ReCent Medical News
December 2023
Cardiac biomarkers in life risk assessment
It is an imperative that life insurers manage underwriting risks, and various risk areas are assessed in both traditional and automated underwriting. The underwriting pentagon depicts five important pillars of underwriting. However, it is generally the medical risk assessment that creates the most uncertainty around whether or not a life is a standard or substandard risk. A medical risk is defined as a health or lifestyle related risk (such as smoking) that may impact morbidity or mortality.
Fig. 1: Underwriting pentagon Hannover Re
Medical risk assessment forms the main part of the underwriting process, and its importance is apparent by the approach insurers have taken to underwriting, with even seemingly healthy lives subjected to screening medical tests, based on their age and the sum assured. Of all the medical risks assessed, cardiovascular risk is a very important component, and the ever-expanding epidemic of poor metabolic health in the general population, and its impact on morbidity and mortality should also be considered in this context.
Cardiovascular disease is a significant contributor to overall disease burden in both the general and insured population, as detailed below. Figure 2 [1] demonstrates global disease burden while figure 3 [2] looks at the insured population in South Africa.
Fig. 2: Share of total disease burden by cause, World, 2019 [1]
Total disease burden, measured in Disability-Adjusted Life Years (DALYs) by sub-category of disease or injury. DALYs measure the total burden of disease – both from years of life lost due to premature death and years lived with a disability. One DALY equals one lost year of healthy life.
Note: Non-communicable diseases are shown in blue; communicable, maternal, neonatal and nutritional diseases in red; injuries in grey.
IHME, Global Burden of Disease (2019) - https://ourworldindata.org/burden-of-disease | CC BY
Fig. 3: Claims proportion by benefit type: Hannover Re South Africa Market Study 2015-2022
Given the increasingly important role of cardiac biomarkers in identifying cardiovascular risk and disease at the earliest possible opportunity, as well as their expanding role in guiding and monitoring therapeutic response, cardiac biomarkers, NT-ProBNP and Highly Sensitive Troponins are newer tests with established clinical utility.
This article will discuss the role of two modern cardiac biomarkers in life insurance assessment.
Cardiac Biomarkers
Cardiac biomarkers are proteins in blood that can indicate heart damage or heart disease.
From a life insurance perspective, these biomarkers are not only predictive of cardiovascular events and cardiovascular mortality, but also assess all-cause mortality risk. Therefore, their use in mortality products and living benefits should be considered.
NT-ProBNP
Brain Natriuretic Peptide (BNP) is a hormone initially identified in the brain but released primarily from the heart, particularly the ventricles. Cleavage of the prohormone ProBNP produces biologically active 32 amino acid BNP as well as biologically inert 76 amino acid, NT-ProBNP. NT-ProBNP is a more stable marker and has become the most widely available and used cardiac biomarker.
BNP, the active hormone, is released by the ventricles or lower chambers of the heart in response to stress and increased pressure, with NT-ProBNP being the more stable but inactive breakdown product. Below is an example of cardiac and related conditions that may cause stress and increased pressure in cardiac myocytes resulting in raised NT-ProBNP [3]:
- Metabolic conditions such as hypertension and diabetes
- Valvular heart disease
- Cardiomyopathy
- Congenital heart defects
- Arrhythmias
- Volume overload
- Myocardial infarction
- Pulmonary hypertension
- Heart failure (often the end point of the conditions listed above)
Studies have found that NT-ProBNP levels provide strong prognostic information for outcomes such as death from any cause, cardiovascular death, and readmission to hospital or cardiac events in patients with cardiac failure or ventricular dysfunction. [4][5] Newer studies have also proven this in healthy populations and populations with cardiovascular risk factors. [6]
As NT-ProBNP testing has become more available in the clinical environment, research has continued to confirm its clinical utility in the management of patients with cardiovascular risk and/or disease. The prognostic ability to predict mortality and morbidity is without question. [6]
While an extensive literature review is not the purpose of this article, it is worth highlighting one insurance-based study in the public literature showing the impact of elevated NT-ProBNP on mortality. Illustrated in figure 4 below, we can see that in insurance applicants with and without heart disease, mortality increases as the measured level of NT-ProBNP increases. [7]
Fig 4: Impact of elevated NT-ProBNP on mortality [7]
Fulks, M., Kaufman, V., Clark, M. and Stout, R.L., 2017. NT-ProBNP predicts all-cause mortality in a population of insurance applicants, follow-up analysis and further observations. Journal of Insurance Medicine, 47(2), pp.107-113.
At Hannover Re we have conducted our own prospective studies in life insurance applicants and done retrospective analyses on a general population, and we have also concluded that rising levels of NT-ProBNP reliably correlate to increasing levels of both composite cardiovascular disease events* and all-cause mortality.
Thus, from an insurance perspective, NT-ProBNP can be used as an assessment tool that allows us to forecast cardiovascular disease along a continuum toward certain endpoints where an applicant is uninsurable.
*Cardiovascular disease events are stroke, heart failure, CAD, CABG, arrhythmia, myocardial infarction, valve disease, angina, thrombosis, embolism and aneurysm.
Fig 5: Risk assessment classification using NT-ProBNP
Highly Sensitive Cardiac Troponins (hs-Trop)
Troponins are a family of proteins found in skeletal and cardiac muscle fibres that, in the case of cardiac muscle, produce myocyte contraction.
Troponin tests, commonly referred to as cardiac biomarkers, are primarily ordered by clinicians to help diagnose a myocardial infarction as well as to rule out other conditions with similar signs and symptoms. Either a Troponin I (Trop I) or Troponin T (Trop T) test can be performed. Based on defined cut-off values, the results are used by clinicians to assess and manage patients.
Detectable levels of hs-Trop have been demonstrated among apparently healthy individuals in the general population as well as American College of Cardiology (ACC) and the American Heart Association (AHA), ACC/AHA stage A heart failure patients.
Elevated hs-TropT has also been found in asymptomatic individuals previously diagnosed with stable cardiovascular diseaseand ACC/AHA stage B heart failure patients, with a prevalence of detectable levels ranging from 60% to 80% in asymptomatic individuals. [8][9][10]
Whereas conventional troponins are generally linked to myocardial necrosis and can only be detected in significantly elevated levels, highly sensitive troponins can be detected at much lower levels. In addition, highly sensitive troponins are released into systemic circulation in response to cardiac myocyte injury such as in myocardial necrosis/ischaemia, myocardial wall stress resulting from increased left–ventricular filling pressures, increased inflammatory cytokines, oxidative stress or catecholamines, and direct cellular destruction. [17]
Thus, elevation and detection of highly sensitive troponins may be caused by multiple mechanisms, in addition to myocardial necrosis, that could cause release into the bloodstream. [11]
Because hs-Trop tests detect lower levels of troponin which are released due to a range of mechanisms, other than pure myocardial necrosis related to atherosclerotic coronary heart disease, elevation of hs-Trop can be viewed as an expression of other structural phenotypes correlated to heart failure and other cardiovascular risks. [8]
The summary table below illustrates three studies showing various levels of hs-TropT and corresponding relative risk mortality ratios.
Table 1: Relative mortality risk of different hs-TropT levels [12][13][14]
For study 1 derived from data corpus by van der Linden, N., Klinkenberg, L.J., Bekers, O., van Loon, L.J., van Dieijen-Visser, M.P., Zeegers, M.P. and Meex, S.J., 2016. Prognostic value of basal high-sensitive cardiac troponin levels on mortality in the general population: a meta-analysis. Medicine, 95(52). 34
For study 2 derived from data corpus by Sze, J., Mooney, J., Barzi, F., Hillis, G.S. and Chow, C.K., 2016. Cardiac troponin and its relationship to cardiovascular outcomes in community populations–a systematic review and meta-analysis. Heart, Lung and Circulation, 25(3), pp.217-228. 35
For study 3 derived from data corpus by Oluleye, O.W., Folsom, A.R., Nambi, V., Lutsey, P.L., Ballantyne, C.M. and ARIC Study Investigators, 2013. Troponin T, B-type natriuretic peptide, C-reactive protein, and cause-specific mortality. Annals of epidemiology, 23(2), pp.66- 33
Thus, from an insurance perspective, like NT-ProBNP, hs-TropT can also be used as an assessment tool that allows us to forecast cardiovascular disease along a continuum toward certain endpoints where an applicant is uninsurable.
Fig. 6: Risk assessment classification using hs-TropT
NT-ProBNP and hs-TropT in combination
When used in combination, these cardiac biomarkers have even more predictive power for future morbidity and/or mortality.
A study by Hillis et al. [15] demonstrated that in patients with type 2 diabetes, levels of both NT-ProBNP and hs-TropT are strongly associated with an increased risk of cardiovascular events and death over the subsequent 5 years.
Another study by Nguyen et al., following study participants for 12.4 +-3.8 years, found that the combination of both biomarkers with traditional risk factors in participants divided into non-diabetic and pre-diabetic/diabetic groups, improved risk prediction for both incident heart failure and total cardiovascular disease events in an ethnically diverse population. [16] While both biomarkers independently predicted heart failure and cardiovascular disease events when elevated above the median level of the cohort, the combination of having both biomarkers above the median level was significantly better at predicting incident heart failure and cardiovascular disease in both groups. Adjusted hazard ratios for combination of both biomarkers above versus below median values according to glucose status is presented in the table below.
Table 2: Relative risk of incident heart failure and cardiovascular disease based on glycaemic status [16]
Nguyen, K., Fan, W., Bertoni, A., Budoff, M.J., Defilippi, C., Lombardo, D., Maisel, A., Szklo, M. and Wong, N.D., 2020. N-terminal Pro B-type natriuretic peptide and high-sensitivity cardiac troponin as markers for heart failure and cardiovascular disease risks according to glucose status (from the Multi-Ethnic Study of Atherosclerosis [MESA]). The American journal of cardiology, 125(8), pp.1194-1201.
Median NT-proBNP level was 54.6 pg/mL and median Hs-cTnT level was 4.5 (pg/mL).
Cardiac biomarkers in underwriting practice
Incorporating NT-ProBNP and hs-TropT biomarkers into the current underwriting models offers improved risk prediction for a broad range of scenarios:
1. Standard underwriting requirements (based on age and sum assured)
Insurers do screening type tests in seemingly healthy individuals. These tests are done to screen for undiagnosed and asymptomatic conditions as well as to avoid anti-selection from life insurance applicants, both of which could impact mortality and morbidity outcomes if otherwise detectable conditions are missed.
An analysis of the impact of missed medical conditions on the actual to expected ratio (A/E), indicates that insurers would incur losses without screening tests being performed. This is particularly severe for higher sums assured and is illustrated in the table below. An A/E of >100% indicates a loss-making product. i.e. claims paid are higher than premiums received.
Table 3: Impact on claims experience due to missed medical conditions picked up through screening in underwriting
From these various scenarios, we can see that the impact of missing a medical condition can be significant, which is why life insurance applicants are subject to screening medicals.
In cases where seemingly healthy applicants are subjected to various tests which may or may not include ECG or Stress ECG, cardiac biomarkers could be used as an additional test or as a substitute for the ECG or stress ECG given the broader range of cardiac pathology that could be detected. In addition, a cardiac biomarker blood test is much easier to administer and interpret than an ECG or Stress ECG.
2. Applicants at risk for future cardiovascular disease
Poor metabolic health, encompassing obesity, hypertension, raised cholesterol, insulin resistance, diabetes and non-alcoholic fatty liver disease, are increasing in prevalence in the population in general. Applicants with any of these metabolic conditions should have cardiac biomarkers included as part of their risk assessment process, especially when considering the fact that sub-clinical cardiovascular disease can go undetected for many years and not be picked up by traditional tests.
3. Applicants with known cardiovascular disease
Fortunately, these applicants increasingly have cardiac biomarkers included in their management by their physicians, particularly NT-ProBNP. Applicants with known cardiovascular disease however, do not always fit neatly into a ratings box. Many present with both favourable and unfavourable features, and the addition of cardiac biomarkers can play a key role in differentiating and segmenting risk in an objective, consistent manner.
At Hannover Re we have developed guidelines in hr│Ascent that allow for the use of cardiac biomarkers in the scenarios depicted above, and also include an approach that includes ECG and Stress ECG. These guidelines are currently available for use in South Africa.
Summary
- It is an imperative that life insurers assess medical risk as accurately as possible.
- Screening medical testing done by insurers on seemingly healthy applicants have a role to play when considering the cost of unexpected claims where medical conditions are missed because they are asymptomatic/undiagnosed, or when applicants anti-select against insurers.
- Cardiac biomarkers are tests with clinical utility that are predictive of cardiovascular events, cardiac specific mortality, and all-cause mortality.
- Cardiac biomarkers have a role to play in the assessment of medical risk in various scenarios:
- In selected individuals without disclosed risk factors, based on age and sum assured - In applicants with cardiac risk factors - In applicants with known cardiac pathology
- Hannover Re South Africa has developed hr-Ascent guidelines to incorporate cardiac biomarkers into the risk assessment process.
If you would like to learn more about cardiac biomarkers and how we can help you incorporate them into your risk assessment please contact your local Hannover Re experts.
Author
Dr Matthew Procter
Chief Medical Officer and Head of Medical Services
Hannover Re South Africa Limited
References
- Max Roser, Hannah Ritchie and Fiona Spooner (2021) - "Burden of disease". Published online at OurWorldInData.org. Retrieved from: 'https://ourworldindata.org/burden-of-disease' [Online Resource]; Institute for Health Metrics and Evaluation, Global Burden of Disease (2019)
- Hannover Re South Africa – Market Analysis 2015-2022
- Colluci, WS, Chen, HH. Natriuretic peptide measurement in heart failure. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2023.
- Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT) Circulation. 2003;107:1278–83. 9
- Goetze JP, Christoffersen C, Perko M, et al. Increased cardiac BNP expression associated with myocardial ischemia. FASEB J. 2003;17:1105–7. 9
- Hussain A, Sun W, Deswal A, et al. Association of NT-ProBNP, blood pressure, and cardiovascular events: the ARIC study. J Am Coll Cardiol. 2021;77:559-571
- Fulks, M., Kaufman, V., Clark, M. and Stout, R.L., 2017. NT-ProBNP predicts all-cause mortality in a population of insurance applicants, follow-up analysis and further observations. Journal of Insurance Medicine, 47(2), pp.107-113.
- de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, Hashim I, Berry JD, Das SR, Morrow DA, McGuire DK. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304:2503–2512. doi: 10.1001/jama.2010.1768. 22
- deFilippi CR, de Lemos JA, Christenson RH, Gottdiener JS, Kop WJ, Zhan M, Seliger SL. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA. 2010;304:2494– 2502. doi: 10.1001/jama.2010.1708.
- Gori, M., Senni, M. and Metra, M., 2017. High-sensitive cardiac troponin for prediction of clinical heart failure: are we ready for prime time?
- Ledwidge, M., Gallagher, J., Conlon, C., Tallon, E., O’Connell, E., Dawkins, I., Watson, C., O’Hanlon, R., Bermingham, M., Patle, A. and Badabhagni, M.R., 2013. Natriuretic peptide–based screening and collaborative care for heart failure: the STOP-HF randomized trial. Jama, 310(1), pp.66-74. 20
- van der Linden, N., Klinkenberg, L.J., Bekers, O., van Loon, L.J., van Dieijen-Visser, M.P., Zeegers, M.P. and Meex, S.J., 2016. Prognostic value of basal high-sensitive cardiac troponin levels on mortality in the general population: a meta-analysis. Medicine, 95(52). 34
- Sze, J., Mooney, J., Barzi, F., Hillis, G.S. and Chow, C.K., 2016. Cardiac troponin and its relationship to cardiovascular outcomes in community populations–a systematic review and meta-analysis. Heart, Lung and Circulation, 25(3), pp.217-228. 35
- Oluleye, O.W., Folsom, A.R., Nambi, V., Lutsey, P.L., Ballantyne, C.M. and ARIC Study Investigators, 2013. Troponin T, B-type natriuretic peptide, C-reactive protein, and cause-specific mortality. Annals of epidemiology, 23(2), pp.66- 33
- Hillis, G.S., Welsh, P., Chalmers, J., Perkovic, V., Chow, C.K., Li, Q., Jun, M., Neal, B., Zoungas, S., Poulter, N. and Mancia, G., 2014. The relative and combined ability of high-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide to predict cardiovascular events and death in patients with type 2 diabetes. Diabetes care, 37(1), pp.295-303.
- Nguyen, K., Fan, W., Bertoni, A., Budoff, M.J., Defilippi, C., Lombardo, D., Maisel, A., Szklo, M. and Wong, N.D., 2020. N-terminal Pro B-type natriuretic peptide and high-sensitivity cardiac troponin as markers for heart failure and cardiovascular disease risks according to glucose status (from the Multi-Ethnic Study of Atherosclerosis [MESA]). The American journal of cardiology, 125(8), pp.1194-1201.
- Omran, F., Kyrou, I., Osman, F., Lim, V.G., Randeva, H.S. and Chatha, K., 2022. Cardiovascular biomarkers: lessons of the past and prospects for the future. International Journal of Molecular Sciences, 23(10), p.5680.
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