Background
The very old (aged 85+), the most rapidly expanding age group worldwide, [
1] comprise an increasing fraction of heart failure (HF) patients [
2]. Early and accurate diagnosis is important as effective therapies are well established for HF with reduced left ventricular (LV) ejection fraction (HF-REF). Furthermore, there is increasing emphasis on identifying asymptomatic LV systolic dysfunction and preventing or delaying its progression to HF [
3]. In older people HF diagnosis is particularly challenging due to atypical clinical presentations, [
4] coupled with high levels of co-morbidity [
2] which can both mimic and mask the presentation of HF. Echocardiography, the diagnostic test of choice, is expensive with limited access in many healthcare systems, [
5] particularly for older people [
6].
The B-type natriuretic peptides, BNP and NT-proBNP, offer a less expensive and more accessible diagnostic test for HF and LV dysfunction. Clinical guidelines advocate their use in the diagnostic work-up of suspected HF to limit the number of potential cases requiring echocardiography, by ruling out the condition where natriuretic peptide level is low, although recommended rule-out cut points vary between guidelines [
7,
8]. A raised natriuretic peptide level is insufficiently specific to rule in a diagnosis, [
9] with echocardiography required for further evaluation. The utility of B-type natriuretic peptides in the very old requires further investigation, and the optimal exclusionary cut points for this age group remain to be established. Natriuretic peptide levels rise with age in non-diseased individuals, [
10] and with many age-related cardiac and non-cardiac morbidities [
11]. Furthermore, their diagnostic accuracy is poorer in HF with preserved ejection fraction (HF-PEF), [
12] which underlies around 50% of HF in people over the age of 70 [
13].
We previously reported high prevalence of LV systolic and diastolic dysfunction in the very old, most cases being both symptomatic and undiagnosed [
14]. We here report a prospective evaluation of the utility of NT-proBNP - alone and in combination with history of myocardial infarction (MI) [as per UK National Institute for Health and Care Excellence (NICE) Chronic HF Diagnostic Algorithm [
7]] – as a rule-out test for LV systolic and diastolic dysfunction in very old people with limiting dyspnoea. Data came from the Newcastle 85+ Study, a population-based longitudinal study of health and ageing in the very old [
15].
Discussion
We report novel data on the utility of NT-proBNP, alone and in combination with MI history, as a rule-out test for LV systolic and diastolic dysfunction in very old people with limiting dyspnoea. The rule-out cut points recommended by the ESC (125ng/l) [
8] and NICE (400ng/l) [
7] guidelines differ widely, and we show that both have limitations in this age group. Focusing on NT-proBNP’s ability as a rule-out test for LV systolic dysfunction, applying the ESC cut point resulted in very few cases being missed; however, 88% of very old people with limiting dyspnoea had NT-proBNP at or above this cut point, thereby warranting echocardiography, with high false positive rates. Using the higher NICE cut point, echocardiography and false positive rates would be lower, although still substantial; however, whilst exclusionary performance was good for moderate/severe systolic dysfunction it was poor for any grade of systolic dysfunction (45% of cases missed). LVEF between 40-50% is much commoner than ≤40% (prevalence 26% and 8% respectively in our sample), and associated with prevalent and incident HF and mortality; [
21] it is therefore important to identify less severe forms of dysfunction and prevent/delay their progression to more severe dysfunction and overt HF [
3]. Incorporating isolated moderate/severe diastolic dysfunction (19% of our sample) into the target condition, generally increased the proportion of cases missed (lower NPV), whilst increasing the number of cases identified and decreasing the false positive rate, when compared with NT-proBNP’s performance for the same severity of systolic dysfunction alone. Although no therapy has proved effective in preventing progression of diastolic dysfunction to HF-PEF, or in improving outcomes in established HF-PEF, [
8] it is important to diagnose it accurately and instigate appropriate management [
22].
Through comparison with our data-derived cut points, it appears that the ESC cut point is generally an appropriate ‘stringent’ rule-out cut point (misses few cases) in the very old, whilst the NICE cut point is an appropriate ‘optimised’ rule-out cut point (cuts down false positives whilst still limiting false negatives). However, whilst these may be the most appropriate cut points for this age group, their performance metrics limit their overall utility. Interestingly, the NICE cut point has been criticised as being too high, with lower age-specific optimised rule-out cut points recommended (for NT-proBNP: <50 years, 50ng/l; 50-75 years, 75ng/l; age 75+, 223ng/l); [
19] our data suggests that the NICE cut point is the appropriate optimised cut point for 87-89 year olds.
NT-proBNP’s limited diagnostic accuracy for LV dysfunction in the very old is likely to reflect the high prevalence of other cardiac and non-cardiac morbidities known to elevate natriuretic peptides, [
11] compounded by the high consumption of medications (for co-morbid conditions such as hypertension) which can potentially lower peptides below threshold levels even in the presence of LV dysfunction [
7]. Including MI history as an additional referral prompt (as per NICE Chronic HF Diagnostic Algorithm [
7]) was of no overall benefit. It resulted in, at best, only a slight drop in cases missed (and no change for moderate/severe systolic dysfunction), at the expense of higher echocardiography and false positive rates.
Few studies have examined the diagnostic accuracy of natriuretic peptides in older people, [
23] with the 85+ age group particularly under-investigated. Study setting (population-based, primary care, care home, emergency department, out-patient department etc.) affects prevalence and severity of LV dysfunction/HF and consequently test performance, and it is not possible to extrapolate findings directly from one setting to another. Our study is among the first in the very old to incorporate detailed home-based assessment of LV function with natriuretic peptide measurement, and to our knowledge is the largest population-based study of very old people with a clinical suspicion of chronic HF. Only two previous studies have focused on the symptomatic very old, both concluding that whilst natriuretic peptides have some utility as rule-out tests their performance metrics are inferior compared to younger age groups [
24,
25]. Olofsson et al. examined a sample with symptoms/signs suggestive of HF from a single primary care centre (estimated n=67 aged 80+), with the emphasis on detecting systolic HF [
24]. Chenevier-Gobeaux et al. investigated emergency department attendees with acute dyspnoea (n=210, aged 85+); [
25] in acute studies, higher threshold natriuretic peptide values are observed in comparison to chronic dyspnoea [
19]. The utility of HF diagnostic algorithms was examined by Oudejans et al. in geriatric out-patients with a clinical suspicion of new slow onset HF (n=206, aged 70-98) [
26]. The performance of the NICE algorithm was superior to that found in our study, which may reflect the different target conditions studied; Oudejans et al. focused on clinical HF in contrast to our study of LV dysfunction in which natriuretic peptide performance is known to be poorer [
9]. Like us, Oudejans et al. concluded that the performance of NT-proBNP alone was superior to algorithms additionally incorporating MI history.
Strengths of this study are its population-based sample, including the institutionalised and cognitively impaired, and its domiciliary echocardiographic approach incorporating assessment of both systolic and diastolic dysfunction. Hospital-based assessment of this age group is known to introduce selection bias [
27]. A limitation is our use of LV dysfunction as the target condition rather than clinical HF; full clinical assessment for HF was not possible within the scope of this study. However, our focus on the use of natriuretic peptides to rule out LV dysfunction in a sample with a clinical suspicion of HF is in accordance with other important work in the field [
19,
28‐
33]. A potential limitation is our use of limiting dyspnoea without clinical examination to define a sample with a suspicion of HF, although classical physical signs such as basal crepitations and oedema are known to lack both sensitivity and specificity in this age group [
9]. Dyspnoea has a high sensitivity (89%) for chronic HF, although low specificity (51%) [
9]. We did not exclude participants with other potential causes of dyspnoea as we were interested in NT-proBNP’s performance in a ‘real life’ unselected sample of dyspnoeic very old people. Furthermore, the co-existence of multiple morbidities is common in this age group [
15]. Clearly the full diagnostic work-up of dyspnoeic patients should include consideration of non-cardiac conditions. The practical considerations of performing domiciliary echocardiography with a handheld instrument meant that data for some measurements was more incomplete than might have been achieved in a hospital setting [
14].
Conclusions
High echocardiography rates and poor exclusionary performance for mild degrees of systolic dysfunction and for diastolic dysfunction limit NT-proBNP’s utility as a rule-out test for LV dysfunction in very old people with limiting dyspnoea. Therefore alternative strategies merit consideration. These might include other blood-based biomarkers, either singly or in combination panels, although a recent study in a care home population found the novel biomarkers copeptin, MR-proADM and MR-proANP to have little diagnostic utility in older people with significant co-morbidity [
34]. Clinical decision rules, combining natriuretic peptide measurement with additional variables (symptoms, signs and test results), have been proposed although the optimal approach and cost-effectiveness are uncertain [
35]. Atypical HF presentations in the very old, [
4] coupled with high levels of non-specific ECG findings and co-morbidity, [
2] may limit the utility of such approaches in this age group. Optimal evaluation of this age group may require direct access to echocardiography without preliminary peptide measurement, an approach which has recently been advocated for older people with medium/high probability of HF [
22]. Whilst cost-effectiveness needs to be determined, it merits further evaluation given the high costs of HF to healthcare providers [
36] and rapid expansion of the very old population [
1]. If this strategy were adopted, our findings imply that substantially increased echocardiography provision, in accessible settings, would be required. Community-based echocardiography services, including the option of home-based assessment, might best meet the needs of this often frail and multimorbid group.
Acknowledgements
This work was supported by the British Heart Foundation (PG/08/026/24712). The core Newcastle 85+ Study was supported by awards from: UK Medical Research Council and Biotechnology and Biological Sciences Research Council [grant number G0500997]; Dunhill Medical Trust [grant number R124/0509]; and the North of England Commissioning Support Unit. The Newcastle 85+ Study was also supported by the UK NIHR Biomedical Research Centre for Age and Age related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust. BK is supported by a British Heart Foundation Personal Chair. The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the paper; and in the decision to submit the paper for publication.
Thanks are especially due to the older people of Newcastle and North Tyneside for the generous donation of their time and personal information. We appreciate the support of the North of England Commissioning Support Unit (formerly NHS North of Tyne) and local general practices. We thank the research nurses, laboratory technicians, data manager, and project secretary.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
JC participated in: study design; literature review; supervision of data collection; data preparation; data analysis and interpretation; and the development and writing of the paper. AK participated in: data preparation; statistical analysis and interpretation of data; and the critical review of paper drafts. FY participated in: development of cardiac phenotyping protocols; echocardiographic data collection and preparation; and the critical review of paper drafts. KD participated in: participant recruitment; supervision of data collection; data preparation; and critical review of paper drafts. AnK participated in: development of cardiac phenotyping protocols; supervision of data collection; and the critical review of paper drafts. DN participated in: measurement of NT-proBNP; and the critical review of paper drafts. CMR participated in: organisation of blood sampling systems; and critical review of paper drafts. GM participated in: development of manuscript; and critical review of paper drafts. LR participated in: supervision of data collection; and critical review of paper drafts. TBLK participated in: overall leadership and supervision of the Newcastle 85+ Study; and critical review of paper drafts. BK participated in: conception and design of study; obtaining funding; development of cardiac phenotyping protocols; supervision of data collection; data analysis and interpretation; and the development and writing of the paper. All authors read and approved the final manuscript.