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Research digest: cardiac biomarkers for risk prediction
In Focus
Neil Bennet
Research digest: cardiac biomarkers for risk prediction
Published Online October 12, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)30293-5 For the secondary analysis of trial data see JAMA Cardiol 2016; published online Sept 28. DOI:10.1001/ jamacardio.2016.3030 For the Natriuretic Peptides Studies Collaboration study see Articles Lancet Diabetes Endocrinol 2016; 4: 840–49 For the study of silent myocardial infarction see J Clin Endocrinol Metab 2016; 101: 3316–23 For the PONTIAC trial see J Am Coll Cardiol 2013; 62: 1365–72
NS has consulted for Boehringer Ingelheim, Janssen, and Novo Nordisk, and is on the UK Biobank Enhancements Committee. DP and NS are co-investigators on a grant funded by the Chief Scientist Office of the Scottish Government to assess the predictive capacity of high-sensitivity troponin in the Generation Scotland cohort.
890
“Prediction is very difficult, especially about the future”, Danish physicist Niels Bohr (allegedly) commented when answering a question about quantum physics. There is also of course some truth in this quote from a medical perspective. We perpetually wish to better predict which of our patients will or will not suffer a harmful medical event, thereby allowing better allocation of treatment. Prediction algorithms are therefore key components of many guidelines and huge amounts of effort and research funding are spent trying to improve their performance. In the case of cardiovascular medicine, experience shows that once we know someone’s age, sex, whether there is a family history of premature cardiovascular disease, their lipid levels, blood pressure, diabetes status, and where they live, we are reasonably good at predicting their risk of a cardiovascular event, although considerable room for improvement remains. But meaningfully improving risk prediction with novel biomarkers has proved frustratingly difficult. However, cardiac biomarkers, some of which are already commonplace, such as high-sensitivity troponin (hs-TnT and hs-TnI; for myocardial infarction) and natriuretic peptides (for heart failure), have presented themselves as possible contenders to join the established predictors. Recently, some examples relevant to patients with diabetes have emerged. In a secondary analysis of a major multinational diabetes trial, investigators examined the associations of baseline levels of cardiac biomarkers with subsequent cardiovascular events in more than 12 000 participants, most of whom had pre-existing cardiovascular disease. The average age was 65 years and a third of participants were women. Both hs-TnT and N-terminal pro-B-type natriuretic peptide (NT-proBNP) yielded similarly
strong positive associations with subsequent cardiovascular events, independent of established risk factors, such that a 1 SD higher hs-TnT concentration was associated with 40% higher risk of three cardiovascular outcomes (cardiovascular death, myocardial infarction, and stroke), while a similar increment in NTproBNP was associated with 30–100% higher risk of these outcomes. Notably, hs-TnT and NT-proBNP both comfortably outperformed the much debated high-sensitivity C-reactive protein (hs-CRP) in terms of cardiovascular prediction. Furthermore, with respect to participants in the primary prevention setting (ie, patients without previous cardiovascular disease, where most prediction studies are, appropriately, focused), those in the third and fourth highest quartiles of baseline cardiac biomarker levels were typically at a two to five times higher risk of myocardial infarction, stroke, and cardiovascular death compared with the bottom quartile, the strengths of these associations again comfortably beating hs-CRP. Although these results look impressive, average follow-up in this study was only about 2 years and the patient population was known to be at high risk. However, recent results from the Natriuretic Peptides Studies Collaboration also supported a strong association of NT-proBNP levels with cardiovascular outcomes, even stronger than HDL cholesterol in many instances, particularly for fatal events. At this year’s European Association for the Study of Diabetes annual meeting in Munich, researchers presented the results from a crosssectional study in 100 asymptomatic patients with diabetes without known cardiovascular disease (average age 61 years), with the aim of identifying simple indicators of silent myocardial infarction (defined by late gadolinium enhancement on cardiovascular
magnetic resonance [CMR] imaging), a condition itself associated with substantial cardiovascular morbidity and mortality. Candidate predictors included ECG-derived data, echocardiographic parameters, 24 h blood pressure, and cardiac biomarkers (hs-TnT and NT-proBNP). Of the 100 participants, 17 had CMR evidence of a previous myocardial infarction. As expected, these 17 participants were older than their unaffected counterparts (65 vs 60 years). NTproBNP was substantially higher in patients with previous silent myocardial infarction compared with those without (106 vs 52 ng/L), although, surprisingly, hs-TnT showed no difference between groups. CRP was also not different. Using the threshold of >29 ng/L, NT-proBNP was comfortably the strongest single indicator (c-statistic 0·73) of silent myocardial infarction compared with all other variables, including echocardiographic measures and even age (c-statistic 0·67). The future of cardiac biomarkers in cardiovascular risk estimation, in people with and without diabetes, is yet to be determined, but the evidence for their added value in specific groups is gaining some momentum. Major studies like UK Biobank are well placed to provide high-quality prospective data, should these biomarkers be subsequently measured. Of course, one must not forget the thorny issue of costeffectiveness since these cardiac biomarkers remain far more expensive than most other blood tests that are also measured on clinical chemistry analysers, yet much cheaper than imagining modalities. Finally, any conclusion of clinical benefit arising from wider measurement of these cardiac biomarkers should, ideally, be properly assessed—and evidence is accumulating (eg, the PONTIAC trial).
David Preiss, Naveed Sattar
www.thelancet.com/diabetes-endocrinology Vol 4 November 2016
Neil Bennet
Research digest: cardiac biomarkers for risk prediction
Published Online October 12, 2016 http://dx.doi.org/10.1016/ S2213-8587(16)30293-5 For the secondary analysis of trial data see JAMA Cardiol 2016; published online Sept 28. DOI:10.1001/ jamacardio.2016.3030 For the Natriuretic Peptides Studies Collaboration study see Articles Lancet Diabetes Endocrinol 2016; 4: 840–49 For the study of silent myocardial infarction see J Clin Endocrinol Metab 2016; 101: 3316–23 For the PONTIAC trial see J Am Coll Cardiol 2013; 62: 1365–72
NS has consulted for Boehringer Ingelheim, Janssen, and Novo Nordisk, and is on the UK Biobank Enhancements Committee. DP and NS are co-investigators on a grant funded by the Chief Scientist Office of the Scottish Government to assess the predictive capacity of high-sensitivity troponin in the Generation Scotland cohort.
890
“Prediction is very difficult, especially about the future”, Danish physicist Niels Bohr (allegedly) commented when answering a question about quantum physics. There is also of course some truth in this quote from a medical perspective. We perpetually wish to better predict which of our patients will or will not suffer a harmful medical event, thereby allowing better allocation of treatment. Prediction algorithms are therefore key components of many guidelines and huge amounts of effort and research funding are spent trying to improve their performance. In the case of cardiovascular medicine, experience shows that once we know someone’s age, sex, whether there is a family history of premature cardiovascular disease, their lipid levels, blood pressure, diabetes status, and where they live, we are reasonably good at predicting their risk of a cardiovascular event, although considerable room for improvement remains. But meaningfully improving risk prediction with novel biomarkers has proved frustratingly difficult. However, cardiac biomarkers, some of which are already commonplace, such as high-sensitivity troponin (hs-TnT and hs-TnI; for myocardial infarction) and natriuretic peptides (for heart failure), have presented themselves as possible contenders to join the established predictors. Recently, some examples relevant to patients with diabetes have emerged. In a secondary analysis of a major multinational diabetes trial, investigators examined the associations of baseline levels of cardiac biomarkers with subsequent cardiovascular events in more than 12 000 participants, most of whom had pre-existing cardiovascular disease. The average age was 65 years and a third of participants were women. Both hs-TnT and N-terminal pro-B-type natriuretic peptide (NT-proBNP) yielded similarly
strong positive associations with subsequent cardiovascular events, independent of established risk factors, such that a 1 SD higher hs-TnT concentration was associated with 40% higher risk of three cardiovascular outcomes (cardiovascular death, myocardial infarction, and stroke), while a similar increment in NTproBNP was associated with 30–100% higher risk of these outcomes. Notably, hs-TnT and NT-proBNP both comfortably outperformed the much debated high-sensitivity C-reactive protein (hs-CRP) in terms of cardiovascular prediction. Furthermore, with respect to participants in the primary prevention setting (ie, patients without previous cardiovascular disease, where most prediction studies are, appropriately, focused), those in the third and fourth highest quartiles of baseline cardiac biomarker levels were typically at a two to five times higher risk of myocardial infarction, stroke, and cardiovascular death compared with the bottom quartile, the strengths of these associations again comfortably beating hs-CRP. Although these results look impressive, average follow-up in this study was only about 2 years and the patient population was known to be at high risk. However, recent results from the Natriuretic Peptides Studies Collaboration also supported a strong association of NT-proBNP levels with cardiovascular outcomes, even stronger than HDL cholesterol in many instances, particularly for fatal events. At this year’s European Association for the Study of Diabetes annual meeting in Munich, researchers presented the results from a crosssectional study in 100 asymptomatic patients with diabetes without known cardiovascular disease (average age 61 years), with the aim of identifying simple indicators of silent myocardial infarction (defined by late gadolinium enhancement on cardiovascular
magnetic resonance [CMR] imaging), a condition itself associated with substantial cardiovascular morbidity and mortality. Candidate predictors included ECG-derived data, echocardiographic parameters, 24 h blood pressure, and cardiac biomarkers (hs-TnT and NT-proBNP). Of the 100 participants, 17 had CMR evidence of a previous myocardial infarction. As expected, these 17 participants were older than their unaffected counterparts (65 vs 60 years). NTproBNP was substantially higher in patients with previous silent myocardial infarction compared with those without (106 vs 52 ng/L), although, surprisingly, hs-TnT showed no difference between groups. CRP was also not different. Using the threshold of >29 ng/L, NT-proBNP was comfortably the strongest single indicator (c-statistic 0·73) of silent myocardial infarction compared with all other variables, including echocardiographic measures and even age (c-statistic 0·67). The future of cardiac biomarkers in cardiovascular risk estimation, in people with and without diabetes, is yet to be determined, but the evidence for their added value in specific groups is gaining some momentum. Major studies like UK Biobank are well placed to provide high-quality prospective data, should these biomarkers be subsequently measured. Of course, one must not forget the thorny issue of costeffectiveness since these cardiac biomarkers remain far more expensive than most other blood tests that are also measured on clinical chemistry analysers, yet much cheaper than imagining modalities. Finally, any conclusion of clinical benefit arising from wider measurement of these cardiac biomarkers should, ideally, be properly assessed—and evidence is accumulating (eg, the PONTIAC trial).
David Preiss, Naveed Sattar
www.thelancet.com/diabetes-endocrinology Vol 4 November 2016