individuals, and it is possible to define population values for normal populations, taking into account sex, age, and other parameters.4 Many papers show that higher levels of troponin have a clear correlation with cardiovascular mortality, independent of the underlying pathology. The same is true for the prognosis of mortality during surgery (cardiac and noncardiac), as well as after angioplasty, acute coronary syndrome, sepsis, cardiac lesions from drugs, and other clinical episodes.5-9 More sensitive assays show this correlation even with low values, and it is possible to classify patients beginning with 1.2 pg/mL. Clinical trials attempt to test the effects of new procedures or drugs, as well as to determine their safety. The classic observed end points are late-stage: death, myocardial infarction, and cerebrovascular accident. Alternative endpoint measurements that are less severe or irreversible are Funding: None. Conflict of Interest: CESF and CNF have no conflict of interest. FAHF reports receiving lecture fees, and consulting fees from AstraZeneca and Merck in the last 36 months. Authorship: All authors had access to the data and a role in writing the manuscript.
0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved.
early clinical and laboratory assessments, and both should be used to correlate with the later end points.10 With this information, could we use troponin levels as alternate markers for mortality? This could be performed during drug evaluation with anti-inflammatory nonhormonal agents, hunger inhibitors, antihypertensive medications, and chemotherapeutic agents; during comparative surgical procedures, such as myocardial revascularization vs endovascular stents; or during different physical activities. Carlos Eduardo dos Santos Ferreira, MD, MBA, PhDa,b Carolina Nunes França, PhDb,c Francisco Antonio Helfenstein Fonseca, MD, PhDb a
Hospital Israelita Albert Einstein São Paulo, Brazil b Federal University of São Paulo Brazil c University of Santo Amaro São Paulo, Brazil
http://dx.doi.org/10.1016/j.amjmed.2014.10.050
References 1. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 2012;126(16):2020-2035. 2. Hochholzer W, Buettner HJ, Trenk D, et al. New definition of myocardial infarction: impact on long-term mortality. Am J Med. 2008;121(5):399-405. 3. Wu AH, Lu QA, Todd J, et al. Short- and long-term biological variation in cardiac troponin I measured with a high-sensitivity assay: implication for clinical practice. Clin Chem. 2009;55(1):52-58. 4. Apple FS, Simpson PA, Murakami MM. Defining the serum 99th percentile in a normal reference population measured by a high sensitivity cardiac troponin I assay. Clin Biochem. 2010;43(12):1034-1036. 5. Mills NL, Churchhouse AM, Lee KK, et al. Implementation of a sensitive troponin I assay and risk of recurrent myocardial infarction and death in patients with suspected acute coronary syndrome. JAMA. 2011;305(12):1210-1216. 6. Lansky AJ, Stone GW. Periprocedural myocardial infarction: prevalence, prognosis, and prevention. Circ Cardiovasc Interv. 2010;3(6):602-610. 7. Cavallini C, Verdecchia P, Savonitto S, et al. Prognostic value of isolated troponin I elevation after percutaneous coronary intervention. Circ Cardiovasc Interv. 2010;3(5):431-435. 8. Bessiere F, Khenifer S, Dubourg J, et al. Prognostic value of troponins in sepsis: a meta-analysis. Intensive Care Med. 2013;39(7):1181-1189. 9. Ewer MS, Ewer SM. Troponin I provides insight into cardiotoxicity and the anthracycline-trastuzumab interaction. J Clin Oncol. 2010;28(25):3901-3904. 10. DeGruttola VG, Clax P, DeMets DL, et al. Considerations in the evaluation of surrogate endpoints in clinical trials (summary of a National Institutes of Health Workshop). Control Clin Trials. 2001;22(5):485-502.
