Post on 21-Jul-2020
University of Groningen
Chronic heart failure diagnostics and application of neuropeptides in residential elderlyBarents, Maaike
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.
Document VersionPublisher's PDF, also known as Version of record
Publication date:2015
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):Barents, M. (2015). Chronic heart failure diagnostics and application of neuropeptides in residential elderly.[Groningen]: University of Groningen.
CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.
Download date: 15-09-2020
Chronic heart failure diagnostics and application of neuropeptides
in residential elderly
Maaike Barents
geboren 27 december 1950
te Utrecht
2
Paranimfen:
Els Barents
Christien Enzing
Barents, Maaike
Chronic heart failure diagnostics and application of neuropeptides in residential elderly
Dissertation University of Groningen, The Netherlands – with references – with summary in
English and Dutch.
book: ISBN: 978-90-367-8323-1
Ebook : ISBN: 978-90-367-8322-4
PDF without DRM
All rights reserved. No part of this publication may be reproduced, stored in retrieval system, or
transmitted, in any form or by any means, electronically, mechanically, by photocopying, or oth-
erwise, without the prior written permission of the author.
Cover design: Simone Koster, simone@anderkaliber.nl
Druk & lay-out: Gildeprint Drukkerijen B.V., Enschede www.gildeprint.nl
3
Chronic heart failure diagnostics and applica-tion of neuropeptides in residential elderly
Proefschrift
ter verkrijging van de graad van doctor aan de
Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 23 december 2015 om 16:15 uur
door
Maaike Barents geboren op 27 december 1950
te Utrecht
4
Promotores
Prof. F.A.J. Muskiet
Prof. J.L. Hillege
Copromotor
Dr. M.J.L. de Jongste
Beoordelingscommissie
Prof. A.W. Hoes
Prof. W.P.A. Achterberg
Prof. A.A. Voors
Financial support by the Dutch Heart Foundation for the publication of this study was
gratefully acknowledged.
5
We recognize thankfully the support for this thesis given by Corparis Welzijn met Zorg, www.corparis.nl.
6
7
CONTENTS List of abbreviations 10
Chapter 1 15
General introduction to heart failure 1.2 Rationale 15
1.3 Mortality 16
1.4 Morbidity 17
1.5 Defining heart failure and its causes 18
1.6 Prevalence of heart failure (HF) 20
1.7 HF disease burden (DALY) 20
1.8 Quality of life 21
1.9 Diagnostics and algorithm 22
1.10 Natriuretic peptides 23
1.11 Therapies for heart failure 24
1.12 Residential elderly 27
1.13 Heart failure in residential elderly 27
1.14 Aim and outline of the thesis 29
Chapter 2 Diagnostics and prevalence of heart failure in residential elderly. Chapter 2.1 41
Prevalence and misdiagnosis of chronic heart failure in nursing home
residents: the role of B-type natriuretic peptides. Barents M, van der Horst IC, Voors AA, Hillege JL, Muskiet FA, de Jongste MJ.
Neth Heart J 2008;16(4):123-8.
8
Chapter 2.2 61 Underestimated prevalence of chronic heart failure among the nursing
home residents in Aruba. Stoutjesdijk E, Brouns RM, Barents M, de Jongste MJ, Besselink HJ, Cheng JD,
Wever R, Muskiet FA.
West Indian Med J 2014;63(6):610-5. Chapter 2.3 79 Validation of neuropeptides in stable heart failure patients. Patients with stable chronic heart failure exhibit also high intraindividual
Biological variation of amino-terminal pro-brain natriuretic peptide (NT-proBNP)
in urine when compared to the variation in plasma.
Schimmel AM, Barents M, de Jongste MJ, Römer JW, Steward HN, Muskiet FA.
Accepted for publication in part in Clinical Chemistry.
Chapter 3 111 BNP and NT-proBNP, predictors of 1-year mortality in nursing home residents. Barents M, Hillege HH, van der Horst IC, de Boer RA, Koster J, Muskiet FA, de Jongste MJ. J Am Med Dir Assoc 2008;9(8):580-5. Chapter 4 129 Chronic heart failure, related to help with activities of daily living in nursing
home residents. Barents M, Hillege HH, Muskiet FA, de Jongste MJ.
Act Adapt Aging 2011;35(2):98-110.
9
Chapter 5 151 Physical exercise performed by residential elderly of high age is safe
and does not affect chronic heart failure symptoms, NT-proBNP
and cardiovascular-metabolic indices: a pilot, single-blinded RCT. Barents M, Weening E, Muskiet FA, Hillege HH, de Jongste MJ. Submitted.
Chapter 6 173 Chapter 6.1 Summary 174 Chapter 6.2 Discussion 185 Chapter 6.3 Recommendations and future perspectives 191 Chapter 7 199 Chapter 7.1 Samenvatting 200
Chapter 7.2 Discussie 211
Chapter 7.3 Aanbevelingen en toekomst perspectieven 217
Dankwoord en CV 221
10
ABBREVIATIONS AND DEFINITIONS ACE-i angiotensin-converting enzyme inhibitor
ADL activities of daily living
Advance care planning aims to help patients, establish decisions about future care that
take effect when they lose capacity
AF atrial fibrillation
ARB angiotensin-2 receptor blocker
AWBZ Algemene Wet Bijzondere Ziektekosten, funding source of elderly care
medicine except geriatric rehabilitation (Ziektekosten Wet)
BNP B-type natriuretic peptide or brain natriuretic peptide
CHF chronic heart failure. Actually, “non-acute” heart failure is a better term
because a physician does not wait to diagnose heart failure till it has
become chronic” (three months). But, we have used “chronic” heart
failure in all publications and decided therefore not to replace the term
comorbidity diseases of which a person suffers, near the disease which is focussed at.
Comorbidity is standardised by the Charlson comorbidity index. This com-
bined age and comorbidity is developed to estimate the relative risk of
death from prognostic clinical variables. In many studies, the index is ap-
plied to correct for existing comorbidity (1)
COPD chronic obstructive pulmonary diseases
CRT-P/CRT-D chronic resynchronization therapy-pacemaker/defibrillator
CVD cardiovascular diseases
CVA cerebrovascular accident
CVi intraindividual biological variation
CVRM guideline cardiovascular risk management guideline (2)
11
DALY disability adjusted life years is a measure of overall disease burden, ex-
pressed as the number of years lost due to ill-health, disability or early
death
ECG electrocardiogram
echo echocardiogram
eGFR estimated glomerular filtration rate
elderly persons of 65 years and older; also older persons elderly care physi-
cian the elderly care physician is a physician who specializes in long-
term care for frail elderly people and chronic patients with complex
health problems (3)
ESC European Society of Cardiology
GP general practitioner
HbA1c HbA1c ≤8,5% = GTA (Gron. Transmurale Afspraak ) T2DM
HDL-C high-density lipoprotein cholesterol; HDL-C ≥ 1 mmol/L (39 mg/dL) ma-
les, HDL-C ≥1,2 mmol/L (46 mg/dL) females
HF heart failure
HFpEF heart failure with preserved ejection fraction
HFrEF heart failure with reduced ejection fraction
Hg mercury
ICD implantable cardioverter defibrillator
IR insulin resistance
Lab Noord Laboratorium Noord (Laboratory North) in The Netherlands
LDL-C low-density lipoprotein cholesterol; LDL-C < 2,5mmol/L (100 mg/dL)
LTCFs long-term care facilities comprising nursing homes and care homes for the
elderly
LVEF left ventricular ejection fraction
12
MDS minimum data set, items of the Resident Assistant Instrument (RAI).
MDS-items consist of systematic observations of dependency and de
livered aid through which dependence and aid can be quantified.
These observations focus on self-reliance of the individual
residential elderly during predefined activities of daily living.
MET Metabolic Equivalent Task (MET), an unit for metabolism in rest
METS metabolic syndrome
MeSH medical subject headings; controlled key words of MEDLINE database
MI myocardial infarction
MMSE minimum mental state estimation
multi medication use a daily intake of at least five different drugs (4)
multimorbidity multiple co-occurring, chronic or long-term diseases or conditions, none
considered as index disease (5)
MSD musculoskeletal disorders
NICE guideline National Institute for Health and Care Excellence
NH nursing home
NLM database National Library of Medicine database (Maryland, USA)
NND neurodegenerative disorders
norm physical activity a minimum of physical activity at ≥4 METs for individuals of 20-55
years during 30 min at 5 days a week and ≥3 METs for 55+ years (6)
NP natriuretic peptide
NT-proBNP amino-terminal proB-type natriuretic peptide
NYHA class New York Heart Association classification of heart failure
oldest old persons persons aged > 85 years (medicaldictionary.thefreedictionary.com)
PMC database Pub Med Central database
polypharmacy polypharmacy is defined as the use of five or more drugs, including
prescribed, over-the-counter, and complementary medicines (4)
13
primary care physicians physicians, general practitioners and elderly care physicians
Quol quality of life
RAAS renin-angiotensin-aldosterone system
RAI Resident’s Assessment Instruments, software program for
providing problem lists as base for the individual care-treatment
plan made by the direct care-giver and for the State Governors (7)
RCT randomized controlled trial
RIVM Rijks Instituut voor Volksgezondheid en Milieu
RD renal dysfunction
residential elderly elderly residing in nursing homes or care homes; also
institutionalised frail elderly
TIA transient ischemic attack
TMWD ten meter walk distance
TUG timed up and go test
TG triglycerides; fasting TG ≤8mmol/L
T2DM type 2 diabetes mellitus
Verenso vereniging van specialisten ouderengeneeskunde en sociaal geriaters (So-
ciety of elderly care physicians and social geriatricians)
VZH verzorgingshuis, care home for the elderly. One of the institutes of
LTCFs
14
15
Chapter 1 GENERAL INTRODUCTION.
This chapter provides a comprehensive review of heart failure (HF), which is the central theme
of this thesis. Since HF is a syndrome predominantly affecting the elderly, it imposes an impor-
tant disease burden in elderly medicine. Elderly medicine is a relatively young specialism. On a
daily basis, elderly care physicians deal with the question when and how to apply general me-
dicinal guidelines and in which cases the resident’s high age has to be taken into account. Is-
sues as diagnostics and exercise are relevant for the frailest elderly with HF. Due to the com-
plexity of frail elderly, optimal diagnosis and treatment, remain a major challenge for the practic-
ing physician in order to improve outcome. At the end of this chapter we focus on HF in the
frailest elderly, i.e. those who have to rely on long-term care facilities (LTCFs), since heart fail-
ure in the frailest elderly is the subject of this thesis.
1.2 RATIONALE.
In The Netherlands, the average life expectancy has increased from 70 years for men and 73
years for women in 1950 to 79 and 83 years in 2013, respectively (www.cbs.nl and
www.nationaalkompas.nl). Main determinants of the increased life expectancy are the imple-
mentation of better hygienic and preventive measures, easy availability of sufficient and healthy
food in conjunction with a shrewd and balanced lifestyle and the development of an armamen-
tarium of medical treatments, such as pharmacotherapy and surgical techniques. One of the
most important achievements in reducing overall mortality originates from the enormous pro-
gress made in the management of cardiovascular disease (CVD) during the last 60 years. As a
consequence the many survivors of CVD grow older and acquire other non-CV diseases, single
or multiple, often accompanied by disabilities. When multimorbidity is accompanied by the loss
of psychosocial resources, we speak of frailty (8). Frail elderly are at risk to deteriorate even
16
faster and geriatric interventions are required. The frailest elderly live in LTCFs, like nursing
homes or care homes, and are referred to as ’residential elderly’. Although this group consumes
a growing percentage of the Dutch health care budget they are excluded from research studies
because of high age, multimorbidity and cognitive disorders. Until recently, these elderly were
diagnosed and treated in the same way as adults with a single disease. At the start of this study
there was no HF guideline available for the group of residential elderly. This was because the
HF guideline of Verenso from 1999 was out of date (Verenso, Vereniging van specialisten
ouderengeneeskunde en sociaal geriaters). In 2003 and in 2008, the Dutch multidisciplinary
HF guideline, based on the European Society of Cardiology (ESC) HF guideline, recognised the
lack of research data for females and the 75+ age-group (both genders) (9;10). Meanwhile,
natriuretic peptides (NP) proved their utility for HF diagnostics, prognosis and therapy-
optimization. In addition the importance of non-pharmacological treatment such as physical ex-
ercise was well recognized. These niches of knowledge on CHF diagnostics and non-
pharmacological therapy formed the rationale for studying this excluded group of the residential
elderly.
1.3 MORTALITY FROM CARDIOVASCULAR DISEASES.
Since its peak in the late 1950s (for women) and the early 1970s (for men) cardiovascular
(CV) mortality has gradually declined. This tremendous decrease in CV mortality is remarkable
when we take into account the increasing number of elderly people and the more advanced age
of contemporary Dutch citizens. Also, after correction for age (standardisation), the drop in CV
mortality remains considerable, with a reduction of about 70% (Figure 1).
17
Figure 1. Standardised Cardiovascular Mortality per 100,000 inhabitants in The Netherlands
(8).
1.4 MORBIDITY.
As spin-off of the impressive 68% decrease in CVD mortality, a substantial increase in CVD
morbidity is nowadays reported, with an estimated prevalence of 700,000 subjects in The
Netherlands currently suffering from CVD. Out of these 700,000, around 125,000 have HF
(11). As for CV mortality to date more patients die from HF than from myocardial infarction (MI), since an increasing number of people survive their MI, but subsequently develop HF (Figure 2).
18
Figure 2. Heart failure mortality has surpassed myocardial infarction mortality in The Neth-
erlands since 2011. Number of deaths attributed to myocardial infarction (MI) or heart failure
(HF) as the primary cause of death in The Netherlands from 1980 through 2012 (12).
1.5 DEFINING HEART FAILURE AND ITS CAUSES.
Defining HF is not easy. The most straightforward approach is to define HF as: a condition dur-
ing which the heart is unable to meet the metabolic needs of the body. Unfortunately in daily
practice HF is often more difficult to define. Also, this is caused by the multi-interpretability of
vague key symptoms of HF, notably, fatigue and dyspnea. The significance of symptoms and
signs is even more difficult to interpret in elderly due to the presence of co-morbidities. At pre-
sent three definitions are used to label HF. These definitions describe the diagnosis of HF on a
clinical (symptomatic), a pathophysiological or a therapeutic basis (9;13;14). Given the difficul-ties to define HF, discovery of (the onset of) HF is often late.
Clinical (symptomatic) HF definition: HF is a syndrome in which the patients should have
the following symptoms typical for HF: shortness of breath at rest or during exertion,
0
5000
10000
15000
20000
25000
1980 1985 1990 1995 2000 2005 2010
Myocardial infarction Heart failure
19
and/or fatigue; signs of fluid retention such as pulmonary congestion or ankle swelling;
and objective evidence of an abnormality of the structure or function of the heart at rest
(9). Pathophysiological HF definition: HF is defined as a pathophysiological state in which an
abnormality of cardiac function is responsible for failure of the heart to pump blood at a
rate commensurate with metabolic requirements or to do so only from an elevated filling
pressure (13). Therapeutic definition: cardiomyopathies are a heterogeneous group of diseases of the
myocardium associated with mechanical and/or electrical dysfunction that usually (but
not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a
variety of causes. Cardiomyopathies either are confined to the heart or are part of gen-
eralized systemic disorders, often leading to cardiovascular death or progressive HF–
related disability (14). In addition to the three definitions, HF is classified by course of disease and functionality.
With respect to course: after 3 months HF is considered as chronic. Chronic HF (CHF) can be
stable or gradually progressive, or can exacerbate into acute HF. Regarding the functionality,
HF is distinct in diastolic HF, also named HF with preserved left-ventricular ejection fraction
>40-50% (LVEF; HFpEF), and systolic HF, also named HF with reduced LVEF (HFrEF) (9).
For diagnostic purposes, for both HFrEF and HFpEF, typical signs and symptoms of HF are
obligatory. For HFpEF two more requirements are needed: a non dilated left ventricle and
documentation of diastolic dysfunction. The diagnosis of HFpEF is more difficult than that of
HFrEF because it is largely one of exclusion, e.g. of potential non-cardiac causes of the pa-
tient’s symptoms. As for the individual patient’s restrictions, the New York Heart Association
(NYHA) classification is used (15). NYHA places patients in one of four categories based on
how much they are limited during physical activity.
All possible causes for HF may be divided into derailments of the heart muscle as a result of
20
cardiomyopathy, coronary artery disease (CAD), atrial fibrillation or other rhythm or conducting
disturbances, infection or intoxication. In addition, diseases of the heart valves, afflictions of the
pericardium or (cardiac) shunts may cause HF. Finally, circulatory derangements may induce
HF, such as coarctation, thrombo-embolic process, intoxication, high output failure, infection,
hyperthyroidism and fluid overload. In general, HFrEF is most often caused by CAD which is
predominantly generated through hypertension (HT).
1.6 PREVALENCE OF HEART FAILURE.
Due to an increasingly ageing population, already in 1990 a growing number of individuals with
HF was predicted in The Netherlands (12). After 22 years, the estimation of HF became reality,
with a prevalence of about 120,000 – 130,000 subjects. Moreover, the number of people with
HF is expected to increase to reach about 200,000 individuals in 2018 (16). Between 20 to
30% of the general population will ultimately develop HF, when they are over 70 years of age
(17).
1.7 HEART FAILURE DISEASE BURDEN.
Apart from the increasing HF mortality, the morbidity or disease burden due to HF will rise as
well. The “Rijksinstituut voor Volksgezondheid en Milieu” (RIVM) has quantified “disease bur-
den” in a model of disability-adjusted life-years (DALY) (18), expressed as the number of years
lost due to ill-health, disability or early death through HF. The authors have estimated the DALY
for each of four risk factors for HF separately. These risk factors comprise hypertension (HT;
moderate HT is SBP of 140-160 and serious HT ≥160 mm Hg), moderately-high total choles-
terol (200-239 mg/dL; 5.17-6.18 mmol/L) and seriously-high total cholesterol (≥240 mg/dL;
≥6.20 mmol/L), overweight, obesity and inactivity. Inactivity is defined as <4 metabolic equiva-
lents of tasks (METs) for age 20-55 years and <3 METs for age 55+. A DALY was found of
21
1.6 years for seriously-high total cholesterol and up to 2.9 years for serious HT (Figure 3). The
consequences of DALY for the AWBZ will be that an increasing part of the Dutch health care
budget have to be devoted to the HF disease burden.
Figure 3. Disability-adjusted life-years (DALY). A DALY-model estimated for a Dutch popu-
lation classified by different risk factors for heart failure.
Disability-Adjusted Life-Years (DALY), expressed as number of years lost due to ill-health, dis-
ability or early death. The bars are equally long and the upper bar represents the life-
expectancy (LE) of a 20 year old with a lifelong optimal HF risk profile. The middle parts of the
bars reflect the years lived with HF. The right parts of the bars show the years lost due to HF
(18).
1.7 QUALITY OF LIFE (QUOL).
The DALY quantifies the time lived with reduced Quol due to HF. Not only the direct loss of
Quol by HF symptoms but also the indirect loss by restrictions, as a result of HF, are important.
These restrictions appear in several Quol domains like mobility and independency. For instance,
healthy HF free
overweight with HF
increased cholesterol loss of LE
strongly increased cholesterol
hypertension
obesity
serious hypertension
inactivity
77 78 79 80 81 82
22
dyspnea limits the ability to execute activities of daily living (ADL) and walking distance (19).
From the perspective of the individual, the severity of HF affects a person’s self-reported func-
tioning (20). It is obvious that HF is related to assistance at ADL, but this relation has not been
investigated by others. Such a relation, if causal, is important for the care-giver who needs to
estimate the amount of required ADL assistance and for the individual who needs that help.
The physician may estimate the prognosis of patients using independent predictors of HF such
as high age, NYHA 3 and 4, loss of appetite (21), N terminal pro B-type natriuretic peptide
(NT-pro)BNP (22) and chronic kidney diseases (CKD) (23). Among others these prognostic
predictors enable a patient with CVD to make personal choices for the last phase of his life. The
choices may permit the patient to retain control over his or her life and thereby prevent de-
crease of autonomy, at least on the domain of decision-making.
1.9 HF DIAGNOSTICS AND ALGORITHM.
In primary care elderly-medicine, HF is diagnosed using CV medical history, for HF predispos-
ing diseases and risk factors (chapter 1.5), clinical examination, electrocardiography (ECG),
natriuretic peptides (chapter 1.10) and echocardiography. These are referred to as diagnostic
tools. The reference standard for the, at least functionally undifferentiated HF diagnosis is based
on all of these tools, occasionally extended with chest X-ray (9;10;24). For further examination
of HF causes or treatment, referral to a cardiologist may be required. However, predictive val-
ues of the separate diagnostic tools are moderate which hamper initial HF diagnostics in pri-
mary care and in geriatric outpatients as well (25;26). This hindrance combined with no easy
access to echocardiography or unwanted referral (resident’s preference), needed a solution to
diagnose HF without outpatient referral. For that purpose HF diagnostic algorithms were devel-
oped based on combinations of diagnostic tools including NPs (21;25-28). However a few is
known whether those HF diagnostic algorithms (9;10;21;24-28) are also suitable for the resi-
dential elderly suspected of HF.
23
1.10 NATRIURETIC PEPTIDES.
At the end of the last century, NPs have emerged as reliable biomarkers for the diagnosis and
prognosis of both systolic and diastolic HF. NP testing is regarded to be the single most useful
test to add to the diagnostic pathway for HF in primary care. Tests of NPs have shown to be
cost effective. However, in HFpEF levels of NPs are increased, but somewhat lower compared
to those in patients with HFrEF. Therefore, the relatively higher NP levels are predictive for
HFrEF, but the moderately increased NP levels do not predict HFpEF very well (29). Especially
the NPs specificity and diagnostic accuracy in acute HF are prominent. Currently, NPs, notably
B-type natriuretic peptide (BNP) and N-terminal-proBNP (NT-proBNP), are commonly applied
diagnostic (30) and prognostic (31) biomarkers. Confounders of NP levels are non-cardiac
factors such as high age, sex and renal dysfunction, since these also increase NP levels. Obe-
sity, diuretics, ACE inhibitors, beta-blockers, ARBs and aldosterone antagonists reduce NP lev-
els (32). All the above mentioned confounders occur widely in residential elderly. Many of
them use CV medications and renal dysfunction is widespread. Therefore, NPs may not predict
HF exclusively (32) and NP cut-off values are not fully validated in this particular group. With
regard to treatment optimization, a meta-analysis shows that NP-guided therapy is superior to
symptom-guided therapy in groups of patients with CHF (33). However a study on individual
CHF patients reveals high intra-individual biological variations of NPs as major limitation of NPs
in the optimization of HF treatments (34).
The secretion of NPs by the ventricle wall increases when HF is accompanied by pressure or
volume overload (35). Only BNP regulates actively. BNP stimulates natriuresis, diuresis, vaso-
dilatation and inhibits the renin-angiotensin-aldosterone system (RAAS) and sympathetic nerv-
ous system. BNP is metabolized actively in blood and cells by neuropeptidases (36). The half-
life time of BNP is 20 minutes. These characteristics render BNP appropriate as marker of HF
(30). NT-proBNP has an about six times longer half-life, viz. 1-2 hours (37). As opposed to
BNP, NT-proBNP is passively filtered in the kidney (38), actively reabsorbed by the proximal
24
tubulus brush border cells and catabolised to amino acids. This process of NT-proBNP degra-
dation is usually nearly complete. Thus, only minor amounts of NT-proBNP are recovered in
urine (39).
Both NPs are released into the circulation in an 1:1 molar ratio. The secretion of BNP exhibits a
pulsatile pattern in the circulation (40) and it may be assumed that NT-proBNP is split-off
pulse-shaped as well. Consequently both NPs exhibit high intra-individual biological variations
which hamper their use for treatment optimization of an individual (34). Mainly experimentally,
NPs are determined in urine using immunoassays. Urine NPs may exhibit less intra-individual
biological variation compared to plasma NPs, assuming that the pulsatile secretion becomes
attenuated by NT-proBNP accumulation in the bladder (41-43). Thus, the experimental use of
urine NP is prompted by the high intra-individual biological variation of plasma NPs (34).
1.11 THERAPIES FOR HEART FAILURE.
Following the diagnosis of HF, treatment is based on CV risk management (CVRM) (2) and
correction of underlying causes (10). CVRM for HF differs in the time of intervention (2) from
other HF guidelines. The current trend is not to wait until HF symptoms have developed, but to
start intensive risk management for patients with increased risk of HF (www.RIVM.nl). It is as-
sumed that if HF could be recognized before symptoms emerge, lifestyle adaptations or appro-
priate medication could reduce HF symptoms or the physical decline caused by HF. An example
of lifestyle effects on CV risk factors is presented by a five-year lasting Dutch study. This study
shows that 1% of adults has changed from physically inactive into moderately-active and 1-2%
from overweight/obese or underweight to normal weight (6). Whether such endpoints can also
be reached in HF patients belonging to the elderly and whether such interventions could prevent
HF progression or even accomplish a reverse, is unknown.
25
In addition, it is advised to treat other diseases precipitating to HF. It is assumed that treatment
of anemia, lung diseases, renal dysfunction, thyroid-gland dysfunction, T2DM and intoxications
reduces the risks of HF (9). Treatment of underlying causes of HF consists, among others, of pharmacological therapy. Most pharmacological therapies are specific for HFrEF (Table 1).
26
Table 1. Treatment of Heart Failure with reduced left ventricular ejection fraction (HFrEF)
(26).
HF with reduced ejection fraction treatment start diuretics to relieve signs/symptoms
and ACE-i (or ARB) When clinically stable, add beta-blocker
Titrate to the target doses of When complaints are not persisting
ACE-i (or ARB) and beta-blocker no complementary therapy indicated
When complaints are persisting, add MR antagonist
When instable (SR and HR ≥ 70/min), add Ivabradine
When complaints does not persist, EF≤35% No further specific treatment
When complaints are persisting and QRS≥120ms Consider CRT-P/CRT-D
When complaints are persisting and QRS ≤120ms consider ICD
When complaints are persisting Consider digoxin and/or hydralazine or isosorbide nitrate
Angiotensin Converting Enzyme inhibitor, ACE-i; Angiotensin Receptor II Blocker, ARB; ejection fraction, EF; sinus rhythm, ARB; heart rate, HR; mineralocorticosteroid receptor, MR; cardiac resynchronization therapy pacemaker, CTR-P/CRT-D, defibrillator.
Since patients with advanced CHF (EF ≤35 - 40%) are at risk of sudden death, an implantable
cardioverter defibrillator (ICD) is placed, for preventive reasons according to guidelines. Finally,
non-pharmacological treatments to improve systolic function of the left ventricle function com-
prise, among others, revascularization procedures, valvular or ventricular surgery, rhythm opti-
mization (electrocardioversion, ablation), cardiac resynchronization therapy (CRT) and heart
transplantation. For HFpEF no specific therapy is available, yet. For these patients only the un-
27
derlying cause such as hypertension is treated (10). For the elderly, the same treatment is
available provided that dosages are adjusted to decreased kidney function and the life expec-
tancy is at least 0.5 years with good quality of life (10).
1.12 THE RESIDENTIAL ELDERLY.
The residential elderly belong to the frailest elderly (chapter 1.2). They reside in care or nursing
homes (LTCFs). Care and nursing homes differ in intermittently or continuously provided sup-
port and ADL-help, respectively. During the final stage of writing this thesis in 2015, financing of
Dutch care homes had just ended. As a consequence most care home elderly had to move to
private houses with care at home or to a nursing home.
In primary care elderly medicine, preferences of the residential elderly are inventoried and taken
as the starting point for further treatment decisions in case they become incompetent in future.
These preferences concern diagnostics, treatment and hospital referral in the event of emer-
gency. These choices or preferences are set out in agreements that are evaluated twice a year,
or more often when indicated. These agreements may include renouncing invasive and intensive
care treatments and hospital referral. As an exception, hospital referral for (surgical) treatment
of bone-fractures are seldom renounced.
1.13 HEART FAILURE IN RESIDENTIAL ELDERLY.
The increasing HF prevalence on the one hand, and lack of specific HF research data on the
other hand challenge healthcare professionals in the provision of optimal patient care in the
residential elderly. We expected the HF diagnostics to be less accurate due to high age, female
sex, multimorbidity (44;45), ’treatment agreements’ and absence of a specific HF guideline. At
the start of this study, it was unknown whether general HF guidelines could be applied to the
residential elderly (9;10;24). Therefore, we set out to study HF prevalence and diagnostic ac-
28
curacy in this particular group of elderly people. We planned also to investigate whether HF
diagnostics could be improved by adding NPs to the usual HF diagnostics.
Furthermore, HF guidelines, the CVRM guideline and family members recommend residential
elderly to be physically active (2;9;10;24) aiming to maintain or improve physical health. The
residential elderly, however, seems to have little motivation to train physically on a regular ba-
sis. He or she faces a limited life expectancy wondering whether his exertion will provide bene-
fits. Not much is known as to whether non-elective exercise might be beneficial in residential
elderly (46). Staffs of nursing and care homes doubt whether they should invest in regular ex-
ercise programmes and whether such interventions will be safe and effective. Therefore, we
experimented with an exercise program based on a review specific to the residential elderly
(47).
In addition, when facing a limited life expectancy, accurate information on prognosis will become
more important. Prognostic information allows residential elderly to take their own decisions so
that loss of Quol at least in the area of autonomy is reduced (chapter 3). Natriuretic peptides
have been shown a powerful prognostic marker in adults with HF and may have similar prog-
nostic value in residential elderly. However, the prognostic properties of NPs have not been not
examined in this particular group. Moreover, many confounders influence NP levels in such a
way that they hamper to inform on prognosis in this residential target group. Therefore we
aimed to study whether NPs could be used as a prospective and independent predictor in those
frail elderly with HF.
Independency of care takers determines Quol to a high degree. It was surprising to learn, at the
start of this study, that the HF diagnosis was not on the list of geriatric chronic diseases in the
‘Resident Assessment Instrument’ (RAI). The RAI is in use in American and Dutch nursing
homes for care-planning at an individual, organizational and state level (48). Nevertheless, we
presumed a relationship between HF state and help-with-care in residential elderly. In that line
of reasoning, NP concentrations might be related to help-with-care as well. However a relation
29
between HF and or NPs with ADL-assistance was not observed until now. Therefore, we set out
to test these research questions.
1.14 AIM AND OUTLINE OF THE THESIS.
In a broad perspective, the studies in this thesis aim to determine whether application of parts of
the HF guidelines can be accurately applied to the specific group of the residential elderly. The
doubts on the applicability of HF guidelines in residential elderly is based on the systematic ex-
clusion of this group from HF research. There is also dubiety based on the observed higher cut-
off values of NPs at a higher age, in renal dysfunction and comorbidity. Evidence as to what
extent HF guidelines can be applied is important to elderly care physicians. These questions
have undermined the accuracy of HF diagnostics resulting in no treatment or inappropriate
treatment, and less well-being. Therefore, we aimed to obtain insight into certain HF aspects,
such as prevalence, diagnostic accuracy, diagnostic and prognostic values of NPs and the rela-
tion of HF with help-at-care. To this end, we screened the residential elderly of a single nursing
home in Groningen on the presence of CHF. To examine its external validity we repeated this
screening program in Aruban nursing homes.
Furthermore, we sought to investigate whether physical activity was to the benefit of care home
elderly on the basis of cardio-metabolic endpoints. These comprise waist circumference, blood
pressure, glucose-homeostasis and lipids. We were also interested to see whether complaints
and NPs ameliorate in the care home elderly with HF. With both aims, we conducted a random-
ized controlled trial employing a 16-weeks lasting supervised exercise intervention. For this, we
collaborated with investigators examining partly the same care home elderly for other, more
functional, endpoints (46).
At last, aiming to gain insight into the feasibility of NPs for treatment optimization, we estimated
the intra- and inter-individual variations of NPs in urine and plasma of stable CHF patients living
in Curaçao.
30
Specific aims of this study are described in the following paragraphs: In Chapter 1 we provide a general introduction of HF with special emphasis on HF diagnostics
in residential elderly. In Chapter 2.1 we study both prevalence and accuracy of HF diagnostics in the Groningen resi-
dential elderly. In the meantime, we aim to find out whether improvements can be achieved by adding NPs to the diagnostic process in use in a Dutch nursing home. The aim of Chapter 2.2
is similar to that of Chapter 2.1. but now applied to all residential elderly in Aruba. In Chapter
2.3 we study the intra-individual variations of NPs with the purpose of finding out whether urine
NPs may exhibit less variations compared to those in plasma in the Curacao population In Chapter 3 we study the prognostic value of NPs on one year mortality of the Groningen resi-
dential elderly, aiming to better inform those facing a limited life expectancy. The aim of Chap-
ter 4 is to determine the relationship between CHF and the required need for ADL-help in the
residential elderly in Groningen. The aim of Chapter 5 is to examine the effects of a physical
exercise program for the Groningen care home elderly. We investigated whether such a pro-
gram may be beneficial with respect to cardiovascular-metabolic (soft) endpoints. Here, we
could collaborate with an investigator who would perform the same intervention, but aiming at
other, more functional endpoints. In Chapter 6.1 we summarized and in Chapter 6.2 we discussed the results of the above de-
scribed studies and in Chapter 6.3 we provided recommendations for future studies. In Chap-
ter 7 a Dutch summary (“Samenvatting”) is given.
31
Figure 4. Flowchart of studies presented in this thesis with the corresponding populations in
which the studies have been conducted.
ADL, Activities of daily living.
Heart failure diagnostics
Heart failure and 1-year mortality
Heart failure and ADL-assistance
Heart failure and exercise
All nursing homes on Aruba N=51
1 nursing home Groningen N=103; ADL-assist. N=93
Heart failure patients on Curaçao N=25
4 care homes in Groningen N=52
Natriuretic peptides urine versus plasma
32
References
1 Charlson ME, Charlson RE, Peterson JC, Marinopoulos SS, Briggs WM, Hollenberg JP.
The Charlson comorbidity index is adapted to predict costs of chronic disease in primary
care patients. J Clin Epidemiol 2008;61(12):1234-40.
2 Wiersma T, Smulders YM, Stehouwer CD, Konings KT, Lanphen J. [Summary of the
multidisciplinary guideline on cardiovascular risk management (revision 2011)]. Ned
Tijdschr Geneeskd 2012;156(36):A5104.
3 Koopmans RT, Lavrijsen JC, Hoek JF, Went PB, Schols JM. Dutch elderly care physici-
an: a new generation of nursing home physician specialists. J Am Geriatr Soc
2010;58(9):1807-9.
4 Hilmer SN, Mager DE, Simonsick EM, Cao Y, Ling SM, Windham BG, et al. A drug bur
den in dex to define the functional burden of medications in older people. Arch Intern
Med 2007;167(8):781-7.
5 Akner G. Analysis of multimorbidity in individual elderly nursing home residents. Devel-
opment of a multimorbidity matrix. Arch Gerontol Geriatr 2009;49(3):413-9.
6 Wendel-Vos W, Droomers M, Kremers S, Brug J, van Lenthe F. Potential environmental
determinants of physical activity in adults: a systematic review. Obes Rev
2007;8(5):425-40.
7 Hirdes JP, Ljunggren G, Morris JN, Frijters DH, Finne, Soveri H, et al. Reliability of the
interRAI suite of assessment instruments: a 12-country study of an integrated health in-
formation system. BMC Health Serv Res 2008;8:277-88.
33
8 Smets IH, Kempen GI, Janssen-Heijnen ML, Deckx L, Buntinx FJ, van den Akker M.
Four screening instruments for frailty in older patients with and without cancer: a diag-
nostic study. BMC Geriatr 2014;14:26.
9 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC
Guide lines for the diagnosis and treatment of acute and chronic heart failure 2012: The
Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of
the European Society of Cardiology. Developed in collaboration with the Heart Failure
Association (HFA) of the ESC. Eur Heart J 2012 33(14):1787-847.
10 Voors AA, Walma EP, Twickler TB, Rutten FH, Hoes AW. [Multidisciplinary guideline
'Heart failure 2010']. Ned Tijdschr Geneeskd 2011;155:A2957.
11 National Institute for Public Health and the Environment (RIVM). National Public
Health Compass. 2013 [November 19, 2013]; Available from:
http://www.nationaalkompas.nl/ gezondheid-en-ziekte/ziekten-en- aandoenin- gen/hartvaatstelsel).
12 Vaartjes I, Koopman C, van Dis I, et al. Hart- en vaatziekten in Nederland 2013, cijfers
over leefstijl, risicofactoren, ziekte en sterfte. The Hague: Dutch Heart Foundation; 2013.
13 Braunwald E. Pathophysiological of HF. In: Braunwald’s Heart Disease. A textbook of
Cardio vascular Medicine. 10th ed. 2014.14.
14 Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. Contempo-
rary definitions and classification of the cardiomyopathies: an American Heart Association
Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Trans
34
plantation Committee; Quality of Care and Outcomes Research and Functional Genom-
ics and Translational Biology Interdisciplinary Working Groups; and Council on
Epidemiology and Prevention. Circulation 2006;113(14):1807-16.
15 Raphael, Claire; Briscoe, C; Davies, J; Ian Whinnett, Z; Manisty, C, et al (2007).
"Limitations of the New York Heart Association functional classification system and
self-reported walking dis- tances in chronic heart failure." Heart (British Cardiac So-
ciety) 93(4):476–82.
16 Engelfriet PM, Hoogenveen RT, Poos MJJC, Blokstra A, van Baal PHM, Verschuren
WMM. Hartfalen: epidemiologie, risicofactoren en toekomst. Heart failure: epidemiology,
risk factors and future. In: Rijksinstituut voor Volksgezondheid en Milieu, RIVM. Rapport
260401006. 2012.
17 Bleumink GS, Knetsch AM, Sturkenboom MCJM, Straus SM, Hofman A, Deckers
JW, et al. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk
and prognosis of heart failure the Rotterdam study. Eur Heart J 2004;25:1614–1619.
18 Murray, C. J. and Lopez, A. D. Evidence-based health policy-lessons from the Global
Burden of Disease Study. Science 274(5288), 740-743. 1-11-1996.
19 Steptoe A, Deaton A, Stone AA. Subjective wellbeing, health, and ageing.
Lancet 2015;385(9968):640-8.
20 Munyombwe T, Hofer S, Fitzsimons D, Thompson DR, Lane D, Smith K, et al. An
evaluation of the Minnesota Living with Heart Failure Questionnaire using Rasch analy
35
sis. Qual Life Res 2014;23(6):1753-65.
21 Oudejans I, Mosterd A, Zuithoff NP, Hoes AW. Applicability of current diagnostic algo-
rithms in geriatric patients suspected of new, slow onset heart failure. Age Ageing
2012;41(3):309-16.
22 Don-Wauchope AC, Santaguida PL, Oremus M, McKelvie R, Ali U, Brown JA, et al.
Incremental predictive value of natriuretic peptides for prognosis in the chronic stable
heart failure population: a systematic review. Heart Fail Rev 2014;19(4):521-40.
23 Damman K, Voors AA, Navis G, van Veldhuisen DJ, Hillege HL. Current and novel renal
biomarkers in heart failure. Heart Fail Rev 2012;17(2):241-50.
24 NICE Guideline No 5: Chronic Heart Failure;
www.pathways.nice.org.uk/pathways/chronic-heart-failure.
25 Kelder JC, Cramer MJ, van Wijngaarden J, van Tooren R, Mosterd A, Moons KG, et al.
The diagnostic value of physical examination and additional testing in primary care pa
tients with suspected heart failure. Circulation 2011;124:2865–2873.
26 Oudejans I, Mosterd A, Bloemen JA, Valk MJ, van Velzen E, Wielders JP, et al. Clinical
evalua tion of geriatric outpatients with suspected heart failure: value of symptoms, signs,
and additional tests. Eur J Heart Fail 2011;13:518–527.
27 Roalfe AK, Mant J, Doust JA, Barton P, Cowie MR, Glasziou P, et al. Development and
initial validation of a simple clinical decision tool to predict the presence of heart failure in
36
primary care: the MICE (Male, Infarction, Crepitations, Edema) rule. Eur J Heart Fail
2012;14(9):1000-8.
28 Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, et al. Systematic review
and individual patient data meta-analysis of diagnosis of heart failure, with modelling of
implications of different diagnostic strategies in primary care. Health Technol Assess.
2009;13(32):1-207, iii.
29 Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et
al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of
heart failure with normal left ventricular ejection fraction by the Heart Failure and Echo
cardiography Associations of the European Society of Cardiology. Eur Heart J
2007;28(20):2539-50.
30 Januzzi JL, Jr. Natriuretic peptide testing: a window into the diagnosis and prognosis of
heart failure. Cleve Clin J Med 2006;73(2):149-7.
31 Sato T, Yamauchi H, Suzuki S, Yoshihisa A, Yamaki T, Sugimoto K, et al. Distinct prog-
nostic factors in patients with chronic heart failure and chronic kidney disease. Int Heart
J 2013;54(5):311-7.
32 Fent G, Hall I, Watt V, O'Toole L, Al-Mohammad A. 43 Raised Natriuretic Peptides are
not Ex clusively Indicative of Heart Failure: A Service Review of a Diagnostic Heart Fail-
ure Clinic. Heart 2014;100 Suppl 3:A23-A24.
33 De Vecchis R, Esposito C, Di BG, Ariano C, Giasi A, Cioppa C. B-type natriuretic pep
tide-guided versus symptom-guided therapy in outpatients with chronic heart failure: a
37
systematic review with meta-analysis. J Cardiovasc Med (Hagerstown) 2014;15(2):122-
34.
34 Bruins S, Fokkema MR, Romer JW, Dejongste MJ, van der Dijs FP, van den Ouweland
JM, et al. High intraindividual variation of B-type natriuretic peptide (BNP) and amino-
terminal proBNP in patients with stable chronic heart failure. Clin Chem
2004;50(11):2052-8.
35 Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, et al. B-type natriuretic
peptide strongly reflects diastolic wall stress in patients with chronic heart failure: com-
parison between systolic and diastolic heart failure. J Am Coll Cardiol 2006;47(4):742-
8.
36 Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med
1998;30;339(5):321-8.
37 Balion CM, Santaguida P, McKelvie R, Hill SA, McQueen MJ, Worster A, et al. Physio-
logical, pathological, pharmacological, biochemical and hematological factors affecting
BNP and NT- proBNP. Clin Biochem 2008;41(4-5):231-9.
38 Gekle M. Renal tubule albumin transport. Annu Rev Physiol 2005;67:573-94.
39 Palmer SC, Endre ZH, Richards AM, Yandle TG. Characterization of NT-proBNP in hu-
man urine. Clin Chem 2009;55(6):1126-34.
40 Pedersen EB, Bacevicius E, Bech JN, Solling K, Pedersen HB. Abnormal rhythmic os-
cillations of atrial natriuretic peptide and brain natriuretic peptide in chronic renal failure.
38
Clin Sci (Lond) 2006;110(4):491-501.
41 Cortes R, Portoles M, Salvador A, Bertomeu V, Garcia de BF, Martinez-Dolz L, et al.
Diagnostic and prognostic value of urine NT-proBNP levels in heart failure patients. Eur
J Heart Fail 2006;8(6):621-7.
42 Song J, Li P, Li H, Wang Q. The clinical significance of a urinary B-type natriuretic pep
tide as say for the diagnosis of heart failure. Clin Chim Acta 2011;412(17-18):1632-6.
43 Michielsen EC, Bakker JA, Kimmenade RR, Pinto YM, Dieijen-Visser MP. The diagnos-
tic value of serum and urinary NT-proBNP for heart failure. Ann Clin Biochem
2008;45(Pt 4):389-94.
44 Daamen MA, Schols JM, Jaarsma T, Hamers JP. Prevalence of heart failure in nursing
homes: a systematic literature review. Scand J Caring Sci 2010;24(1):202-8.
45 Rutten FH, Cramer MJ, Grobbee DE, Sachs AP, Kirkels JH, Lammers JW, et al. Unrec-
ognized heart failure in elderly patients with stable chronic obstructive pulmonary dis
ease. Eur Heart J 2005;26(18):1887-94.
46 Chin APM, van Poppel MN, van MW. Effects of resistance and functional-skills training
on habitual activity and constipation among older adults living in long-term care facilities:
a randomized controlled trial. BMC Geriatr 2006;6:9.
47 Weening-Dijksterhuis E, de Greef MH, Scherder EJ, Slaets JP, van der Schans CP.
Frail institutionalized older persons: A comprehensive review on physical exercise, physi
39
cal fitness, activities of daily living, and quality-of-life. Am J Phys Med Rehabil
2011;90(2):156-68.
48 Grebe C, Brandenburg H. [Resident assessment instrument. Application options and
relevance for Germany]. Z Gerontol Geriatr 2015;48(2):105-13.
40
41
Chapter 2.1
PREVALENCE AND MISDIAGNOSIS OF CHRONIC HEART FAILURE
IN NURSING HOME RESIDENTS: THE ROLE OF B-TYPE NATRI-
URETIC PEPTIDES. Barents M, van der Horst IC, Voors AA, Hillege JL, Muskiet FA, de Jongste MJ.
Neth Heart J. 2008;16(4):123-8.
42
ABSTRACT BACKGROUND/OBJECTIVES. Without knowing the exact CHF prevalence, chronic heart failure
(CHF) occurs frequently in elderly people both inside and outside nursing homes (NH). For a
diagnosis we have to rely on physical examination and additional tests. We therefore run risks
of missing CHF diagnoses or of diagnosing CHF when we should not. Natriuretic peptides as-
says have emerged as a diagnostic test but their use in NH residents is limited. We examined
the number of misdiagnoses, the CHF prevalence and the role of natriuretic peptide. METHOD. Residents in one centre without aphasia, cognitive impairments or metastatic cancer
were screened on CHF. The natriuretic peptide levels were measured separately. RESULTS. Of the 150 residents, 103 (64%) were included (79 ± 11 years). The diagnosis of
CHF was established in 24 of these 103 residents with NT-proBNP 1871 (interquartile range
(IQR) 539-4262) and of BNP 194 (IQR 92-460) pg/mL. A striking result was that of the 24
residents found to have CHF after the screening, 15 (66%) had previously been undetected:
NT-proBNP 1146 (IQR 228-3341) and BNP 200 (IQR 107-433) pg/mL). Moreover, in 13 out
of 22 (62%) residents who had previously been thought to have CHF, the diagnosis was re-
jected: NT-proBNP 388 (IQR 174-719) and BNP 90 (IQR 35-128) pg/mL respectively. Re-
garding the diagnostic accuracy of NT-proBNP and BNP, the optimal cut-off level of NT-
proBNP was 450 pg/mL with a sensitivity 0.71 and a specificity 0.67, and of BNP was 100
pg/mL with a sensitivity 0.71 and a specificity 0.70. CONCLUSION. Both undetected and incorrect CHF diagnoses were largely observed. NT-
proBNP and BNP were moderately accurate at CHF diagnosis. The CHF prevalence was 23%.
43
INTRODUCTION Nursing home (NH) residents are characterized by high age and co-morbidity. Chronic heart failure
(CHF) occurs frequently, but is a relatively neglected diagnosis (1). The main reasons why CHF is less
frequently detected are non-specific complaints, co-morbidity and limited access to echocardiography
(2;3;4). On the other hand, some residents may be diagnosed with CHF, while their symptoms may be
caused by other disorders. Both undetected diagnosis and incorrect diagnosis will lead to inadequate
treatment of the underlying disease, and will impair the quality of life.
Natriuretic peptides are increasingly used to aid the diagnosis of CHF. Its diagnostic value is particularly
strong in dyspnoeic patients admitted to the emergency department but less strong in general practices
(5). NH residents are mostly of high age and have multiple chronic diseases, such as renal dysfunction
and diabetes. The role of natriuretic peptides for the diagnosis of CHF in this specific population may be
limited, but so far it has not extensively been studied. In the present study we therefore aim to look at
the prevalence of CHF, both undetected and incorrect diagnoses of CHF, and the diagnostic accuracy of
NT-proBNP and BNP in NH residents.
METHODS During the course of this study there were 150 persons in the departments for residents with diseases of
somatic origin in NH “het Zonnehuis”. Their impairments are based on cardiovascular, pulmonary, neu-
rodegenerative, skeletal muscle and other disorders. Most of them were receiving long-term care (long-
stay). Some residents with musculoskeletal or cerebrovascular disorders were rehabilitated , one-third of
whom could be discharged (short-stay) but should remain care dependent in primary care. Both long-
stay and short-stay groups were invited to take part between 25 September 2004 and 24 May 2005.
Both groups of residents were included if they understood the impact of the study on themselves (com-
petent) and if they agreed to participate by written informed consent. Residents with aphasia or a cogni-
tive impairments, measured by the mini-mental state estimation (MMSE) test, were excluded. The
MMSE test contains 30 questions and a MMSE ≤ 20 is suspect for cognitive impairments (6). Persons
with metastatic cancer who stayed in a department specialized in palliative terminal care were excluded.
Persons were also excluded if the echocardiographic frames could not be sufficiently visualized or if they
44
refused to have their blood sample taken. CHF was defined according to the definition of the Chronic
Heart Failure Guidelines of the European Society of Cardiology (7). Two experienced heart failure cardi-
ologists independently decided on the diagnosis of CHF, based on medical history, physical examination,
ECG, routine blood tests and echocardiography. In case of disagreement a third cardiologist reviewed
the case and made the final diagnosis. At this stage none of the cardiologist knew the levels of BNP or
NT-proBNP. The study was approved of by the Medical Ethical Committee in Groningen, University
Medical Center, The Netherlands.
MATERIALS
In this cross-sectional study, all data were collected anonymously and within one week (ques-
tionnaire, neurohormone sampling, ECG, echocardiography).
One physician collected the data of the patients’ medical history (CHF with NYHA classification,
coronary artery diseases (CAD), hypertension, peripheral vascular disorders, diabetes mellitus
and other comorbidity), of their symptoms (fatigue and dyspnea at great or light effort and in
rest, when laying down and at night, breast pain, palpitation), and of their medication. He also
examined blood pressure, central jugular pressure (CJP), the heart (third heart sound, gallop
rhythm, cardiomegaly by percussion), the lungs (rales), the liver (liver-percussion), length and
weight and looked at periphery oedema (8). A 12 leads electrocardiogram (ECG) was made
with the electrocardiograph Cardioline delta three plus (Cardioline, Milan, Italy, www.cardioline.it) with the patient in a horizontal position. One blood sample per resident (12
mL) was taken if one was in fasting condition and at rest. Assessments of creatinine, haemo-
globin and mean corpuscular volume (MCV) were performed in the NH laboratory. Since the
coefficient of variation of neurohormones is reported to be about 100% we chose not to repeat
the neurohormone sampling (9). For determination of levels of (NT-pro)BNP, a 5 µl aprotinine
solution was adjusted to the 250 µl plasma samples in EDTA and to 250 µl serum samples. At
the UMCG Clinical Chemical Laboratory (CCL) both were frozen at -20˚C and stored in batches
45
for a maximum of 10 months. The assays were run in one go for both NT-proBNP and BNP.
Both NT-proBNP and BNP were measured by immunoassays (Elecsys®1010/2010/modular
analytics 2004 Roche diagnostics Indianapolis IN US, and AXSYM system® BNP 2003 Axis–
shield diagnostics LTD ABBOT Wiesbaden Germany). NT-proBNP and BNP had coefficients of
variation of 3.3% and 7.8% respectively, and measuring ranges of 5-35000 pg/mL and 0-
3465 pg/mL. The renal function has been defined as glomerular filtration rate (GFR) measured
by the Cockcroft and Goult formula in mL/min.
On the UMCG department of Cardiology, echocardiography was performed by four experienced
echocardiographists using a hand held cardiograph ‘Opti Go’ (Philips, Eindhoven, The Nether-
lands, www.philips.com). The left-ventricular ejection fraction was assessed semi-quantitatively
by the two-dimensional visual estimate method (10). A LVEF ≤ 45% was considered to be a
left ventricular systolic dysfunction (LVSD). If the echocardiogram was of insufficient quality, the
subject was transported to the UMCG hospital where an echocardiogram was produced with the
General Electric Vingmed Ultrasound five (www.gemedicalsystems.com, Zoetermeer, The Neth-
erlands).
Statistics Statistical analyses were performed using SPSS 12.0.1 software (SPSS Inc., 233 S. Wacker,
11th Floor, Chicago IL US). Differences of base characteristics of residents with and without CHF
were submitted at Student t tests, of gender at Chi-square test and the Mann Whitney test for
non-parametric continuous data, as appropriate. ROC curves were made of NT-proBNP and
BNP levels. The Area Under the Curve (AUC) presents the test accuracy and the significance
of the difference of both AUCs was estimated by a Chi-square test. Influences of age, gender,
renin-angiotensin system blocker (ACE-inhibitor or angiotensin receptor blocker) and renal
dysfunction on (NT-pro)BNP cut-off points were determined by Mann Whitney tests. All statisti-
cal comparisons were two-tailed, and a P-value <0.05 was considered to be statistically sig-
nificant.
46
RESULTS
A total of 150 individuals was screened. Fourteen residents refused to participate, 30 were ex-
cluded because of cognitive impairment and aphasia. Three persons were excluded because of
incomplete data (two poor quality echocardiograms and one refusing the blood sample). The
remaining 103 residents were included. The mean age of the population was 78 ± 11 years.
Twenty two persons had CHF before the study. Twenty four persons had CHF after the study
and we found 3 groups: subjects diagnosed with CHF before the study whose diagnosis was
confirmed afterwards (CHF confirmed), subjects diagnosed with CHF before the study whose
diagnosis was rejected afterwards (CHF rejected) and subjects not diagnosed with CHF before
the study but diagnosed with CHF after the study (CHF de novo). Of the 24 CHF, nine had CHF confirmed and 15 had CHF de novo. Thirteen subjects had CHF rejected (Table 1).
The CHF prevalence was 23% (24/103).
Residents with CHF more often had CAD, used a renin-angiotensin system blocker, complained
of fatigue, had a raised CJP, had a cardiac thoracic ratio of more than a half, had a third heart
tone and or gallop rhythm, had pulmonary rales, had left ventricle hypertrophy, suffered more from renal dysfunction and from left ventricular dysfunction (see Table 2).
Residents with CHF after compared to those without CHF had NT-proBNP medians of 1871 and
239 pg/mL (P<0.001) respectively and BNP medians of 194 and 68 pg/mL (P<0.001).
Residents with CHF before compared to those without CHF had NT-proBNP medians of 552
and 241 pg/mL.(P=0.013) and BNP medians of 92 and 76 pg/mL respectively (P=0.270) (see Table 3).
The predictive values of the two neurohormones presented by the AUC of NT-proBNP (0.815)
and of BNP (0.758) did not differ significantly (P= 0.234) as is shown in Figure 1. Table 4
presents the sensitivity, specificity, positive and negative predictive values at several cut-offs
points of NT-proBNP and BNP. In search of threshold values with the best combination of ex-
cluding and including CHF, threshold values of NT-proBNP at 450 pg/mL (sensitivity 0.71,
specificity 0.67, positive and negative predictive values of 0.42 and 0.91) and of BNP at 100
47
pg/mL (sensitivity 0.71, specificity 0.70, positive and negative predictive values of 0.63 and
0.89 respectively) were found. Both BNP and NT-proBNP were influenced by renal function
and estimated in subjects with GFR > 75 mL/min and <75 mL/min: NT-proBNP means and
SDs were 619 ± 1240 compared to 2010 ± 4191 pg/mL (P =0.005). BNP means and SDs
were 110 ± 171 compared to 251 ± 457 pg/mL (P =0.004). BNP and NT-proBNP were influ-
enced significantly by age and renal dysfunction (age and BNP Z=-2,220, P=0.026; renal dys-
function and BNP Z=-2,001, P=0.045; age and NT-proBNP Z=-4,196, P=0.000; renal dys-
function and NT-proBNP Z=-3,663, P=0.000). NT-proBNP and BNP cut-off points were not
significantly influenced by gender nor by use of renin angiotensin blockers.
DISCUSSION
In this NH study, CHF was present in almost one quarter of the residents. We found that the
majority of these residents had previously not been diagnosed with CHF. In addition, there were
several residents, who had been diagnosed with CHF before the study, whose diagnosis had
to be rejected after careful examination. Blinded values of both BNP and NT-proBNP differed
significantly between residents who were diagnosed with CHF and those whose previous CHF
diagnosis was rejected. In initial screening, NT-proBNP and to a lesser extent BNP, were mod-
erately accurate in predicting the presence of CHF.
A prevalence of 23% in this NH cohort is roughly twice as much compared with the prevalence
of CHF in the general population but concomitant with another NH population and with a popu-
lation of 70 years and over (11-13).
Both undetected diagnoses and incorrect diagnoses of CHF were expected, but they exceeded
our expectations to a large extent. Reasons for an incorrect diagnosis of CHF were a history of
atrial fibrillation (5 cases) and the coexistence of COPD (3 cases). COPD as a reason for mis-
diagnosis has earlier been described by Rutten (14). In addition, the majority of individuals with
rejected CHF had NYHA class I and II (12/13) and one had class III. Eleven out of 15 CHF de
48
novo may have been overlooked because of mild complaints (7 NYHA class I and 4 class II).
All 4 other subjects with CHF de novo with NYHA class III and IV were missed because multiple
co-morbidity confused their symptoms of cardio-vascular origin. Thus, both incorrect CHF diag-
noses and undetected CHF diagnoses seemed to have been caused by the existence of co-
morbidity. The unspecific clinical presentation of elderly people and the aspecificity of the diag-
nostic tools add to the number of misdiagnoses.
Moreover, this study shows that thorough physical examination in combination with echocardi-
ography can improve the accuracy of the CHF diagnostics. In addition, natriuretic peptides can
improve the CHF diagnostics if added to the usual diagnostic procedure even without cardiac
ultrasounds.
Failures of the expert panel are possible but unlikely, since standard diagnostic tests were per-
formed, and the panel existed of specialized heart failure cardiologists. In addition, NT-proBNP
and BNP levels supported both undetected diagnoses and incorrect CHF diagnoses.
Both NT-proBNP and BNP were moderately accurate in predicting CHF. However, depending
on the cut-offs, the CHF diagnosis will still be missed in a substantial number of residents.
Moreover, one should realize that (NT-pro) BNP levels will increase not only with CHF but also
in conditions like high age and renal dysfunction. So the use of natriuretic peptides alone will
not be sufficient for an adequate diagnosis, although the results have been significantly im-
proved when compared to the baseline situation, especially for physicians not specialized in
cardiology (15). If natriuretic peptides are used as an initial test, we suggest NT-proBNP and
BNP cut-offs of 450 and 50 pg/mL respectively for excluding CHF, and 900 and 200 pg/mL
for establishing CHF. When values are within the cut-off values, a regular assessment should
be performed. The NT-proBNP cut-off of 450 pg/mL is suggested as an age specific cut-point.
The BNP cut-off of 50 pg/mL is lower than in other studies where 100 pg/mL is proposed.
NT-proBNP and BNP were influenced by age and renal dysfunction in accordance with other
studies (16-19). In contrast with other studies, they were not influenced by gender nor by the
use of renin angiotensin system blockers (20-22).
49
A limitation of the study is the small population of 103 NH-residents in one centre, which could
lead to a selection bias in arriving at the prevalence of CHF being 23%. On the other hand, our
prevalence of chronic heart failure is concomitant with the prevalence in other NH residents and
in the elderly (12;23;24). Moreover, the population studied is representative of other NH popu-
lations, in terms of distribution of gender, age, diabetes and the use of ACE-inhibitor therapy,
although not representative in terms of the presence of hypertension and renal dysfunction
(24;25). Furthermore, despite good criteria, setting the diagnosis of CHF remains difficult be-
cause of the lack of diagnostic accuracy of physical examination and the lack of easy access to
echocardiography.
CONCLUSION
At present the overall accuracy of the diagnosis CHF is limited. In this study both undetected
and incorrect CHF diagnoses were observed in a large number of residents. Moreover, the
study shows that a more thorough investigation of residents on CHF will lead to more accurate
diagnostics, which in turn will improve residents’ quality of life. The use of NT-proBNP and BNP
as additional diagnostic instruments is promising also in nursing home residents but needs fur-
ther evaluation. The CHF prevalence in care-dependent elderly people was almost 25%, which
is twice as much as in old people living independently. The use of NT-proBNP and BNP as
additional diagnostic instruments is promising also in NH residents but needs further evaluation.
ACKNOWLEDGMENTS
This study was subsidised by the “Vereniging het Zonnehuis”, Soesterberg, The Netherlands. Financial disclosure: the authors have nothing to disclose. Author contribution: Dr. Voors was
responsible for the echocardiography, Dr. Muskiet was responsible for the biochemistry, Dr. Hil-
lege was responsible for the statistics, Dr. de Jongste was responsible for the design and Drs.
50
Barents was principal investigator and responsible for the manuscript. (Dr. Voors, Dr. van der Horst and
Dr. de Jongste were also independent panel members and responsible for the proofreading).
51
References
1 Cleland JG, Swedberg K, Follath F, Komajda M, Cohen-Solal A, Aguilar JC, Dietz R,
Gavazzi A, Hobbs R, Korewicki J, Madeira HC, Moiseyev VS, Preda I, van Gilst WH,
Widimsky J, Freemantle N, Eastaugh J, Mason J. The Euro Heart Failure survey pro -
gramme - a survey on the quality of care among patients with heart failure in Europe.
Part 1: patient characteristics and diagnosis. Eur Heart J 2003 March;24(5):442-463.
2 Luchi RJ, Taffet GE, Teasdale TA. Congestive heart failure in the elderly. J Am Geriatr
Soc 1991 August;39(8):810-825.
3 Januzzi JL, Jr., Camargo CA, Anwaruddin S, Baggish AL, Chen AA, Krauser DG, Tung
R, Cameron R, Nagurney JT, Chae CU, Lloyd-Jones DM, Brown DF, Foran-Melanson S,
Sluss PM, Lee-Lewandrowski E, Lewandrowski KB. The N-terminal Pro-BNP investiga-
tion of dyspnea in the emergency department (PRIDE) study. Am J Cardiol 2005 April
15;95(8):948-954.
4 Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of
a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung
disease in patients presenting with dyspnea. J Am Coll Cardiol 2002 January
16;39(2):202-209.
5 Smith H, Pickering RM, Struthers A, Simpson I, Mant D. Biochemical diagnosis of ven-
tricular dysfunction in elderly patients in general practice: observational study. BMJ
2000 April 1;320(7239):906-908.
6 Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive re -
view. J Am Geriatr Soc 1992 September;40(9):922-935.
52
7 Krum H. The Task Force for the diagnosis and treatment of chronic heart failure of the
European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic
heart failure: full text (update 2005). Eur Heart J 2005 November;26(22):2472-
2474.
8 Shamsham F, Mitchell J. Essentials of the diagnosis of heart failure. Am Fam Physician
2000 March 1;61(5):1319-1328.
9 Bruins S, Fokkema MR, Romer JW, Dejongste MJ, van der Dijs FP, van den Ouweland
JM, Muskiet FA. High intraindividual variation of B-type natriuretic peptide (BNP) and
amino-terminal proBNP in patients with stable chronic heart failure. Clin Chem 2004
November;50(11):2052-2058.
10 Quinones MA, Waggoner AD, Reduto LA, Nelson JG, Young JB, Winters WL, Jr.,
Ribeiro LG, Miller RR. A new, simplified and accurate method for determining ejection
fraction with two-dimensional echocardiography. Circulation 1981 October;64(4):744-
753.
11 Mosterd A, Hoes AW, de Bruyne MC, Deckers JW, Linker DT, Hofman A, Grobbee DE.
Prevalence of heart failure and left ventricular dysfunction in the general population; The
Rotterdam Study. Eur Heart J 1999 March;20(6):447-455.
12 Heckman GA, Misiaszek B, Merali F, Turpie ID, Patterson CJ, Flett N, McKelvie RS.
Management of heart failure in Canadian long-term care facilities. Can J Cardiol 2004
August;20(10):963-969.
53
13 Mair J. Monitoring of patients with heart failure. Scand J Clin Lab Invest Suppl
2005;240:99-106.
14 Rutten FH, Cramer MJ, Grobbee DE, Sachs AP, Kirkels JH, Lammers JW, Hoes AW.
Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary
disease. Eur Heart J 2005 September;26(18):1887-1894.
15 Cowie MR, Jourdain P, Maisel A, Dahlstrom U, Follath F, Isnard R, Luchner A,
McDonagh T, Mair J, Nieminen M, Francis G. Clinical applications of B-type natriuretic
peptide (BNP) testing. Eur Heart J 2003 October;24(19):1710-1718.
16 Bando M, Ishii Y, Sugiyama Y, Kitamura S. Elevated plasma brain natriuretic peptide
levels in chronic respiratory failure with cor pulmonale. Respir Med 1999
July;93(7):507-514.
17 Buckley MG, Sethi D, Markandu ND, Sagnella GA, Singer DR, MacGregor GA. Plasma
concentrations and comparisons of brain natriuretic peptide and atrial natriuretic peptide
in normal sub jects, cardiac transplant recipients and patients with dialysis-independent
or dialysis-dependent chronic renal failure. Clin Sci (Lond) 1992 October;83(4):437-
444.
18 Sayama H, Nakamura Y, Saito N, Kinoshita M. Why is the concentration of plasma brain
natriuretic peptide in elderly inpatients greater than normal? Coron Artery Dis 1999 Octo
ber;10(7): 537-540.
19 Wallen T, Landahl S, Hedner T, Saito Y, Masuda I, Nakao K. Brain natriuretic peptide in
an elderly population. J Intern Med 1997 October;242(4):307-311.
54
20 Kohno M, Yokokawa K, Yasunari K, Kano H, Minami M, Hanehira T, Yoshikawa J.
Changes in plasma cardiac natriuretic peptides concentrations during 1 year treatment
with angiotensin-con verting enzyme inhibitor in elderly hypertensive patients with left
ventricular hypertrophy. Int J Clin Pharmacol Ther 1997 January;35(1):38-42.
21 Missouris CG, Grouzmann E, Buckley MG, Barron J, MacGregor GA, Singer DR. How
does treatment influence endocrine mechanisms in acute severe heart failure? Effects on
cardiac natriuretic peptides, the renin system, neuropeptide Y and catecholamines. Clin
Sci (Lond) 1998 June;94(6):591-599.
22 Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC, Jr.
Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll
Cardiol 2002 September 4;40(5):976-982.
23 Mair J, Friedl W, Thomas S, Puschendorf B. Natriuretic peptides in assessment of left-
ventricular dysfunction. Scand J Clin Lab Invest Suppl 1999;230:132-142.
24 Gambassi G, Lapane K, Sgadari A, Landi F, Carbonin P, Hume A, Lipsitz L, Mor V,
Bernabei R. Prevalence, clinical correlates, and treatment of hypertension in elderly
nursing home residents. SAGE (Systematic Assessment of Geriatric Drug Use
via Epidemiology) Study Group. Arch Intern Med 1998 November
23;158(21):2377-2385.
25 Kohno M, Yokokawa K, Yasunari K, Kano H, Minami M, Hanehira T, Yoshikawa J.
Changes in plasma cardiac natriuretic peptides concentrations during 1 year treatment
with angiotensin-con verting enzyme inhibitor in elderly hypertensive patients with left
ventricular hypertrophy. Int J Clin Pharmacol Ther 1997 January;35(1):38-42.
55
Table 1. Three chronic heart failure groups found after the study.
n nyha NT-proBNP BNP I II III IV CHF confirmed 9 1 5 3 0 2632 (1044-5737) 118 (59-706) CHF rejected 13 7 5 1 0 388 (174-719) 90 (35-128) CHF de novo 15 7 4 1 3 1146 (228-3341) 200 (107-433) Chronic heart failure, CHF; CHF diagnosed before the study and confirmed afterwards, CHF
confirmed; CHF diagnosed before the study and rejected afterwards, CHF rejected; CHF unde-
tected before the study and diagnosed afterwards, CHF de novo; number, n; New York Heart
Association, nyha; N-terminal-pro B-type natriuretic peptide, NT-proBNP; B-type natriuretic
peptide, BNP; median and interquartile range of pg/mL.
56
Table 2. Baseline characteristics of nursing home residents.
Total CHF+ (%) CHF- (%) P age male (%) immobility wheelchair/bed (%) medical history Hypertension (%) CAD (%) rhythm disorder (%) Diabetes type 2 (%) PAD (%) Medication ACE and ARB (%) Beta blockers (%) Ca-antagonists (%) Anti-coagulants (%) Diuretics (%) Anti-diabetics (%) Major symptoms Fatigue (%) Dyspnea Physical examination vCJP Cardiomegaly Murmur 3th tone, gallop Rales Hepatomegaly edema
78±11 39 (38)
40 (39)
57 (55) 28 (27) 24 (23) 26 (25) 16 (16)
42 (41) 24 (23) 10 (10) 63 (61) 50 (49) 21 (20)
40 (39) 31 (30)
11 (11) 22 (21) 24 (23) 20 (19) 17 (17) 4 (4)
40 (39)
80±9 11 (46)
13 (54)
13 (54) 14 (58) 9 (38) 9 (38) 66 (25)
14 (58) 7 (29) 4 (17) 19 (78) 15 (62) 8 (33)
15 (52) 11 (45)
7 (29) 10 (42) 9 (38) 10 (20) 9 (40) 1 (4)
15 (60)
78±11 28 (35)
27 (34)
44 (49) 14 (18) 15 (19) 17 (22) 10 (13)
28 (35) 17 (22) 6 (8)
44 (53) 35 (44) 13 (16)
25 (32) 20 (25)
4 (5)
12 (15) 25 (32) 10 (13) 8 (8) 3 (3)
35 (44)
0.351 0.358
0.078
0.680 <0.001 0.060 0.114 0.144
0.046 0.438 0.189 0.055 0.118 0.072
0.007 0.055
<.001 0.006 0.587 0.587 <0.001 0.935 0.116
57
systolic blood pressure diastolic blood pressure body mass index Electrocardiogram atrial fibrillation ischemia LVH Laboratory Hemoglobin (SD) eGFR (SD) NT-proBNP md IQR BNP md IQR echocardiogram mn SD
141±22 81±13 25± 5
10 (10) 5 (5)
32(31)
7.7±1 76±32
324 (163-1146) 87 (28-187)
51±9
143 (27) 79 (13) 25 (5)
3 (13) 2 (8)
16(67)
7.7±1 63±26
1871(539-4262) 194 (92-460)
43±9
140 (20) 81 (13) 25 (5)
7 (8) 3 (28) 16(20)
7.7±1 80±32
239 (118-674) 68 (20-123)
54±6
0.534 0.590 0.897
0.598 0.365 <0.001
0.834 0.022 <0.001 <0.001 0.016
Coronary artery diseases, CAD; peripheral artery disease, PAD; angiotensin converting enzyme inhibitor, ACE-inhibitor and alfa 2-receptor blocker, ARB; anti-coagulants and anti-platelets, anti-coagulants; ve-nous central jugular pressure, vCJP; left ventricular hypertrophy, LVH; estimated glomerular filtration rate, eGFR; N-terminal-pro B-type natriuretic peptide, NT-proBNP; B–type natriuretic peptide, BNP; md, median IQR, interquartile range; SD, standard deviation.
58
Table 3. Median NT-proBNP and BNP concentrations in residents with and without
chronic heart failure (CHF + and CHF -), before and after the study.
NT-proBNP CHF + CHF - P-value
median (IQR) (n) median (IQR) (n)
before study
after study
552 (309-2477) (22)
1871(539-4262) (24)
241 (128-892) (81)
239 (118-674) (79)
0.013
<0.001
BNP median (IQR) (n) median (IQR) (n)
before study 92 (33-187) (22) 76 (23-187) (81) 0.270
after study 194 (92-460) (24) 68 (20-123) (79) <0.001
Interquartile range, IQR; number of subjects, n; natriuretic peptides in pg/mL; Before the study, medians of NT-proBNP in residents with and without CHF (CHF+ and CHF -) differed
(P=0.013) and medians of BNP in CHF+ and CHF- did not differ (P=0.270). After the study,
medians of both NT-proBNP and BNP differed convincingly (NT-proBNP in CHF+ 1871 and in
CHF – 239, P<0.001, BNP in CHF+ 194 and in CHF – 68 pg/mL, P<0.001).
59
Table 4. N-terminal-pro B-type natriuretic peptide (NT-proBNP) and B-type natriuretic
peptide (BNP) cut-off values with positive and negative predictive values.
Cut-off pg/mL Sensitivity Specificity PPV NPV
NT-proBNP 450 0.71 0.67 0.42 0.91
NT-proBNP 900 0.67 0.85 0.56 0.89
NT-proBNP 1350 0.58 0.86 0.56 0.86
NT-proBNP 1800 0.46 0.94 0.69 0.85
Cut-off pg/mL Sensitivity Specificity PPV NPV
BNP 50 0.88 0.63 0.42 0.89
BNP 100 0.71 0.70 0.63 0.89
BNP 150 0.54 0.79 0.69 0.82
BNP 200 0.50 0.87 1.00 0.80
PPV , positive predictive value; NPV, negative predictive value.
60
61
Chapter 2.2
UNDERESTIMATED PREVALENCE OF CHRONIC HEART FAILURE
AMONG RESIDENTS OF CARE-HOMES IN ARUBA. Stoutjesdijk E, Brouns RM, Barents M, DeJongste MJ, Besselink HJ, Cheng JD,
Wever R, Muskiet FA.
West Indian Med J. 2014 Nov 4;63(6). doi: 10.7727/wimj.2013.277.
62
ABSTRACT
OBJECTIVES. We aimed to study the frequency and accuracy of chronic heart failure diagno-
ses in a group of stable Aruban residential elderly with low physical activity. METHODS. A total of 235 residents were assessed in a cross-sectional designed pilot study.
Residents with dementia, aphasia, a history of psychiatry or terminal illness were excluded.
Physical examination and electrocardiograms were performed in conjunction with blood samples
to determine a./o. B-type natriuretic peptides (BNP) and renal function. A general practitioner
and a cardiologist established or withdraw the diagnosis CHF. RESULTS. Out of, 235 residents, 184 were excluded. Fifty-one (22%) subjects, 78±8 years of
age, were included in the study. CHF was established in 16 [BNP 156 (72-1029) ng/L] out of
the 51 residents. Eleven residents were not previously diagnosed with CHF [BNP 152 (61-
1029) ng/L]. Of two out of the seven residents diagnosed with CHF before the screening, the
diagnosis CHF was rejected [BNP 71 (59-83) ng/L].
CONCLUSION. In Aruban residential elderly, identification of chronic heart failure is severely
underestimated. The detection of CHF was improved by implementing an appropriate guideline
and by including the determination of BNP.
63
INTRODUCTION
During the last one-and-half-century, in the industrialized society the average age of dying has
doubled. This observation is mainly resulting from introduction of hygienic measures (sewers,
water supply, food, life style) and improved treatments such as for ischemic heart diseases. The
drawback of increased survival from cardiac diseases is a subsequent growth in sequelae, such
as heart failure. In addition, the onset of cardiovascular diseases is adversely affected by the
development of an unhealthy lifestyle, as is the case in more prosperous societies. As a result
of an insalubrious life style, the prevalence is raising of acquired afflictions like hypertension,
diabetes, obesity and hypercholesterolemia more often. In this regard it is worth notifying that
Mexican Americans, to which Arubans belong develop atherosclerosis much more frequently
most likely because of an imbalance between intake and leisure-time physical activities (1;2).
Hence, in Arubans cardiovascular morbidity has become a substantial part of the multimorbidity
in the elderly. Multimorbidity is related to care dependency and more help in activities of daily
living (3). Accordingly, the most care dependent elderly live in a nursing home, here referred to
as residential elderly. It is unknown however likely that a substantial part of Aruban residential
elderly suffer from CHF. In Canada and The Netherlands CHF prevails in one to two% of all
adults, ten% in a community dwelling elderly and 20% in residential elderly (4-6). The life-time
risk to develop CHF is estimated to be 20%. The prognosis of CHF greatly depends on the se-
verity of symptoms (7). For instance, persons with CHF of NYHA class III-IV have an one-year
mortality of 60%, those with NYHA class I-II have 20% and half of the latter is deceased within
five years (8-10).
Heart failure is a syndrome defined as the presence of at least one symptom and a heart disor-
der. Key symptoms are dyspnea and fatigue, both at rest and during exertion. Heart failure may
be caused by hypertension, atherosclerotic heart diseases, valve and rhythm disorders and a
variety of cardiomyopathies. When CHF is accompanied by pressure or volume overload, na-
triuretic peptides, as B-type Natriuretic Peptide (BNP) secretion by the ventricle wall is one of
the regulating mechanisms. BNP stimulates natriuresis, diuresis, vasodilatation and inhibition of
64
the renin-angiotensin-aldosterone system - and sympathetic nervous system. BNP is cleared by
binding to natriuretic peptide receptors and the half-life time of this binding is 20 minutes. The-
se characteristics make BNP appropriate as marker of CHF. However, many factors increase
the secretion of BNP as well (11;12).
In residential elderly, it is even more difficult to identify subjects with CHF since there are no
CHF guidelines for residential elderly (4;13;14). Moreover, BNP is not validated for elderly ≥ 75
years or for elderly with multimorbidity (15). Finally, access to echocardiography is limited. All
these confounders have attributed to regular misjudgment of CHF in Dutch community-dwelling
and residential elderly (4;13). In Aruba, it can be predicted that in a population of residential
elderly, with a presumably higher incidence of not recognized CHF, comparable difficulties are
met. Therefore, we aim to investigate the diagnostic accuracy and role of BNP in diagnosing
CHF in Aruban residential elderly with low physical activity.
METHOD
Design: this study was designed as multi-centre cross-sectional pilot study.
Persons: from February till August 2009, 235 residents live in the “Stichting Algemeen
Bejaardenzorg Aruba” located in San Nicolas, Savaneta and Oranjestad. Half the residents were
immobile for the most part because they had an amputation. Some were admitted because of
lacking family care. All residents were invited to participate in the study. They were included if
they signed the informed consent. They were excluded in case of cognitive impairments as de-
mentia (Korsakov’s syndrome), incompetency (one does not understand the impact of the study
on himself), aphasia, serious psychiatric and neurological disorders and terminal illness.
From the included residents, one of the investigators collected data on medical history and
medication. One general practitioner examined the residents on CHF symptoms. He also meas-
ured blood pressure and heart rate. He examined the central jugular pressure, cardiac size
(percussion) and heart rhythm. He also looked for the presence of murmurs, deviate breath
65
sounds and peripheral edema. A 12-leads electrocardiogram was made at rest (Burdick Eclipse
LE (www.Burdick.com)). The general practitioner and cardiologist decided on the diagnosis
CHF, independently. The general practitioner suggested the diagnosis CHF based on medical
history, physical examination, electrocardiogram and blood tests except BNP. The cardiologist
came to the diagnosis CHF based on the same data as the general practitioner but now with
BNP included. They discussed all cases and in case of disagreement, the cardiologist prevailed.
All data were retrieved anonymously from the resident files.
According to CHF guidelines (16;17), BNP is determined when CHF is suspected. When BNP is
lower than 100ng/L and the electrocardiogram is not deviating, CHF can be excluded in most
cases leaving a small risk of still having CHF of less than 10% (5;18).
Laboratory assistants took non-fasting blood samples in tubes prepared with lithium heparin and
EDTA. They stored all samples in a cooler and analyzed them within four hours only in the La-
boratory. Sodium, potassium, urea, kreatinin, thyroid-stimulating hormone, BNP, hemoglobin,
haematocrit and mean corpuscular volume were determined.
BNP was determined with the Triage BNP assay (www.biosite.com) at a Beckman Coulter
Unicel DxC600i Immunoassay System (www.beckmancoulter.com). BNP had coefficients of
variation of <7% with a range of 5 to 4970ng/L. Kreatinin was measured by a standardized
isotope dilution mass spectrometry. Renal function was defined by the estimated glomerular-
filtration rate (eGFR) measured by the Modification of Diet in Renal Disease formula
(mL/min/1.73 m2) = 175 * (Sc/88.4)-1.154 * (age)-0.203 * 0,742 if female *1.212 if negroïd.
Serious renal dysfunction was defined as eGFR less than 30 mL/min/1.73m2 (19;20).
We requested the laboratory to deliver us the percentage of BNP tests ordered by general prac-
titioners during the study period.
Statistical analyses were performed using PASW Statistics 17 software. We compared the char-
acteristics of residents with and without CHF with the Student’s t-test and Mann-Whitney test for nonparametric continuous data, as appropriate (Table 2). The x2- test was used in parametric
and the Mann-Whitney test in nonparametric binominal variables. The predictive values of the
66
BNP test was calculated at different cut-off points from 50 – 200 ng/L as described in Table
3. Influences of age, gender, angiotensin-converting enzyme inhibitor (ACE-i) and eGFR on
BNP were examined with linear regression analyses with a log transformation. All statistical
comparisons were two-tailed, and a p value less than 0.05 was considered to be statistically
significant.
RESULTS
Out of all 235 residents, 184 (78%) were excluded for a variety of reasons such as dementia in
half of them. Out of 184 residents, 165 were not eligible according the exclusion criteria. And,
19/184 dropped out because of refusal to participate (eight), cognitive impairments (five), ad-
mission to a hospital beforehand (four), incomplete data (one), and for not living in a nursing
home (one). The remaining 51 (22%) were included and screened.
The included residents were aged 78 (range 56-93) years and 29 were females with 22
males. The majority (55%) of the individuals was immobilized and bound to wheelchair or bed
(55%), as a consequence of various disorders, such as cerebrovascular accidents (31%), CHF
(31%) and serious sequelae of T2DM (59%), like amputation of a leg. The estimated GFR was
46±22 mL/min.
Chronic heart failure was diagnosed in sixteen residents (16/51, 31%). We distinguished four
groups: seven residents were judged to have CHF before the screening (CHF before study). In
two of these seven, the CHF diagnoses were not confirmed (CHF rejected). In five of these
seven, the CHF diagnoses were confirmed (CHF confirmed). In addition, eleven CHF diagno-
ses were first established after the screening while they were undetected before (CHF de novo) (Figure 1 and Table 2) The cardiologist overruled the general practitioner in 4 out of 16 resi-
dents in which there was disagreement with regard to CHF (BNP 134, 392, 440, 459ng/mL).
67
Comparing the 16 residents with CHF to those without, the first group used more anticoagulants
and suffered more from dyspnea, fatigue and edema. In addition, the CHF group had higher
BNP levels and a lower renal function, on average.
Regarding the ECG observations, residents with CHF had more LVH and atrial fibrillation com-
pared to those without CHF. And, within the other ECG disorders, residents with and without
CHF contained two and four atrial-ventricular conduction disorders, zero and two rhythm disor-
der and seven and six implanted artificial cardiac pacemaker, respectively and none significant-
ly. One resident with CHF had LVH and an atrial-ventricular conduction disorders.
The predictive values of BNP, calculated at different cut-off points from 50 to 200ng/L with
each 25 ng/L difference in between, were presented in Table 3.
Of the included confounders, we found renal function inversely related to BNP (β= -0.49,
p=0.002) while age, gender and ACE-i did not influence BNP levels, significantly (p=0.452,
p=0.314, p=0.787, respectively). During the study period, general practitioners ordered 6-15%
of all ordered BNP tests.
DISCUSSION
In Aruban residential elderly, the CHF frequency was unknown and undetected CHF was pre-
sumed because of several reasons. We aimed to investigate the frequency and diagnostic accu-
racy in diagnosing CHF in that population. Therefore, all eligible residential elderly were
screened on CHF in three nursing homes. We found that the CHF frequency was about one-
third of the residents. And, that in the majority of them the diagnosis of CHF had not been made
previously. Undetected diagnoses were expected but the number exceeded our expectations.
Reasons for undetected CHF diagnoses were the lack of consensus on the sequence of the
diagnostic procedures, incomplete data documentation in the medical files and limited use of
BNP testing by general practitioners.
68
The main etiology of CHF existed of atherosclerosis. Arguments for this assumption were high
coexistence of T2DM in residents with CHF and physical inactive lifestyle.
Quite a percentage of residential elderly had T2DM which was well documented. This occur-
rence corresponded to Palloni et al. who found an high or higher frequency of T2DM in residen-
tial elderly of 60+ years living in the Caribbean compared to those from the U.S.A.. And, the
high T2DM frequency corresponded to a study in the Netherland Antilles. In that study, T2DM
was also related to gender (more females), social status and a Western lifestyle.
Near the high T2DM frequency, the studied population was characterized, surprisingly, by a
residents’ mean age comparable to the Aruban life expectancies of 75 and 76 years in 2009
and 2011, respectively (www.indexmundi.com). So, it is likely that our population represented
the Aruban elderly as regards T2DM occurrence and age. However, our population represented
only the Aruban residential elderly as regards the distribution over the Island.
Although the population was too small to speak of predictive values of BNP, the calculated sen-
sitivity and specificity were in line with a comparable study on CHF diagnosis in NH residents of similar age (4) (Table 3). And, from the estimated confounders, BNP was only inversely influ-
enced by renal function which was to be expected from the moderate to severe renal dysfunc-
tion (23;25). Thus, these findings do not limit the additional value of BNP to the CHF diagnos-
tics in residential elderly.
The sense of improving CHF diagnoses for residential elderly was a better quality of life. Since,
more correct CHF diagnoses will lead to adequate treatment, ADL help and planning of care
givers (3;26). And, from another view, less unjust CHF diagnoses save unnecessary treatments
and costs.
Altogether, we observed that the carefully medical work-up according to the applied guideline
improved the CHF diagnostics in residential elderly (17).
This study had some shortcomings. The studied residents did not represent all since widely half
of them were demented and the characteristics of all excluded could not have been uncovered
because of ethical reasons. However, the studied residents represented Aruban elderly as re-
69
gards T2DM occurrence and age. Therefore, we could not rule out a selection bias. So, we cit-
ed a frequency of CHF rather than prevalence. The lack of a panel as standard of diagnosing
CHF was another shortcoming. This could have influenced the CHF frequency but to a limited
extent because the cardiologist was specialized in heart failure and the diagnosis CHF was
made up according to the guideline including BNP (17). Main limitation of this pilot study was
the small population.
In the future, a study is recommended on the detection of CHF in a representative cohort of
residential elderly.
CONCLUSION
In Aruban residential elderly, identification of chronic heart failure is severely underestimated.
The detection of CHF was improved by implementing an appropriate guideline including deter-
mination of BNP.
ACKNOWLEDGMENTS
We thank Stichting Algemeen Bejaardenzorg Aruba, dr. Horacio E. Oduber Hospitaal and Cen-
tro Medico: dr. Rudy Engelbrecht for their participation in this study. None of the authors re-
ported conflicts of interest.
70
References
1 Bielak LF, Yu P, Ryan KA, Rumberger JA, Sheedy PF, Turner ST, et al. Differences in
preva lence and severity of coronary artery calcification between two non-Hispanic
white populations with diverse lifestyles. Atherosclerosis 2008;196(2):888-95.
2 Kurian AK, Cardarelli KM. Racial and ethnic differences in cardiovascular disease risk
factors: a systematic review. Ethn Dis 2007;17(1):143-52.
3 Barents M, Boersma F, Van Der Horst ICC, Hillege HH, de Jongste MJL. Increase of
Help at Activities of Daily Life Given to Frail Elderly With Chronic Heart Failure in a
Nursing Home. Activities, Adaptation & Aging 2011;35(2):98-110.
4 Barents M, van der Horst IC, Voors AA, Hillege JL, Muskiet FA, de Jongste MJ.
Prevalence and misdiagnosis of chronic heart failure in nursing home residents: the role
of B-type natriuretic peptides. Neth Heart J 2008;16(4):123-8.
5 Rutten FH, Cramer MJ, Grobbee DE, Sachs AP, Kirkels JH, Lammers JW, et al. Un rec-
ognized heart failure in elderly patients with stable chronic obstructive pulmonary dis
ease. Eur Heart J 2005;26(18):1887-94.
6 Heckman GA, Misiaszek B, Merali F, Turpie ID, Patterson CJ, Flett N, et al. Manage
ment of heart failure in Canadian long-term care facilities. Can J Cardiol
2004;20(10):963-9.
7 Barents M, Hillege HH, van der Horst IC, de Boer RA, Koster J, Muskiet FA, et al. BNP
and NT-proBNP, predictors of 1-year mortality in nursing home residents. J Am Med Dir
Assoc 2008;9(8):580-5.
71
8 Cowie MR, Fox KF, Wood DA, Metcalfe C, Thompson SG, Coats AJ, et al. Hospitaliza-
tion of patients with heart failure: a population-based study. Eur Heart J
2002;23(11):877-85.
9 Bleumink GS, Knetsch AM, Sturkenboom MC, Straus SM, Hofman A, Deckers JW, et
al. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and
prognosis of heart failure The Rotterdam Study. Eur Heart J 2004;25(18):1614-9.
10 Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of
congestive heart failure in Framingham Heart Study subjects. Circulation
1993;88(1):107-15.
11 Januzzi JL, Jr. Natriuretic peptide testing: a window into the diagnosis and prognosis
of heart failure. Cleve Clin J Med 2006;73(2):149-7.
12 Beleigoli A, Diniz M, Nunes M, Barbosa M, Fernandes S, Abreu M, et al. Reduced
brain natriuretic peptide levels in class III obesity: the role of metabolic and cardiovas-
cular factors. Obes Facts 2011;4(6):427-32.
13 Rutten FH, Grobbee DE, Hoes AW. Differences between general practitioners and car-
diologists in diagnosis and management of heart failure: a survey in every-day
practice. Eur J Heart Fail 2003;5(3):337-44.
14 Barents M, van der Horst IC, Voors AA, Hillege JL, Muskiet FA, de Jongste MJ.
Prevalence and misdiagnosis of chronic heart failure in nursing home residents: the role
of B-type natriuretic peptides. Neth Heart J 2008;16(4):123-8.
72
15 Voors AA, Walma EP, Twickler TB, Rutten FH, Hoes AW. [Multidisciplinary guideline
'Heart failure 2010']. Ned Tijdschr Geneeskd 2011;155:A2957.
16 Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson
PA, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic
Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration
with the Heart Failure Association of the ESC (HFA) and endorsed by the European
Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29(19):2388-442.
17 van LJ, Rutten FH, Walma EP, Wiersma T, Goudswaard AN. [Summary of the prac-
tice guide line 'Heart failure' (first revision) from the Dutch College of General Practitio-
ners]. Ned Tijdschr Geneeskd 2005;149(48):2668-72.
18 Cleland JG, Swedberg K, Follath F, Komajda M, Cohen-Solal A, Aguilar JC, et al. The
EuroHeart Failure survey programme- a survey on the quality of care among patients
with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart
J 2003;24(5):442-63.
19 Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, et al. Obesity
and the risk of heart failure. N Engl J Med 2002;347(5):305-13.
20 Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, III, Feldman HI, et al. A new
equation to estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604- 12.
73
21 Palloni A, McEniry M. Aging and health status of elderly in Latin America and the Car-
ibbean: preliminary findings. J Cross Cult Gerontol 2007;22(3):263-85.
22 Grievink L, Alberts JF, O'Niel J, Gerstenbluth I. Waist circumference as a measure
ment of obe- sity in The Netherlands Antilles; associations with hypertension and dia-
betes mellitus. Eur J Clin Nutr 2004;58(8):1159-65.
23 DeFilippi C, van Kimmenade RR, Pinto YM. Amino-terminal pro-B-type natriuretic
peptide test ing in renal disease. Am J Cardiol 2008;101(3A):82-8.
24 deFilippi CR, Christenson RH. B-type natriuretic peptide (BNP)/NT-proBNP and renal
function: is the controversy over? Clin Chem 2009;55(7):1271-3.
25 van Kimmenade RR, Januzzi JL, Jr., Bakker JA, Houben AJ, Rennenberg R, Kroon
AA, et al. Renal clearance of B-type natriuretic peptide and amino terminal pro-B-type
natriuretic peptide a mechanistic study in hypertensive subjects. J Am Coll Cardiol
2009;53(10):884-90.
74
51 included
2 CHF rejected 5 CHF confirmed After the study 11 CHF de novo
184 excluded
7 CHF before the study
16 (31%) CHF 35 (69%) no CHF
Figure 1. Flow chart of included and excluded residents, and of CHF diagnoses before
and after the study in Aruba.
Chronic heart failure, CHF.
235 residents
75
Table 1. Characteristics of 51 residents.
CHF+ n=16
(%) CHF- n=35
(%) p-value
Age (years) mn (SD) 79 (9) 78 (8) 0.460 Female 11 69 18 51 0.248 Wheelchair/bed 7 44 21 60 0.288 Medical history Cerebrovascular accident 4 25 12 32 0.517 Coronary artery disease 2 13 1 3 0.298 Diabetes Mellitus type 2 12 75 18 54 0.151 Medication Antidiabetics 12 75 14 40 0.018 Diuretics 8 50 11 26 0.211 Calcium-ion antagonists 2 13 6 23 0.680 Beta-blockers 4 25 4 9 0.287 ACE-i or AT2Ri 6 38 10 29 0.533 Heart glycosides 2 13 3 9 0.665 Anticoagulants 13 81 19 37 0.049 Symptoms, signs Dyspnea 13 81 11 31 0.020 Fatigue 14 87 19 54 0.009 Edema 8 50 5 14 0.020 Systolic tension mm Hg 135 28 133 17 0.782 Diastolic tension mmHg 72 16 76 10 0.378 Heart rate beats/min. 74 11 79 9 0.133 Increased CVP 10 63 5 14 0.002 Cardiomegaly 2 13 0 0 0.164 Pacemaker 3 19 2 13 0.243 Electrocardiogram Normal electrocardiogram 3 19 19 54 0.011
76
Left ventricular hypertrophy 4 25 0 0 0.041 Atrial fibrillation 2 0 2 0 0.413 Ischemia 2 0 4 0 0.917 Other 6 56 12 34 0.343 Laboratory data BNP ng/L md (range) 156 72-1029 59 9-191 0.008 Hb mmol/L mn (SD) 7(1) 8(1) 0.290 MCV femtoL mn (SD) 91 (6) 90 (6) 0.763 eGFR mL/min/1.73m² n(SD) 33(20) 58(24) 0.001 TSH mE/L mn (SD) 1(1) 2(1) 0.346
Numbers, n and percentage unless other indicated; mn, mean and SD, standard deviation ;
CVP, central jugular pressure; ACE-I, angiotensin-converting enzyme inhibitor; AT2Ri, angio-
tensin II receptor inhibitor; other, rhythm or conduction disorder, pacemaker or no-specified dis-
order.
77
Table 2. CHF diagnoses after the screening with matching BNP values.
N residents B-type natriuretic peptide median (ng/L) chronic heart failure rejected 2 71 (59 – 83)
chronic heart failure confirmed 5 105 (84 – 392)
chronic heart failure de novo 11 152 (61 – 1029)
Table 3. Predictive values of BNP at different cut-off points. BNP cut-off point ng/L sensitivity specificity PPV NPV 50 1.00 0.37 0.42 1.00 75 1.00 0.64 0.54 1.00 100 0.75 0.69 0.52 0.86 125 0.63 0.74 0.53 0.81 150 0.56 0.89 0.69 0.82 200 0.44 1.00 1.00 0.80 PPV, positive predictive value; NPV, negative predictive value; cut-off points are rounded num-bers.
78
79
Chapter 2.3
HIGH INTRA-INDIVIDUAL VARIATION OF AMINO-TERMINAL PRO-
BRAIN NATRIURETIC PEPTIDE (NT-PROBNP) IN URINE OF PA-
TIENTS WITH STABLE CHRONIC HEART FAILURE.
COMPARISON WITH PLASMA. Schimmel AM, Barents M, de Jongste MJL, Römer JWP, Steward HN, Muskiet FAJ.
Accepted for publication in part in Clinical Chemistry.
80
ABSTRACT
BACKGROUND. The large intra-individual variation (CVi) of plasma N-terminal prohormone-
brain natriuretic peptide (NT-proBNPp) limits its applicability for guided therapy optimization in
individual patients with chronic heart failure (CHF). We investigated whether urine NT-proBNP
(NT-proBNPu) has lower CVi compared with NT-proBNPp. METHODS. CVis were measured in 25 patients with stable CHF (NYHA classes I-III). Blood
and urine samples were collected on a single day (6 2-h blood samples and spontaneously
voided urines during 24-h), 5 consecutive days (5 blood samples, 5 enforced urine samples, 5
full 24-h urines) and 6 consecutive weeks (6 blood samples, 6 enforced urine samples, 6 full
24-h urines). NT-proBNP was measured by immunoassay. Within-day, day-to-day and week-
to-week total CVs (CVts), CVis and reference change values (RCVs) were calculated. RESULTS. Median age was 61 y (range 36-80), 60% was male and mean±SD left ventricular
ejection fraction was 36±15%. Median CVis for NT-proBNPp were 9 (within-day), 18 (day-to-
day) and 30% (week-to-week). For NT-proBNPu they were 34, 21 and 28%, respectively.
RCVs of NT-proBNPu, NT-proBNPu/creatinineu and NT-proBNPu/h were higher than, or equal
to, those of NT-proBNPp. NT-proBNPu did not correlate with NT-proBNPp up to 310 pg/mL NT-
proBNPp, but related almost linearly from thereon. NT-proBNPp increased during the day, while
NT-proBNPu tended to decrease. CONCLUSION. Measurement of NT-proBNP in urine provides no advantages over plasma NT-
proBNP for therapy optimization in CHF patients.
81
INTRODUCTION
Improvements in diagnostics and treatment have contributed considerably to the increasing sur-
vival of patients with cardiac diseases (1). As a consequence, also the prevalence and hence
the impact on society of chronic heart disease, notably chronic heart failure (CHF), has grown
tremendously (2). CHF has become a major health care issue in therapy, hospital admissions
and costs. Measurements of biomarkers may favourably affect the cost-benefit ratio. An ideal
biomarker has high diagnostic sensitivity and specificity, should be a true reflection of
(patho)physiological changes, has low analytical variation (CVa), and is applicable in
(sub)groups irrespective of their demographic background (3). Natriuretic peptides, notably
brain natriuretic peptide (BNP) and amino-terminal pro-brain NP (NT-proBNP) are well estab-
lished CHF biomarkers. They are widely used for CHF diagnosis, follow-up and prognosis (4),
while they also provide opportunities for biomarker-guided treatment optimization (5-8). Meta-
analyses have shown that natriuretic peptide (NP)-guided therapy is superior to symptom-
guided therapy in groups (5-7). However, because of high intra-individual variations compared
to expected changes, it is not possible to establish whether longitudinal changes of BNP or NT-
proBNP in individual patients differ with 95% certainty following therapy-adjustment (8).
BNP has natriuretic, diuretic and vasodilator properties (9;10). NT-proBNP becomes co-
secreted in equimolar amounts, but is physiologically inactive (11). Both are released by cardiac
atria and ventricles upon myocyte stretch, mostly due to volume overload (9). Like many, if not
all, hormones, natriuretic peptides exhibit pulsatile secretion patterns (12). Plasma BNP has a
half-life of about 20 min, while that of NT-proBNP is about 120 min. BNP is rapidly deactivated
in the circulation and tissues by neuropeptidases (10). In contrast, NT-proBNP becomes pas-
sively filtered in the kidneys to become excreted in urine, notably in the form of smaller peptides
that are at least in part immunoreactive (13). In the brush border of the renal tubules low-
molecular-weight proteins may become hydrolyzed to smaller peptides and amino acids that are
subsequently reabsorbed. Usually, this process is nearly complete, suggesting that only minor
82
amounts reach the finally voided urine (14;15). Another mechanism is by endocytosis followed
by lysosomal degradation, secretion via either apical or basolateral membranes, or by transcy-
tosis of the intact protein (16). With increasing plasma, and thereby filtered, concentrations all
enzymatic and active processes may ultimately be expected to reach saturation. From this
threshold, the renal clearance may be expected to increase to finally reach the glomerular filtra-
tion rate.
We have previously established that plasma NT-proBNP (NT-proBNPp) in patients with CHF
exhibits high within-day (mean CVi 9%; range 0-20%), day-to-day (CVi 20%; 3-80%) and
week-to week (CVi 35%; 8-103%) intra-individual variations (CVis) (17). This high CVi, calcu-
lated by correcting total variation (CVt) for analytical variation (CVa, 3%), hampers the useful-
ness of NT-proBNPp for treatment optimization of individual HF patients. Establishment of a
genuine difference between pre and post-treatment NT-proBNP concentrations requires infor-
mation of the minimal change value (also named reference change value; RCV). The RCV for
95% certainty is calculated by 2.8*CVt in which CVt is composed mostly of CVi in case of NT-
proBNPp (17).
Measurement of immunoreactive NT-proBNP in urine voidings (abbreviated NT-proBNPu) may
provide us with a tool that is less affected by the pulsatile secretion of NT-proBNP into plasma.
As a long term plasma ultrafiltrate, NTproBNPu may exhibit less intra-individual variation, at
least theoretically (18-20), but there may be many confounding factors. Measurements in urine
may especially be useful in CHF patients with NTproBNPp concentrations beyond the renal re-
absorption threshold. In this study we calculated CVis for NT-proBNP in both plasma and urine
of patients with stable CHF. To do so we collected corresponding plasma and urine samples for
the establishment of the within-day, day-to-day and week-to-week CVt, CVa, CVi and RCV. The
ultimate goal was to predict whether measurements in urine would allow treatment optimization
for the individual patient at the level of 95% certainty.
83
PATIENTS AND METHODS
The study was conducted from March–July 2008 in the island of Curaçao (12° 12' N, 68° 5'
W). The protocol was approved by the Medical Ethics Committee of the St. Elisabeth Hospital
and was in agreement with local ethical standards and the Helsinki Declaration of 1975, as re-
vised in 2008. All patients were assured that their data were anonymized. Written informed
consent was obtained from all of them.
Study design Within a study period of six weeks we collected blood and urine samples during home visits.
Participants were asked whether they preferred to participate in one, two or all sampling proto-
cols. These protocols were: 1) a within-day protocol; 6 blood samples (taken every 2-h starting
at 08:00 and ending at 18:00) and collection of spontaneously voided urine portions during 24-
h (starting 08:00 after discarding an enforced voiding and ending with a collected enforced
voiding at 08:00 the next day), 2) a day-to-day protocol; one blood sample (collected from
08:00 to 10:00), an enforced urine portion (immediately after blood sampling) and a full 24-h
urine taken during 5 consecutive days, and 3) a week-to-week protocol; one blood sample
(collected from 08:00 to 10:00 each week, an enforced urine portion (immediately after blood
sampling) and a full 24-h urine, on the same day of the week during 6 consecutive weeks.
Clock times of urine voidings were documented. The sampling protocols were integrated where
possible, to limit the number of sampling moments. For example, the 08:00 samples of the
within-day protocol were also part of the day-to-day protocol and samples of one sampling day of the day-to-day protocol was also part of the week-to-week protocol (Figure 1).
84
Patients CHF patients of 18 years and older were recruited from two cardiological practices. The inclu-
sion criteria were: stable CHF (defined as unchanged CHF treatment during the last two
months) living in the vicinity of the hospital and speaking Dutch or English. The exclusion crite-
ria were obstructive heart valve diseases, obstructive or restrictive heart diseases, potentially
transient causes of HF (e.g. acute myocarditis), myocardial infarction, unstable angina, uncon-
trolled arrhythmias and pregnancy or lactation. Information on date of birth, body mass index
and use of medication was collected at baseline. The most recent New York Heart Association
(NYHA) classes and the left ventricular ejection fractions (LVEF) were retrieved from the medi-
cal files. In addition to the NYHA classification, we established whether there was systolic or
diastolic CHF, defined as having a LVEF ≥45%, or >45%, respectively (21).
Samples and analyses Ten mL EDTA-anticoagulated blood samples were collected by venapuncture. They were stored
at 4°C until further handling in the laboratory. Urine voidings and full 24-h urines were collected
in containers and immediately stored in cool boxes. Blood samples were centrifuged within 2 h
after sampling (1,500 g-force, 15 min, 4 °C). Volumes of the spontaneous voidings, enforced
voidings and full 24-h urines were measured. Ten mL of each urine portion was taken and cen-
trifuged (1,500 g-force, 15 min, 4 °C). Plasma and urine samples were aliquoted and stored in
Eppendorf tubes at -80 °C until transportation to The Netherlands. NT-proBNP was analyzed
within nine months after collection in the Clinical Chemical Laboratory of the University Medical
Center Groningen, The Netherlands. Plasma and urine samples of a single patient were ana-
lyzed in a single series to minimize the influence of the CVa. For measurements of NT-proBNP
we applied the sandwich technique [Elecsys 2010 immunoassay system, Roche Diagnostics,
Mannheim, Germany (22)]. Creatinine was measured in all urine samples (creatinineu).
Creatinine was also measured in the firstly collected plasma sample of each patient to calculate
the estimated glomerular filtration rate (eGFR). In these calculations we used the factor of 1.112
85
for patients with African-American backgrounds (23). NT-proBNPu concentration (pg/mL) was
also expressed as NT-proBNPu/creatinineu (pg/nmol) and NT-proBNPu/h (pg/h). NT-
proBNPu/NT-proBNPp represents the apparent filtration fraction of NT-proBNP.
The detection limit of the NT-proBNP immunoassay was 5 pg/mL. An NT-proBNP <5 pg/mL
was documented as 0 pg/mL. The within-series CVa of NT-proBNPp was 3% (17). Since NT-
proBNPu ranges from about 5-50 pg/mL, we used 4 quality-control samples with NT-proBNPu
concentrations of 8, 10, 42 and 48 pg/mL. These samples were selected from the total patient
sample collection. They were analyzed six times to calculate the CVa of NT-proBNPu. The CVa
of creatinineu was calculated from all quality control measurements of creatinineu in the labora-
tory as performed in the month preceding the NT-proBNP analyses.
Statistical analysis Data of participants sampled three times or less within a sampling protocol were excluded from
evaluation in that specific protocol. The remaining data were processed with Microsoft Office
Excel 2007 and statistically analyzed using SPSS (SPSS 20.0; SPSS, Inc). Results were ex-
pressed as mean±SD or medians (range). The relations of NT-proBNPp and NT-proBNPu with
the patients’ characteristics were analyzed by Spearman’s correlation tests. Spearman’s correla-
tion tests were also employed for correlating NT-proBNPp with NT-proBNPu, using all data from
the day-to-day and week-to-week samples.
For comparison of within-day NT-proBNPu with NT-proBNPp, we employed the spontaneously
voided urine portion within 2 h following venapuncture. For example, the urine portion of 10:00
should be voided from 10:00 to 12:00, the portion of 12:00 from 12:00 to 14:00 etc. In case of
two spontaneously voided urine portions obtained within 2 h, the mean NT-proBNPu concentra-
tion of those samples was taken. If no urine was voided within 2 h, the NT-proBNPu of 10:00
was labelled as missing. The Shapiro-Wilk test was used to examine the distribution of NT-
86
proBNP at different clock times for normality. NT-proBNPp, NT-proBNPu and NT-proBNPu/NT-
proBNPp ratio at 8:00 and 18:00 were compared with Wilcoxon rank-sum test. NT-proBNP lev-
els at six different clock times within one day were analyzed for differences between those six
measurements using Friedman’s’ test. To identify differences between NT-proBNPp, NT-
proBNPu and NT-proBNPu/NT-proBNPp measurements from the same patient at different clock-
times, we used the Wilcoxon signed-rank test. The outcomes were corrected for type 1 errors
(p<0.01).
The plasma and urine total variations (CVt) of NT-proBNP for each patient and each of the 3
sampling protocols were calculated. CVi was calculated using (CVi)2 = (CVt)2 – (CVa)2 (17).
Reference change values (RCVs) at 95% probability were calculated from median CVas and
CVis, according to: RCV = Z × 21/2 × (CVa2/na + CVi
2/ns)1/2 (22;24;25), where Z is 1.96
(i.e. Z-score for 95% CI); na is the number of replicate assays; and ns the number of patient
samples needed to estimate each of the two homeostatic set points, ns=1 in the present study.
RCVs reflect the minimum percentage change in serial results that is different from the com-
bined analytical and biological variation, with 95% confidence. The CVis of the within-day, day-
to-day and week-to-week data were compared with the Wilcoxon signed-rank test. Only for
these comparisons the significance was set at p<0.01. All other significances were set at
p<0.05 (see above).
RESULTS
Patients and samples Twenty-five patients (mean age 61±10 years, 60% males) were included into the study (Table
1). Fifteen patients (60%) participated in all three sampling protocols. The main reasons for not
participating in all protocols were interference with work or holidays. All together, we were able
to collect samples from 20 patients participating in the within-day protocol, 18 patients following
87
the day-to-day protocol and 22 patients completing the week-to-week protocol (Figure 2). This
translated into 329 out of the maximum of 342 blood samples (96%), 187 spontaneously
voided urine portions, 212 of the maximum of 222 enforced urine voidings (95%), and 207 of
the maximum of 222 full 24-h urines (93%). Four participants (16%) exhibited NT-proBNPu
levels below the detection limit of 5 pg/mL. These levels were set at 0 pg/mL. In two of these
four patients, all NT-proBNPu values were set at 0 pg/mL. The NYHA classes of these two
patients were II and unknown. In the other two patients 89% and 50% of the NT-proBNPu val-
ues were below the detection limit and their NYHA classes were II and III, respectively.
Within-day, day-to-day and week-to-week intra-individual coefficients of variation
The calculated CVas of NT-proBNPu quality-control samples were 12% at 8 pg/mL, 15% at 10
pg/mL, 3% at 42 pg/mL and 3% at 48 pg/mL. The CVa of NT-proBNPu was inversely related
to NT-proBNPu (r= -0.983, p<0.05). The CVa for NT-proBNPu levels between 5 and 48
pg/mL was derived from CVa (%) = 119.67*(NT-proBNPu)-1.0016. For NT-proBNPu levels
above 48 pg/mL, a CVa of 3% was used. The CVa of creatinineu, calculated from all measure-
ments in a single month, was 2%.
The median CVis for NT-proBNPp in the within-day, day-to-day and week-to-week protocols were 9, 18 and 30%, respectively (Table 2). The corresponding median CVis for NT-proBNPu
were 34, 21 and 28%, respectively. The within-day CVi of NT-proBNPu was higher than the
corresponding CVi of NT-proBNPp (p=0.003). This was also the case for the CVis of NT-
proBNPu/creatinineu (p=0.002) and NT-proBNPu/h (p<0.001). The within-day CVi of NT-
proBNPu/h (pg/h) was higher than that of NT-proBNPu (pg/mL; p=0.031). For the day-to-day
and week-to-week protocols, the CVis of NT-proBNPu did not differ from the CVis of NT-
proBNPp. For the day-to-day protocol, the CVi of NT-proBNPu/h was higher compared to the
CVi of NT-proBNPu (p=0.044). The same statistical differences as for the CVis are applicable
for the comparisons between RCVs, because of the proportionality between these two parame-ters (Table 2).
88
Correlations Baseline NT-proBNPp (i.e. firstly collected blood sample of each patient) was inversely related
to body mass index (r= -0.548, p=0.005). Inversely related to LVEF were: baseline NT-
proBNPp (r= -0.599, p=0.009), baseline NT-proBNPu (i.e. the firstly voided urine) (r= -0.596,
p=0.009), baseline NT-proBNPu/creatinineu (r= -0.481, p=0.043), and baseline NT-
proBNPu/h (r= -0.538, p=0.021). Baseline NT-proBNPp and baseline NT-proBNPu were not
related to other patient characteristics, such as age, eGFR and NYHA class. Related to baseline
NT-proBNPp were: baseline NT-proBNPu (r=0.841, p=<0.001), baseline NT-
proBNPu/creatinineu (r=0.804, p=<0.001), and baseline NT-proBNPu/h (r=0.835,
p=<0.001).
When the data of the day-to-day and week-to-week protocols were pooled, NTproBNPp corre-
lated with NT-proBNPu in the corresponding enforced urine voidings (r=0.739, p<0.001) and
also with NT-proBNPu in the full 24-h urines (r=0.735, p<0.001). NT-proBNPu correlated also
with NT-proBNPu/creatinineu (r=0.932, p<0.001) and NT-proBNPu/h (r=0.950, p<0.001).
Figure 3 shows the relation between NT-proBNPp and NT-proBNPu in the corresponding en-
forced urine voidings collected in the day-to-day and week-to-week protocols. Initially, NT-
proBNPp did not correlate with NT-proBNPu. However, there was a clear relation from an NT-
proBNPp of about 500 pg/mL, obeying the equation NT-proBNPu = 0.0226 × (NT-
proBNPp)1.1563. The median NT-proBNPu in the lower NT-proBNPp region was 17 pg/mL.
Substituting this value into the equation gave an estimated intersection at an NT-proBNPp of
310 pg/mL.
Analysis of a subgroup with NT-proBNPp of 310 pg/mL We investigated whether the RCVs for NT-proBNPp were better for concentrations beyond 310 pg/mL, i.e. the concentration from which NT-proBNPu correlated with NT-proBNPp (Figure 3).
89
This appeared not to be the case. Except for a decrease in RCVs for week-to-week NT-
proBNPp (from 83 to 59%) and NT-proBNPp/creatinineu (from 113 to 107%), and day-to-day
NT-proBNPu/h (87 to 72%), all other RCVs increased while that of the day-to-day NT-proBNPp remained constant (Supplemental Table 1).
Changes of NT-proBNP in plasma and urine during the day The within-day courses, relative to baseline, for NT-proBNPp, NT-proBNPu and NT-
proBNPu/NT-proBNPp, all calculated from the concentrations in pg/mL, are shown in Figure
4A-4C. Concomitant p-values are in Supplemental Table 2. Data were expressed relative to
levels at 08:00 h (set at 100%). Within-day NT-proBNPp increased from 08:00 to 18:00 (Wil-coxon rank-sum p=0.006; Friedman p<0.001). No other changes were detected (Figure 4A).
No concomitant changes were observed for the within-day NT-proBNPu. The apparent decrease of NT-proBNPu from 08:00 to 18:00 was insignificant (Figure 4B). There were also no
changes in NT-proBNPu/creatinineu and NT-proBNPu/h from 08:00 to 18:00. NT-proBNPu/h
fluctuated from 12:00 to 16:00: there was a decrease from 12:00 to 14:00 and an increase
from 14:00 to 16:00 (Wilcoxon signed-rank test p=0.006 and p=0.007, respectively). There
was no change of the NT-proBNPu/ NT-proBNPp ratio from 8:00 to 18:00, but it decreased from 8:00 to 10:00 (Wilcoxon signed-rank test p=0.009; Figure 4C).
DISCUSSION
We investigated whether the within-day, day-to-day (5-days) and week-to-week (6-weeks;
collection at the same day of week) CVis of NT-proBNPu were more favorable compared to the
corresponding NT-proBNPp in patients with stable CHF. In contrast to expectation, we found
that the within-day CVi of NT-proBNPu was higher than that of NT-proBNPp. The day-to-day
and week-to-week CVis of NT-proBNPu did not differ from the CVis of NT-proBNPp. This con-
clusion also applies for NT-proBNPu levels adjusted for dilution (by creatinine) or expressed as
90
an excretion rate (per h). The CVis did not improve by restricting the analyses to NT-proBNPp
concentrations ≥310 pg/mL, i.e. the levels from which there was an almost linear relation be-
tween NT-proBNPu and NT-proBNPp.
In the present study the within-day, day-to-day and week-to-week CVis of NT-proBNPp
amounted to 9, 18 and 30%. These outcomes were similar to those of our previous study,
where Bruins et al. (17) reported 9, 20 and 35%, respectively. They are also in line with the
week-to-week CVis of 30% for natriuretic peptides reported by others (26;27). High NT-
proBNPp CVis are accompanied by proportionally higher RCVs that in the present study were 25
(within-day), 51 (day-to-day) and 83% (week-to-week). The latter RCV was comparable to the
week-to-week (8-weeks) RCV of 90% for NTproBNPp as reported by Wu et al. (26). The
nowadays well established high RCVs for NT-proBNP in both plasma and urine preclude the
use of these parameters for guided therapy of individuals, if longitudinal differences are to be
detected with 95% certainty (17).
It is as yet unclear why the CVis of (immunoreactive) NT-proBNPu are higher than those of
(immunoreactive) NT-proBNPp. NT-proBNPu reflects NT-proBNPp over an extended period and
thereby dampens fluctuation of NT-proBNPp, caused by its pulsatile secretion together with
BNP in a stoichiometric manner (12). Fluctuations of filtration fraction, eGFR, glomerular per-
meability of proteins and proximal tubule function are candidates. Permeability may not be limit-
ing for low molecular weight proteins that are usually filtered without difficulty. Larsson et al.
(28) observed no consistent changes of the eGFR during the day in healthy subjects. Other
determinants might relate to proteolytical cleavage in tubular microvillar membranes (14;15) and
receptor-mediated endocytosis by proximal tubule cells. In the latter, the megalin/cubilin recep-
tor complex may play a central role by its ability to bind structurally very different proteins (29),
but other mechanisms of protein internalization, like the caveolin-pathway and fluid-phase en-
docytosis have also been described (16). Megalin is involved in proximal tubular uptake of
91
glomerular-filtered albumin, other low-molecular weight proteins and their cargos (such as vita-
mins, minerals), including albumin, hemoglobin, transcobalamin-vitamin B12, and vitamin D-,
retinol- and folic acid-binding proteins, but also many peptides including parathormone, insulin,
epidermal and insulin-like growth factor and leptin (16;29;30). Following endocytosis, the cap-
tured proteins may become cycled to the plasma or tubular fluid by exocytosis, either as the
intact protein (transcytosis) or after (partial) degradation in lysosomes (16).
Our data suggest that (immunoreactive) NT-proBNPu is not related to (immunoreactive) NT-proBNPp (Figure 3) up to an NT-proBNPp threshold of about 310 pg/mL. From this threshold
filtration seems to be the dominant determinant, suggesting that at lower levels either filtration,
reabsorption, or both, might be limiting. Given the passiveness of filtration, NT-proBNPp above
310 pg/mL might be consistent with saturation of tubular reabsorption/metabolism, either by
co-filtered proteins like albumin, or the reach of maximum reabsorption/metabolism capacity of
NT-proBNP itself. Whatever the cause, we found that CVis for NTproBNPu at NTproBNPp levels
above 310 pg/mL were not more favorable than those applicable for the entire range. More
detailed studies on the renal handling of plasma proteins and notably NT-proBNPp are needed
to elucidate the factors causing the presently encountered high CVis of NT-proBNPu.
Consistent with our previous study (17), we found that NTproBNPp steadily increased during the day (Figure 4A). This seems to coincide with a decrease of NTproBNPu, notably between
08:00 and 10:00 (Figure 4B), although it did not reach significance. Increased volume load
(e.g. salt and fluids) related to breakfast and other meals, but also the prescribed medication
(Table 1) might contribute to the observed pattern, which is at least in part responsible for the
observed high within-day CVis.
The strength of this study was its prospective design with simultaneous collections of blood
samples and urines. This resulted in a reliable comparison of NT-proBNP levels in both plasma
92
and urine, collected in a single day (10-h), from day-to-day (5-days) and from week-to-week
(6-weeks), all taken during usual daily life activities. A limitation was some shortcomings in the
sampling within a single day. The number of urine portions differed per patient. Our solution was
to categorize the samples in periods of 2 h to provide the most reliable figure. The patients
noted the times of voiding themselves and these were verified by us during every visit to mini-
mize potential bias. Second, participants may not have collected the entire 24-h volumes, de-
spite our frequent visits. Correction for creatinine and expression as an excretion rate at least
partially overcame this problem. Finally, most participants used diuretics which may have caused higher water and salt excretion from 08:00 to 14:00 h (Figure 4A and 4B).
CONCLUSION
We conclude that measurement of urine NT-proBNP provides no advantages over plasma NT-
proBNP for therapy optimization in patients with chronic heart failure.
ACKNOWLEDGEMENTS
We thank all patients for their kind cooperation and Roche Diagnostics Netherlands b.v. (Mr.
Ben Aalderink) for partial financial support.
93
References
1 Leening MJ, Siregar S, Vaartjes I, Bots ML, Versteegh MI, van Geuns RJ, et al. Heart
disease in The Netherlands: a quantitative update. Neth Heart J 2014;22(1):3-10.
2 Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, et al. Fore
casting the impact of heart failure in the United States: a policy statement from the
American Heart Association. Circ Heart Fail 2013;6(3):606-19.
3 Morrow DA, de Lemos JA. Benchmarks for the assessment of novel cardiovascular
biomarkers. Circulation 2007;115(8):949-52.
4 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart
Failure 2012 of the European Society of Cardiology. Developed in collaboration with the
Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33(14):1787-847.
5 Pfisterer M, Buser P, Rickli H, Gutmann M, Erne P, Rickenbacher P, et al. BNP-guided
vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical
Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial.
JAMA 2009;301(4):383-92.
6 De Vecchis R, Esposito C, Di BG, Ariano C, Giasi A, Cioppa C. B-type natriuretic pep-
tide-guided versus symptom-guided therapy in outpatients with chronic heart failure: a
systematic review with meta-analysis. J Cardiovasc Med (Hagerstown )
2014;15(2):122-34.
94
7 Savarese G, Trimarco B, Dellegrottaglie S, Prastaro M, Gambardella F, Rengo G, et al.
Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 pa
tients in 12 randomized trials. PLoS One 2013;8(3):e58287.
8 Fent G, Hall I, Watt V, O'Toole L, Al-Mohammad A. 43 Raised Natriuretic Peptides are
not Exclusively Indicative of Heart Failure: A Service Review of a Diagnostic Heart Fail-
ure Clinic. Heart 2014;100 Suppl 3:A23-A24.
9 Rodeheffer RJ. Measuring plasma B-type natriuretic peptide in heart failure: good to go
in 2004? J Am Coll Cardiol 2004;44(4):740-9.
10 Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med
1998;339(5):321-8.
11 Balion CM, Santaguida P, McKelvie R, Hill SA, McQueen MJ, Worster A, et al.
Physiological, pathological, pharmacological, biochemical and hematological factors af-
fecting BNP and NT- proBNP. Clin Biochem 2008 Mar;41(4-5):231-9.
12 Bentzen H, Pedersen RS, Pedersen HB, Nyvad O, Pedersen EB. Abnormal rhythmic
oscillations of atrial natriuretic peptide and brain natriuretic peptide in heart failure. Clin
Sci (Lond) 2003;104(3):303-12.
13 Palmer SC, Endre ZH, Richards AM, Yandle TG. Characterization of NT-proBNP in hu
man urine. Clin Chem 2009;55(6):1126-34.
14 Kenny AJ, Maroux S. Topology of microvillar membrance hydrolases of kidney and in-
testine. Physiol Rev 1982;62(1):91-128.
95
15 Maack T, Johnson V, Kau ST, Figueiredo J, Sigulem D. Renal filtration, transport, and
metabolism of low-molecular-weight proteins: a review. Kidney Int 1979;16(3):251-70.
16 Dickson LE, Wagner MC, Sandoval RM, Molitoris BA. The proximal tubule and albu-
minuria: really! J Am Soc Nephrol 2014;25(3):443-53.
17 Bruins S, Fokkema MR, Romer JW, Dejongste MJ, van der Dijs FP, van den Ouwe-
land JM, et al. High intraindividual variation of B-type natriuretic peptide (BNP) and
amino-terminal proBNP in patients with stable chronic heart failure. Clin Chem
2004;50(11):2052-8.
18 Ng LL, Geeranavar S, Jennings SC, Loke I, O'Brien RJ. Diagnosis of heart failure us
ing urinary natriuretic peptides. Clin Sci (Lond) 2004;106(2):129-33.
19 Cortes R, Portoles M, Salvador A, Bertomeu V, Garcia de BF, Martinez-Dolz L, et al.
Diagnostic and prognostic value of urine NT-proBNP levels in heart failure patients. Eur
J Heart Fail 2006;8(6):621-7.
20 Michielsen EC, Bakker JA, Kimmenade RR, Pinto YM, Dieijen-Visser MP. The diag
nostic value of serum and urinary NT-proBNP for heart failure. Ann Clin Biochem
2008;45(Pt 4):389-94.
21 Solomon SD, Anavekar N, Skali H, McMurray JJ, Swedberg K, Yusuf S, et al. Influ-
ence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart fail-
ure patients. Circulation 2005;112(24):3738-44.
96
22 Barnes SC, Collinson PO, Galasko G, Lahiri A, Senior R. Evaluation of N-terminal
pro-B type natriuretic peptide analysis on the Elecsys 1010 and 2010 analysers. Ann
Clin Biochem 2004;41(Pt 6):459-63.
23 Stevens LA, Coresh J, Feldman HI, Greene T, Lash JP, Nelson RG, et al. Evaluation
of the modification of diet in renal disease study equation in a large diverse population.
J Am Soc Nephrol 2007;18(10):2749-57.
24 Steele BW, Wang E, Palomaki GE, Klee GG, Elin RJ, Soldin SJ, et al. An evaluation
of analytic goals for assays of drugs: a College of American Pathologists Therapeutic
Drug Monitoring Sur vey Study. Arch Pathol Lab Med 2001;125(6):729-35.
25 Petersen PH, Sandberg S, Fraser CG, Goldschmidt H. Influence of index of individual-
ity on false positives in repeated sampling from healthy individuals 162. Clin Chem Lab
Med 2001;39(2):160-5.
26 Wu AH, Smith A, Wieczorek S, Mather JF, Duncan B, White CM, et al. Biological varia-
tion for N-terminal pro- and B-type natriuretic peptides and implications for therapeutic
monitoring of patients with congestive heart failure. Am J Cardiol 2003;92(5):628-31.
27 Melzi dG, Tagnochetti T, Nauti A, Klersy C, Papalia A, Vadacca G, et al. Biological
variation of N-terminal pro-brain natriuretic peptide in healthy individuals. Clin Chem
2003;49(9):1554-5.
28 Larsson A, Akerstedt T, Hansson LO, Axelsson J. Circadian variability of cystatin C,
creatinine, and glomerular filtration rate (GFR) in healthy men during normal sleep and
after an acute shift of sleep. Chronobiol Int 2008;25(6):1047-61.
97
29 Shankhajit De 1 SK2aAS2. The Endocytic Receptor Megalin and its Associated Pro-
teins in Proximal Tubule Epithelial Cells. 4[membranes 4030333], 333-355. 2014.
ww.mdpi.com/journal/membranesw, Membranes. 11-7-2014.
30 Christensen EI, Birn H, Storm T, Weyer K, Nielsen R. Endocytic receptors in the renal
proximal tubule. Physiology (Bethesda ) 2012;27(4):223-36.
98
Week-to-week protocol
week 1 week2 week 3 week 4 week 5 week 6
Day-to-day protocol
day 1 day 2 day 3 day 4 day 5
08:00
10:00
12:00
14:00
16:00
18:00 Within-day protocol
Figure 1. Protocol for blood and urine sampling: an example.
The total study duration was six weeks. We employed three different protocols for establish-
ment of within-day, day-to-day and week-to-week variation, respectively. The samples of the
week-to-week protocol were collected on the same day of the week.
99
Figure 2. Overview of collected and missing blood samples and urine portions of within-day, day-to-day and week-to-week sampling protocols. Spont., spontaneously; p.p., per person.
20 patients 6 times 18 patients 5 days 22 patients 6 weeks
maximum: 120 samples maximum: 90 samples maximum: 132 samples
116 plasma samples 4 missing 89 plasma samples 1 missing 124 plasma samples 8 missing
187 spont.voided urine portions 89 forced urine portions 1 missing1 missing 123 forced urine portions 9 missing
mean 9 (6-14) urine portions p.p. 84 full 24-h urine portions 6 missing 123 full 24-h urine portions 9 missing
patient recruitment from
2 cardiologists' practices
25 participants
Within-day Day-to-day Week-to-week
100
Figure 3. Relation between NT-proBNP in plasma and NT-proBNP in the enforced
urine voidings collected in the day-to-day and week-to-week protocols.
Data derive from 22 patients and in total 182 comparisons of NT-proBNP in plasma and urine.
Samples were from the day-to-day and week-to-week protocols. For urine we used the en-
forced voidings. NT-proBNPp was unrelated to NT-proBNPp up to a concentration of 310 pg/mL
(corresponding with NT-proBNPp of 17 pg/mL). The relation from NT-proBNPp of 310 pg/mL
was: NT-proBNPp= 0.0226*(NT-proBNPp)1.1563.
101
102
Figure 4. Within-day courses for NT-proBNP in plasma, urine and the NT-proBNP
urine/plasma ratio. Data are medians (interquartile range, IQR) relative to 08:00. Numbers
underneath clock time refer to numbers of patient samples. #significance of 8:00 – 18:00 time-
period; *significance of two hours time-period; NT-proBNP, amino terminal pro-brain natriuretic
peptide. All p-values are reported in Table 3.
103
Table 1. Baseline characteristics of the study group.
Participants, numbers 25
Age, mean±SD, years 61±10
Gender (male/female), numbers 15/10
Body mass index mean±SD, kg/m2 28±6
eGFR, mean±SD, mL/min/1.73 m2 81±31
left ventricular ejection fraction, mean±SD, % 36±15
New York Heart Association classes, number (%)
I 2 (8)
II 14 (56)
III 8 (32)
Medication, number (%)
Beta-blocking agent 19 (76)
Angiotensin-converting enzyme inhibitor 10 (40)
Diuretics 22 (100)
Digoxin 5 (20)
NT-proBNPp, median (range)
NT-proBNPp, pg/mL 205 (12-3,404)
NT-proBNPub, median (range)
NT-proBNPu, pg/mL 19 (0-173)
NT-proBNPu/NT-proBNPp 2 (0-49)
NT-proBNPu/h, pg/h 1 (0-18)
NT-proBNPu/NT-proBNPp, median (range) 0.06 (0.00-1.86)
eGFR, estimated glomerular filtration rate; NT-proBNP, amino terminal pro-brain natriuretic peptide; p, plasma; u, urine; a Retrieved from medical files. Seven out of 25 LVEF data were missing. One out of 25 NYHA classifications was missing. b full 24-h urine portions.
104
Table 2. Analytical variations (CVa), intra-individual variations (CVi), total variations (CVt)
and reference change values (RCV), for plasma and urine NT-proBNP.
Within-day Day-to-day Week-to-week
NT-proBNPp, pg/mL
CVa, % 3 3 3
CVi, % 9 (0-21) c 18 (5-90) 30 (6-215)
CVt, % 9 (3-22) 19 (6-90) 30 (7-215)
RCV, % 25 51 83
NT-proBNPu, pg/mL
CVa, % 5 (0-15) 7 (0-14) 4 (0-87) e
CVi, % 34 (0-71) c 21 (0-60) d 28 (0-180) e
CVt, % 35 (0-71) 23 (0-60) 29 (0-200) e
RCV, % 96 62 80
NT-proBNPu/creatinineu,
pg/nmol
CVa, % 6 (2-15) 8 (2-15) 4 (2-87) e
Cvi, % 29 (0-93) c 27 (0-112) 40 (0-180) e
CVt, % 29 (0-93) 27 (0-113) 40 (0-200) e
RCV, % 81 77 113
NT-proBNPu/hour, pg/h
CVa, % 5 (0-15) 7 (0-14) 4 (0-87) e
Cvi, % 47 (0-174) c 31 (0-67) d 33 (0-180) e
CVt, % 48 (0-174) 32 (0-67) 34 (0-200) e
RCV, % 132 87 92
Data are medians (ranges). For within-day urine amino-terminal pro-brain natriuretic peptide
(NT-proBNPu) we used spontaneously voided urine portions; for day-to-day and week-to-week
105
NT-proBNPu we used the full 24-h urine portions. c Within-day CVis of NT-proBNPu, NT-
proBNPu /creatinineu, and NT-proBNPu/h were higher than the CVi of NT-proBNPp (p=0.003
for pg/mL; p=0.002 for pg/nmol and p<0.001 for pg/h). Within-day CVi of NT-proBNPu/h (pg/h) was higher than that of NT-proBNPu (pg/mL; p=0.031). d Day-to-day CVi of NT-
proBNPu/h (pg/h) was higher than that of NT-proBNPu (pg/mL; p=0.044). e Analytical variation (CVa) increased with decreasing NT-proBNP outcome; the upper-limit of
the presented CVa was determined by one patient.
106
Table 3. Within-day time-period differences for NT-proBNP in plasma, urine and the
urine/plasma ratio.
p-values
time-period
W
08-18
F
08-18
WSR
08-10
10-12
12-14
14-16
16-18
NT-proBNPp 0.006f 0.000f 0.015 0.019 0.327 0.586 0.557
NT-proBNPu 0.064 0.261 0.100 0.650 1.000 0.701 0.790
NT-proBNPu/creatu 0.638 0.286 0.036 0.861 0.347 0.028 0.657
NT-proBNPu/h 0.695 0.054 0.088 0.152 0.006g 0.007g 0.286
NT-proBNPu/NT-
proBNPp
0.091 0.215 0.009f 0.152 0.790 0.480 0.445
W, Wilcoxon test; F, Friedman test; WSR, Wilcoxon Signed Ranks test using p<0.01 for signifi-
cance; NT-proBNP, amino-terminal pro-B-type natriuretic peptide; f significant at p<0.05; g significant at p<0.01.
107
Supplemental Table 1.
Analytical variations (CVa), intra-individual variations (CVi), total variations (CVt) and refer-
ence change values (RCV), for plasma and urine NT-proBNP in the subgroup with NT-
proBNPp>310 pg/mL.
Within-day Day-to-day Week-to-week NT-proBNPp, pg/mL
CVa, % 3 3 3 CVi, % 12 (7-21) h 18 (9-90) 21 (6-66) i
CVt, % 12 (7-22) 19 (10-90) 21 (7-66) RCV, % 34 51 59
NT-proBNPu, pg/mL CVa, % 2.55 (2.55-8) 2.55 (2.55-9) 2.55 (1.76-8) CVi, % 48 (36-71) h 36 (1-60) 36 (19-101) i
CVt, % 49 (39-71) 36 (4-60) 36 (19-101) RCV, % 135 100 100
NT-proBNPu/creatinineu, pg/nmol
CVa, % 3 (3-9) 3 (3-9) 3 (3-8) Cvi, % 32 (10-93) h 27 (4-86) 38 (22-134) i
CVt, % 32 (11-93) 27 (5-86) 38 (22-140) RCV, % 89 75 107
NT-proBNPu/hour, pg/h CVa, % 2.55 (2.55-8) 2.55 (2.55-9) 2.55 (1.76-8) Cvi, % 56 (38-107) h 26 (14-66) 55 (26-94) i
CVt, % 56 (39-107) 28 (14-66) 55 (26-94) RCV, % 157 72 154
Data are median (range). For within-day urine amino-terminal pro-brain natriuretic peptide (NT-
proBNPu), spontaneously voided urine portions were used; for day-to-day and week-to-week NT-proBNPu, full 24-h urine portions were used. h The within-day CVis of NT-proBNPu were
108
higher than the CVi of NT-proBNPp (p=0.018 for pg/mL; p=0.028 for pg/nmol and p=0.018
for pg/h). i The week-to-week CVis of NT-proBNPu were higher than the CVi of NT-proBNPp (p=0.013 for
pg/mL; p=0.020 for pg/nmol and p=0.028 for pg/h). Analytical variation, CVa; intra-individual
variation, CVi; total variation, CVt; p, plasma; u, urine; reference change value, RCV.
109
110
111
Chapter 3
BNP AND NT-PROBNP, PREDICTORS OF 1-YEAR MORTALITY IN
NURSING HOME RESIDENTS. Barents M, Hillege HH, van der Horst IC, de Boer RA, Koster J, Muskiet FA, de Jongste MJ.
J Am Med Dir Assoc. 2008;9(8):580-5. Epub 2008 7.
112
ABSTRACT
OBJECTIVES. To investigate on one-year mortality prediction of B type natriuretic peptide
(BNP) and N terminal-proBNP (NT-proBNP) in institutionalized elderly with multiple-morbidity. METHODS. A prospective, cross-sectional study in one nursing home was designed. Partici-
pants: 93 residents (mean age 81 ± 3 years, 66% female). Residents with serious cognitive
impairments, aphasia or metastatic cancer were excluded.
Measurements: clinical assessment, immobilization, medical history, electrocardiogram (ECG),
echocardiogram, blood samples. One general geriatrician assessed non-cardiovascular dis-
eases, a cardiologist panel established the diagnosis of chronic heart failure (CHF). Subjects
were tracked for 1 year as far as status of death. RESULTS. 18/93 enrolled individuals died. BNP was significant higher in non-survivors com-
pared to survivors (138 (49-753) versus 87 (27-162) P 0.029), NT-proBNP was higher but
did not reach significance 1382 (193-5683) versus 335 (175-900) pg/mL (interquartile range
(IQR), P 0.059). The adjusted value on one-year mortality, of six predefined chronic diseases,
immobilization, age, sex, NT-proBNP and BNP was estimated by means of Cox proportional
hazard regression analyses. Finally, both for NT-proBP and BNP, a mutually adjusted multivari-
ate Cox proportional hazard analysis with the covariates presented that BNP and NT-proBNP
predicted one-year mortality significantly (HR 1.16 and P 0.003, HR 1.02 and P 0.001, respec-
tively).The mortality risk increased at rising BNP and NT-proBNP levels. CONCLUSION. BNP and NT-proBNP are predictors of one-year mortality independently of age,
gender and morbidity.
The mortality risk increases at elevating natriuretic peptide concentrations. We postulate that
plasma levels of BNP and NT-proBNP are also of use to predict prognosis in institutionalized
elderly with multiple morbidity.
113
INTRODUCTION
Elderly with multiple morbidity admitted to a nursing home are faced with questions concerning
their health, living conditions and social life. Information about the prognosis of their diseases is
essential for them to make decisions on these questions and therefore of importance for the
quality of their life. Aside existing chronic diseases and their progression, also body mass index
(BMI), waist-hip ratio, biomarkers as albumin and natriuretic peptides predict 1-year mortality
(1-11). Natriuretic peptides (BNP and NT-proBNP) have become available as tools for the di-
agnosis of heart failure and for the prognosis (4;7-9). Their prognostic role was evaluated in-
dependently of the presence of chronic heart failure and found to be of importance. However,
most of these data are obtained from specialized clinics treating relatively younger patients with
heart failure without comorbidity. In addition, BNP levels also increase in noncardiac conditions
such as old age, being female, pulmonary diseases (pulmonary hypertension or embolism,
chronic obstructive pulmonary disease) and renal dysfunction (12-15). Although nearly all nurs-
ing home residents suffer from multiple morbidity, data on the value of use of natriuretic pep-
tides in them are limited. We therefore investigated whether BNP and NT-proBNP plasma levels
remain of prognostic value in elderly patients with multiple morbidity.
METHODS
During the course of this study there were 140 persons in the departments for residents with
diseases of somatic origin in NH “het Zonnehuis”. Their impairments are based on cardiovascu-
lar, pulmonary, endocrine, neurodegenerative, skeletal muscle, renal dysfunction (16) and other
disorders. Most of them receive long-term care. Some residents with skeletal muscle or cere-
brovascular disorders were reactivated, one-third of whom could be discharged (short stay) but
who should remain care dependent in primary care. Both groups were invited to take part if they
were 65 years of over. The long-term and short-stay residents were included if they understood
114
the impact of the study on themselves (competent) and if they agreed to participate by written
informed consent.
Persons with aphasia or a cognitive impairment measured by the mini-mental state estimation
(MMSE) test ≤20 were excluded. The MMSE test contains 30 questions and a MMSE ≤20 is
suspect for cognitive impairments (17). Persons with metastatic cancer who stayed in a de-
partment specialized in palliative terminal care were excluded. Persons were also excluded if
the echocardiographic frames could not be sufficiently visualized or if they refused to have their
blood sample taken.
The study was approved of by the Medical Ethical Committee in Groningen, University Medical
Center Groningen, The Netherlands (METc number 2004.107).
Diagnostics In this cross-sectional study, all data were collected anonymously and within one week (ques-
tionnaire, neurohormone sampling, ECG, echocardiography). One physician collected data of
the patients’ medical history and (chronic) diseases of the cardiovascular, pulmonary, endo-
crine, neurodegenerative and skeletal muscle system, of their symptoms and medication. He
also examined blood pressure, height and weight and performed full physical examination (18).
Aside number and type of chronic disorder, we registered immobilization defined as being
wheelchair dependent or bedridden. We regarded immobilization as a consequence of the
chronic diseases on the individual and therefore as a parameter of progression of the present
chronic diseases. The diagnosis of chronic heart failure (CHF) was made by two experienced
cardiologists. A third colleague decided in cases of disagreement. Of note, the cardiologists
were unaware of resident’s BNP and NT-proBNP levels. A 12-lead electrocardiogram (ECG)
was made with the electrocardiograph Cardioline delta three plus (Cardioline, Milan, Italy,
www.cardioline.it), with the patient in a horizontal position.
The left-ventricular ejection fraction (LVEF) was assessed semi-quantitatively by the two-
dimensional visual estimate method (19). A LVEF ≤ 45% was considered to be a left-
115
ventricular systolic dysfunction (LVSD) or diminished LVEF(dLVEF). The hand held cardiograph
‘Opti Go’ (Philips, Eindhoven, The Netherlands, www.philips.com) was used. One blood sample
per resident (12 mL) was taken if one was fasting and at rest. Assessments of creatinine, hae-
moglobin and mean corpuscular volume (MCV) were performed in the NH laboratory. Since the
neurohormone levels may vary about 100% we choose not to repeat the neurohormone sam-
pling. For determination of levels of (NT-pro)BNP, a 5 µl aprotinine solution was adjusted to the
250 µl plasma samples in EDTA and to 250 µl serum samples. At the UMCG Clinical Chemi-
cal Laboratory (CCL) both were frozen at -20˚C and stored in batches for a maximum of 10
months. The assays were run in one go for both NT-proBNP and BNP. Both NT-proBNP and
BNP were measured by immunoassays (Elecsys®1010/2010/modular analytics 2004 Roche
diagnostics Indianapolis IN US, and AXSYM system® BNP 2003 Axis–shield diagnostics LTD
ABBOT Wiesbaden Germany). NT-proBNP and BNP had coefficients of variation of 3.3% and
7.8%(ranges of 5-35000 pg/mL and 0-3465 pg/mL respectively).
Renal function has been defined as estimated glomerular filtration rate (eGFR) measured by
the Cockcroft -Gault formula in mL/min.
Anemia was defined as haemoglobin (Hb) ≤ 7.5 mmol/l ≈12 g/dL (7). The status of death or
alive of each resident was recorded after one year following initial data collection.
Statistical analysis To address as to BNP and NT-proBNP predict one-year mortality in a cohort of old age with
multiple chronic diseases we used different statistic tests. Differences in basic characteristics of
survivors and non-survivors were analysed using Students ’t test, X 2 test or the Fisher exact
test for categorical data and the Mann-Whitney test for non-parametric continuous data, as ap-
propriate. The association between underlying diseases or immobilization and NT-proBNP and
BNP levels divided into tertiles, was tested with X2 statististics.
The adjusted value of the six predefined chronic diseases, immobilization, NT-proBNP and
BNP, unadjusted and adjusted for age and sex were estimated by means of Cox proportional
116
hazard regression analyses. The six chronic diseases were CHF all cases (or CHF with dLVEF
or CHF pLVEF), COPD, diabetes, renal dysfunction, neurodegenerative diseases, skeletal-muscle system diseases (Table 3).
Finally, both for NT-proBP and BNP, a mutually adjusted multivariate Cox proportional hazard
analysis was made with the covariates in the equation. The quantitative relationship between NT-proBNP and BNP levels and one-year mortality was expressed in Figure 1 and 2, respec-
tively.
Statistical analyses were performed using SPSS 12.0.1 software (SPSS Inc., 233 S. Wacker,
11th Floor, Chicago IL US). All statistical comparisons were two-tailed, and a p value <0.05 was
considered to be statistically significant.
RESULTS
A total of 93 (62%) individuals out of 140 residents were included. Individuals were excluded
because of cognitive impairment [30 (21%)], missing ECG data [2 (1.4%)], missing laboratory
values [1 (0.7%)], and unwillingness to participate [14 (10%)].
The mean age of the studied population was 81 ± 3 years and approximately 66% of the resi-dents were females (Table 1).
After a follow-up period of one year, 18/93 individuals died. Patients who survived did not differ
in age from non-survivors (80 ± 7 years and 81 ± 9 versus, p 0.796). In comparison with sur-
vivors, non-survivors had more often CHF (all cases), diabetes and higher BNP levels.
Out of the 10 non-survivors with CHF, two subjects had symptoms and eight had no symptoms
of heart failure, 4/10 had pLVEF and 6/10 dLVEF. BNP and NT-proBNP were elevated in
CHF compared to no-CHF, but only BNP differed significantly (median BNP in CHF 194, IQR
92-460 versus BNP in no-CHF 87, IQR 28-187 pg/mL (p<0.001) and NT-proBNP in CHF
1871, IQR 539-4262 versus NT-proBNP in no-CHF 324, IQR 163-1146 pg/mL (p< 0.001)).
117
Renal dysfunction (p 0.046 and p 0.004), CHF all cases (p 0.014 and p 0.004) and CHF
with dLVEF (p 0.018 and p 0.001) were more observed in the highest BNP and NT-proBNP tertiles (p-values respectively) (Table 2).
CHF all cases (P=0.014 and P=0.004) and CHF with dLVEF (P=0.018 and P=0.001) were
observed more in the highest BNP and NT-proBNP tertiles (P values respectively). BNP and
NT-proBNP predicted 1-year mortality significantly after adjustment for age, sex, the 6 chronic
diseases, and immobilization (with CHF all cases, the analysis had a hazard ratio [HR] of 1.67
and P=0.000, HR 0.60 and P=0.000; with CHF with pLVEF HR 1.76 and P=0.000, HR 2.06
and P=0.000; with CHF with dLVEF HR 1.03 and P=0.000, HR 0.93 and 4.86, respectively) (Table 3). The mortality risk was increasing at rising NT-proBNP and BNP levels. An increase
of 10 pg/mL BNP was related to a 2.2% rise of the HR of the mortality risk. Moreover, an in-
crease of 10 pg/mL NT-proBNP was associated with a 0.27% rise of the HR of mortality risk (Figures 1 and 2, Table 3).
DISCUSSION
The major finding of this study is that in NH-residents BNP and NT-proBNP are independent
predictors of mortality, after adjustment for age, sex, chronic diseases and immobilization. One
of the main characteristics of NH-residents is the presence of multiple morbid conditions. Resi-
dents have an average of four chronic diseases each. Moreover, CHF all cases and diabetes are more frequently represented in those who died, compared to those who did survive (Table
1). We had to consider the skewed distribution of BNP and NT-proBNP caused by extended
morbidity in a relatively small population. Therefore, medians instead of means of neurohor-
mones were used and an adjustment for all confounders of neurohormone levels was made as is presented in Table 2 and 3. After adjustment for all confounders, the neurohormones pre-
dicted one-year mortality significantly in NH-residents. Another aspect of morbidity, aside of
number and type is the progression of each chronic disease. In this study however we did not
register the progression of chronic diseases. To address this shortcoming we determined immo-
118
bilization as parameter of consequences of morbidity (22-24). Aside mortality risks as age and
sex, we had to count with chronic diseases and their consequences influencing individuals. So,
after adjustment for age, sex and morbidity, BNP and NT-proBNP still remained predictors of one-year mortality in nursing home residents (Table 3). Moreover, the quantitative relation be-
tween natriuretic peptides and mortality revealed high levels of natriuretic peptides required for prognosis compared to their use for diagnosis (Figure 1 and 2 ). For instance, an increase of
BNP or NT-proBNP with 10 pg/mL is related to an increase of mortality risk of 2,2% or 0.27%,
respectively. To date, there is a scarcity of reports on the value of BNP and NT-proBNP in eld-
erly in nursing homes. Comparisons with other populations should therefore only be made,
taken these flaws into account.
In NH residents BNP and NT-proBNP are of prognostic value at higher levels, compared to a
non-elderly population (25;26). In a study of ambulatory CHF patients (mean age 76 ±11
years) with preserved LVEF and with readmission or death for cardiac reasons as endpoints,
Valle et al. found predictive values of BNP at 200-499 and >500 pg/mL (HRs of 2.2 and
5.8) after six months follow-up (27). Though there were differences in design and population
between Valle’s and the present study, both studies suggest that BNP levels for prognostic use
were found to be two- to fourfold higher than advised for diagnostic purpose. Bibbins et al. found NT-proBNP to be a marker of long-term mortality, independently of other prognostic
markers. In subjects with stable coronary heart disease with a mean age of 67 to 72 ± 9 year,
they also found increasing mortality risks at incremental NT-proBNP levels (28). McKie et al. studied a younger community-based cohort without heart and renal failure (mean age of 62
years), and found BNP and NT-proBNP to be biomarkers for mortality at much lower levels
(biosite assay of BNP was 63 vs. 22 and NT-proBNP 206 vs. 63 pg/mL median levels, non-
survivors vs. survivors) (29). Regarding a different range, the relationship between increasing
mortality risk and elevating natriuretic peptide levels was comparable to our results (30).
Altogether, we have demonstrate in this study that BNP and NT-proBNP are of prognostic value
also in care dependent elderly with multiple morbidity. However, the cut-off points for prognostic
119
purpose of neurohormones seem higher and should be identified in future studies keeping track
on comorbidity. A limitation of the study is the small population of 93 nursing home residents, in
one centre. On the other hand, the population studied is representative of other nursing home
populations in terms of distribution of age, gender, diabetes, CHF, the use of ACE-inhibitor
therapy and number of chronic diseases, although not representative in terms of the presence of
hypertension and renal dysfunction (31-33).
CONCLUSION
In a cohort of NH-residents, BNP and NT-proBNP levels are independent predictors of one-year
mortality, after adjustment for age, sex, chronic morbidity and immobilization. In the respect of
the prognosis, mortality risk increases with elevated natriuretic peptide levels. We postulate that
plasma levels of BNP and NT-proBNP are also of use to predict prognosis in institutionalized
elderly with multiple co-morbidities.
ACKNOWLEDGEMENTS
All authors had no conflict of interest. Fund: This study was subsidised by the “Vereniging het
Zonnehuis”, Soesterberg, The Netherlands. Financial disclosure: All contributors have no con-
flict of interest to disclose.
120
Table 1. Baseline characteristics of NH residents, survivors compared to non-survivors.
Survivors Non-survivors P value
Number (% of 93) 75 (81) 18 (19)
Age (year) mn±SD 80 ± 7 81 ± 9 0.796
Female 49 (53) 12 (13) 0.740
BP diastolic mmHg mn±SD 80 ± 12 74 ± 11 0.050
BP systolic mmHg mn±SD 142 ± 26 133 ± 23 0.155
Hemoglobin mmol/l mn±SD 7.7 ± 1 7.4 ± 1 0.352
Creatinine umol/l mn±SD 76 ± 27 102 ± 78 0.175
Body mass index kg/m2 mn±SD 26 ± 6 23 ± 3 0.780
LVEF % mn±SD 52 ± 8 49 ± 10 0.254
CHF all cases 13 (14) 10 (10) 0.007
CHF reduced ejection fraction 10 (11) 6 (6) 0.053
CHF preserved ejection fraction 3 (3) 4 (4) 0.190
chronic obstructive pulmonary d. 17 (18) 7 (7) 0.161
Diabetes mellitus type 2 16 (17) 9 (9) 0.038
renal dysfunction 11 (12) 7 (7) 0.066
neurological disorders 39 (41) 7 (7) 0.231
skeletal-muscle disorders 35 (37) 4 (4) 0.060
immobilization 26 (27) 9 (9) 0.232
BNP pg/mL md (IQR) 87 (27 -162) 138 (49 – 753) 0.029
NT-proBNP pg/mL md (IQR) 335 (175-900) 1382 (193-5683) 0.059
Data are numbers (% of the 93 subjects) unless otherwise indicated. BP, blood pressure; im-
mobilization, subjects in wheelchair or bed; md IQR, median with interquartile range; NT-
proBNP, N-terminal-pro B-type natriuretic peptide; BNP, B-type natriuretic peptide.
121
Table 2. BNP and NT-proBNP concentrations divided in tertiles and linear related to chronic
diseases and immobilization.
Tertiles
total
% of 93
BNP
I
%
II
%
III
%
P
NT-
pro
I
%
BNP
II
%
III
%
P
COPD 25 8 13 4 0.276 11 8 6 0.507
diabetes 26 12 6 8 0.433 13 5 8 0.254
RD 19 2 8 9 0.046 2 5 12 0.004
MD 41 17 15 9 0.089 16 13 12 0.443
ND
CHF all
CHFpEF
CHFrEF
Immobilization
48
24
6
18
36
15 4
1
3
11
18 6
2
4
15
15 14
3
11
10
0.904 0.014
0.559
0.018
0.870
18 3
2
1
10
11 6
1
5
12
19 15
3
12
14
0.800 0.004
0.586
0.001
0.434
BNP, B-type natriuretic peptide; NT-proBNP, N-terminal-proBNP; COPD, chronic obstructive
pulmonary disease; RD, renal dysfunction; MSD, musculoskeletal disorder; ND, neurological
disorders; CHF, chronic heart failure; CHFpEF, CHF with preserved ejection fraction; HFrEF,
CHF with reduced.
122
Table 3. Association of BNP and NT-proBNP with 1-year mortality after adjustment for mor-tality risk factors. Neuro- Hormone, NH
HR
BNP 95% CI
P
HR
NT-proBNP 95% CI
P
NH, unadjusted 1.22 1.13-1.32 0.000 1.03 1.02-1.04 0.000 NH, age and sex adj. 1.23 1.13-1.33 0.000 1.03 1.02-1.04 0.000 NH, age and sex adj.+ each of the following added 1 at a time:
CHF all* 1.18 1.08-1.29 0.000 1.02 1.01-1.04 0.000 CHFpEF* 1.20 1.10-1.30 0.000 1.03 1.01-1.04 0.000 CHFrEF* 1.19 1.09-1.30 0.003 1.03 1.01-1.04 0.001 diabetes mellitus type2 1.20 1.09-1.31 0.000 1.03 1.01-1.04 0.000 COPD 1.18 1.08-1.29 0.000 1.02 1.01-1.04 0.000 Renal disorders 1.18 1.08-1.29 0.000 1.02 1.01-1.07 0.000 muscular-skeletal d. 1.17 1.07-1.30 0.001 1.02 1.01-1.06 0.000 neurological disorders 1.15 1.04-1.27 0.004 1.02 1.01-1.06 0.001 Immobilization 1.16 1.05-1.28 0.003 1.02 1.01-1.07 0.001 All diseases 1.16 1.05-1.28 0.003 1.02 1.01-1.07 0.001
CHF, chronic heart failure; * only 1 of them is in the model; CHFpEF, CHF with preserved
ejection fraction; CHFrEF, CHF with reduced EF; COPD, chronic obstructive pulmonary disease
; d. disorders; HR, hazard ratios; CI, confidence interval; BNP, B-type natriuretic peptide; NT-
proBNP, amino-terminal pro natriuretic peptide.
123
BNP pg/ml
0 100 200 300 400 500 600 700 800
Fitte
d Ha
rzar
d Ra
tio
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Figure 1. Hazard ratio’s (HR) of BNP and 1-year mortality risk. HR of B-type natriuretic pep-tide, BNP (X) and mortality risk (Y) with confidence intervals (Cl 3 and Cl 4) presenting the quantitative relation of mortality at increasing BNP. The BNP range is limited to fit in this graph. HR 1 is at BNP level 87 pg/mL.
NT-proBNP pg/ml
0 1000 2000 3000 4000 5000
Fitte
d Ha
rzar
d Ra
tio
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Figure 2. Hazard ratio’s (HR) of N-terminal-proB-type natriuretic peptides, NT-proBNP and
1-year mortality risk. HR according to Nt-proBNP range from 0 to 5000 pg/mL are depicted.
Maximum Nt-proBNP level is fitted to this graph. HR 1 is at Nt-proBNP 450 pg/mL.
124
References
1 Price GM, Uauy R, Breeze E, Bulpitt CJ, Fletcher AE. Weight, shape, and mortality risk
in older persons: elevated waist-hip ratio, not high body mass index, is associated with
a greater risk of death. Am J Clin Nutr 2006;84(2):449-60.
2 Sullivan DH, Roberson PK, Bopp MM. Hypoalbuminemia 3 months after hospital
discharge: significance for long-term survival. J Am Geriatr Soc 2005;53(7):1222-6.
3 van Dijk PT, Mehr DR, Ooms ME, Madsen R, Petroski G, Frijters DH, et al.
Comorbidity and 1 year mortality risks in nursing home residents. J Am Geriatr Soc
2005;53(4):660-5.
4 Wallen T, Landahl S, Hedner T, Nakao K, Saito Y. Brain natriuretic peptide predicts
mortality in the elderly. Heart 1997;77(3):264-7.
5 Yan LL, Daviglus ML, Liu K, Stamler J, Wang R, Pirzada A, et al. Midlife body mass
index and hospitalization and mortality in older age. JAMA 2006;295(2):190-8.
6 Taylor JA, Christenson RH, Rao K, Jorge M, Gottlieb SS. B-type natriuretic peptide and
N-terminal pro B-type natriuretic peptide are depressed in obesity despite higher left
ventricular end diastolic pressures. Am Heart J 2006;152(6):1071-6.
7 Richards M, Troughton R, Lainchbury J, Doughty R, Wright S. Health gains by using
natriuretic peptides in diagnosis, prognosis and treatment. Scand J Clin Lab Invest
Suppl 2005;240:129-37.
8 Valle R, Aspromonte N, Feola M, Milli M, Canali C, Giovinazzo P, et al. B-type
natriuretic peptide can predict the medium-term risk in patients with acute heart failure
and preserved systolic function. J Card Fail 2005;11(7):498-503.
125
9 Wang R, Mouliswar M, Denman S, Kleban M. Mortality of the institutionalized old-old
hospitalized with congestive heart failure. Arch Intern Med 1998;158(22):2464-8.
10 Witham MD, Gillespie ND, Hutcheon SD, Struthers AD, McMurdo ME. B-type
natriuretic peptide is associated with mortality in older functionally impaired patients. J
Am Geriatr Soc 2005;53(11):1991-5.
11 deFilippi CR, Seliger SL, Maynard S, Christenson RH. Impact of renal disease on
natriuretic peptide testing for diagnosing decompensated heart failure and predicting
mortality. Clin Chem 2007;53(8):1511-9.
12 Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC, Jr.
Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll
Cardiol 2002;40(5):976-82.
13 Kiely DG, Kennedy NS, Pirzada O, Batchelor SA, Struthers AD, Lipworth BJ. Elevated
levels of natriuretic peptides in patients with pulmonary thromboembolism. Respir Med
2005;99(10):1286-91.
14 Bozkanat E, Tozkoparan E, Baysan O, Deniz O, Ciftci F, Yokusoglu M. The
significance of elevated brain natriuretic peptide levels in chronic obstructive pulmonary
disease. J Int Med Res 2005;33(5):537-44.
15 Robinson BE. Epidemiology of chronic kidney disease and anemia. J Am Med Dir
Assoc 2006;7(9 Suppl):S3-S6.
16 Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive
review. J Am Geriatr Soc 1992;40(9):922-35.
17 Shamsham F, Mitchell J. Essentials of the diagnosis of heart failure. Am Fam
Physician 20001;61(5):1319-28.
126
18 Quinones MA, Waggoner AD, Reduto LA, Nelson JG, Young JB, Winters WL, Jr., et
al. A new, simplified and accurate method for determining ejection fraction with two-
dimensional echocardiography. Circulation 1981;64(4):744-53.
19 K/DOQl clinical practice guidelines for chronic kidney disease: Evaluation,
classification, and stratification Am J Kidney Dis 2002;39:S1-266.
20 Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. JAMA
1999;281(18):1714-7.
21 Badley EM. An introduction to the concepts and classifications of the international
classification of impairments, disabilities, and handicaps. Disabil Rehabil
1993;15(4):161-78.
22 Johnston M, Pollard B. Consequences of disease: testing the WHO International
Classification of Impairments, Disabilities and Handicaps (ICIDH) model. Soc Sci Med
2001;53(10):1261-73.
23 Porock D, Oliver DP, Zweig S, Rantz M, Mehr D, Madsen R, et al. Predicting death in
the nursing home: development and validation of the 6-month Minimum Data Set
mortality risk index. J Gerontol A Biol Sci Med Sci 2005;60(4):491-8.
24 Galasko GI, Lahiri A, Barnes SC, Collinson P, Senior R. What is the normal range for
N-terminal pro-brain natriuretic peptide? How well does this normal range screen for
cardiovascular disease? Eur Heart J 2005;26(21):2269-76.
25 Valle R, Aspromonte N, Feola M, Milli M, Canali C, Giovinazzo P, et al. B-type
natriuretic peptide can predict the medium-term risk in patients with acute heart failure
and preserved systolic function. J Card Fail 2005;11(7):498-503.
127
26 Valle R, Aspromonte N, Barro S, Canali C, Carbonieri E, Ceci V, et al. The NT-
proBNP assay identifies very elderly nursing home residents suffering from pre-clinical
heart failure. Eur J Heart Fail 2005;7(4):542-51.
27 Bibbins-Domingo K, Gupta R, Na B, Wu AH, Schiller NB, Whooley MA. N-terminal
fragment of the prohormone brain-type natriuretic peptide (NT-proBNP),
cardiovascular events, and mortality in patients with stable coronary heart disease.
JAMA 2007;297(2):169-76.
28 McKie PM, Rodeheffer RJ, Cataliotti A, Martin FL, Urban LH, Mahoney DW, et al.
Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide: biomarkers
for mortality in a large community-based cohort free of heart failure. Hypertension
2006;47(5):874-80.
29 Heckman GA, Misiaszek B, Merali F, Turpie ID, Patterson CJ, Flett N, et al.
Management of heart failure in Canadian long-term care facilities. Can J Cardiol
2004;20(10):963-9.
30 Mair J, Friedl W, Thomas S, Puschendorf B. Natriuretic peptides in assessment of left-
ventricular dysfunction. Scand J Clin Lab Invest Suppl 1999;230:132-42.
31 Mann JL, Evans TS. A review of the management of heart failure in long-term care
residents. Consult Pharm 2006;21(3):222-8.
32 Nygaard HA, Naik M, Ruths S, Kruger K. Clinically important renal impairment in
various groups of old persons. Scand J Prim Health Care 2004;22(3):152-6.
128
129
Chapter 4
CHRONIC HEART FAILURE, RELATED TO HELP AT ACTIVITIES OF
DAILY LIVING IN NURSING HOME RESIDENTS. Barents M, Hillege HH, Muskiet FA, de Jongste MJ.
Activities, Adaptation & Aging 2011;35(2):98-110.
130
ABSTRACT
It is unknown whether CHF is associated with ADL–functioning in nursing home residents there-
fore we studied that association.
METHOD. 103 residents were screened on age, sex, comorbidity, and CHF. ADL-dependence
and ADL-help were scored with the use of Minimum Data Set (MDS)-items of the Resident
Assistant Instrument. Logistic multivariate regressions of ADL-dependence and ADL-help were
performed with age, sex, CHF and comorbidity as independent variables.
RESULTS. age 78 ± 11 years. 24/103 had CHF (23%). CHF was associated with ADL-help
(OR 4.68 and p=0.015) after multivariable adjustment.
CONCLUSION. CHF is associated with increase of ADL-help given to nursing home residents.
CHF is of importance for both residents (loss of autonomy and life satisfaction) and organiza-
tion (workforce planning).
131
INTRODUCTION
Chronic heart failure (CHF) is a major public health care problem in the developed world be-
cause it prevails mostly at high age and takes up quite a part of public health care expenses.
Chronic heart failure is an underestimated diagnosis.
In the United States (US), nearly 5 million patients are suffering of CHF (1). CHF is primarily a
disease of the elderly. In the US and Europe, CHF affects about 1% of persons in their 50s and
rises progressively with age to afflict 10% of persons in their 80s (2). In Canadian and Dutch
nursing homes, the CHF prevalence is higher than in independent living elderly and valued at
15-23% (3;4). In North America, CHF is responsible for large health care costs (1;4;5). In de-
veloped countries, health care expenses on CHF consumes 1-2% of the entire health care
budget. In Sweden and The Netherlands, the costs of public health care are increasing gradu-
ally (5). Health care expenses consist primarily of hospitalization costs followed by costs of
care.
As noted, CHF is often undetected or incorrect diagnosed for several reasons. The key symp-
toms fatigue and dyspnea are unspecific. Older adults attribute fatigue to their age or chronic
diseases in case of multimorbidity. Fatigue and effort intolerance are gradually different symp-
toms. Oxygen poverty related to the body’s need causes fatigue and effort intolerance. Dyspnea
is often taken for chronic obstructive pulmonary disease (COPD) (7). So the lack of symptom
specificity and the contribution of symptoms to aging lead often to under diagnosis of heart fail-
132
ure. Another problem is that diagnostic tests (B-type natriuretic peptide (BNP) exclude but does
not determine CHF in older adults with multimorbidity (3;8). At last, echocardiography is not
easy accessible.
From literature, we know that CHF patients need care at activities of daily life (ADL) because
decreased effort tolerance (9;10). In independent elderly ADL-ability is vital in providing for life
satisfaction (11). Thus, care givers need to know whether persons suffer from CHF not only
from treatment but also from ADL-ability and quality of life point of view.
ADL-ability can be measured by the Resident Assisted Instrument (RAI). RAI is a core set of
assessments developed to provide a picture of, under other things, each nursing home resi-
dent’s ADL-ability (12). Care attendants observe and score specific ADL-settings. They also fill
in standardized diagnoses. RAI is widely used in American and European nursing homes as aid
for staff and care attendants (13). Remarkably, RAI does not contain CHF as standardized di-
agnosis so nursing home staffs which use RAI do not take CHF into account for care planning
and might overestimate ADL-ability of residents with CHF.
In The Netherlands, three questions gave rise to a study of CHF in nursing home residents
(residents): first, we expected under- and incorrect CHF diagnoses also in residents according
to literature in primary care (7). Second and third, the CHF prevalence in residents and the
CHF consequences on ADL-ability were unknown. Results of the first two questions studied
133
were described elsewhere (3;8). Third, we knew that Dutch nursing home staffs didn’t take
CHF into account for care level calculations. Consequently residents with CHF might be under-
valued concerning ADL-functioning and the care planning might be underestimated concerning
residents suffering CHF. We didn’t know whether CHF is associated with ADL–functioning in
residents. Subsequently, we sought to study the association of CHF to ADL-functioning in this
nursing home. We screened residents of one nursing home on CHF, scored ADL-ability with
RAI and compared residents with and without CHF on ADL-ability.
METHODS
Design
This mono-centre study had a non-randomized, prospective screening study design. The Medi-
cal Ethical Commission of the University Medical Centre of Groningen (UMCG) approved the
study under number 2004.107.
Subjects
The study population consisted of 150 residents who stayed in nursing home the “Zonnehuis-
groep Noord” in Zuidhorn, Netherlands between September 2004 and May 2005. The inclusion
criteria were competency (the resident understood the impact of study participation on himself),
age 65 years and over and signing the informed consent. The Mini Mental State Estimation
(MMSE 30) was administered with a required MMSE score of at least 21 when the resident's
134
competency was in doubt (14). The exclusion criteria were age under 65 years, serious apha-
sia, MMSE < 21, metastatic carcinomas and absence of echocardiogram or blood sample.
Data collection
Data of all subjects consisted of a) medical history from medical records, b) standardized
physical examination, c) electrocardiogram and echocardiogram, d) blood tests and e) ADL-
scores.
We collected all data of each person within one week. One physician-investigator summarized
medical history except CHF and performed physical examinations. We categorized the chronic
diseases (comorbidity) on the basis of six organ systems to limit the number of variables. The
six disease categories were chronic obstructive pulmonary diseases (COPD), diabetes, neuro-
logical diseases (ND), muscular-skeletal diseases (MSd), chronic renal dysfunction (CRD) and
blindness. ND comprised of cerebrovascular accidents (CVA), multiple sclerosis, amyotrophic
lateral sclerosis, Parkinson’s disease, ataxia, spasms, neuropathies and paresis /paralysis.
MSd included artrosis, hip artroplasty and all fractures in the past six months, (rheumatism)
arthritis, deformations of body and extremities and myopathies. CRD was defined as creatinine-
clearance ≤ 50 mL/min (Cockgroft-Gault formula). A panel of cardiologists diagnosed CHF on
the basis of medical history, symptoms, electrocardiogram, echocardiogram and blood tests.
This diagnostic method was the golden standard for CHF.
135
Standardized physical examination b) comprised examination of the cardiac pulmonary and
skeletal muscle system, height and weight.
c) Physician assistants made 12-lead-electrocardiograms (ECG) and echocardiographists
echocardiograms on location. The echocardiogram [Opti Go (www.philips.com)] estimated the
left ventricular ejection-fraction (LVEF, percentages) two-dimensionally and visually. We de-
fined a LVEF≤ 45% as left ventricular systolic dysfunction (LVSD) (15). Blood tests d) con-
sisted of a one-time-assessment of haemoglobin (Hb), mean corpuscular volume (MCV) and
creatinine.
Care attendants scored e) ADL divided in ADL-dependence (ADL-D) and ADL-help (ADL-H).
They observed dependence (D) and help (H) during four specified ADL-settings as toilet using,
eating, performing personal hygiene and walking on the ward. They scored dependence level
(D) of the resident and amount of help (H) given to the resident during these four ADL-settings
in the last seven days. ADL-D had a six-point scale so sum scores varied from 0 to 24. ADL-H
had a three-point scale so sum scores varied from 0 to 12.
Higher scores indicated more dependence and help (Table 1). Afterwards, we condensed ADL-
D and ADL–H scores each to ranges from 0 to 6, as advised by experts (www.prismant.nl). In
this way, a data set arose which is known as Minimal Data Set of the Resident Assistant In-
strument (RAI) (16-18). We selected the RAI for ADL measurements because its relative reli-
ability and validity in nursing homes. And, because the care attendants of this nursing home had
experience with RAI (8-10;13;19;20). Blood samples d) were taken from residents at rest and
136
in fasting condition, stored at -20 C° and analyzed in one go by the Laboratory Noord
(www.laboratoriumnoord.nl) to optimize validity.
Statistics
Statistical analyses were performed using SPSS 15.0.01. The question was whether CHF was
associated to more ADL-dependence and ADL-help compared to residents without CHF. Differ-
ences in base characteristics of residents with and without CHF were calculated using Student’s
t, chi-square and the Mann-Whitney test for nonparametric continuous data, as appropriate
(Table 2). Correlations between variables were calculated by Spearman’s correlation coefficient
ro (Table 3). Univariate and multivariate logistic regression analyses were made of ADL-D and
ADL-H. Age, sex, CHF and 6 chronic diseases were put in the analyses. We used the Enter-
method since this method matched theory testing best (Table 4 and 5). All statistical compari-
sons were two-tailed, and a p value <0.05 was considered to be statistically significant.
RESULTS
In total, 150 residents were recruited of whom 47 were excluded. Of the 47 excluded, 14 re-
fused participation, 30 had cognitive impairment or aphasia, 2 had inaccessible echocardiogram
frames and 1 refused to let take blood (1). Thus, 103 residents were recruited of whom 39 men
and 74 women. The distribution of age and sex did not differ between the included and ex-
cluded residents (age 78 ± 11 versus 79 ± 12, p=0.703 and sex male/female 37/63 versus
137
30/70, p=0.340 respectively). Each resident had 2 ± 1 chronic diseases in average with a
distribution of 0-6 not including CHF. Two percentages residents had no other chronic disease
(only CHF), 18% had one chronic disease, 40% had two, 28% had three and 12% had four to
six chronic diseases. The CHF group had more often chronic renal dysfunction as compared to
the non-CHF group (p=0.032). CHF involved more ADL-D and ADL-H compared to residents
without CHF (p=0.005 and p=0.009)(Table 2). For significant correlations see Table 3.
In univariate analyses, CHF was significantly associated with ADL-H after adjustment for sex
and age [odds ratio (OR)=4.44 confidence interval (CI)1.45 – 13.60; p=0.009 and OR=4.46
(CI 1.44-13.88); p=0.015, respectively].
In multivariate analyses, CHF was significant associated with ADL-H after adjustment for sex,
age and 6 chronic diseases [OR=4.68 (CI 1.35- 16.17); p=0.015](Table 5).
DISCUSSION
The question of this study is whether chronic heart failure is associated with ADL-dependence
and ADL-help in nursing home residents. We found that CHF is clearly associated with ADL-
help after adjustment for age, sex and comorbidity [OR=4.68 (CI 1.35- 16.17), p=0.015]. We
also found that CHF is not associated with ADL-dependence. The somatic chronic diseases
examined are neither associated with ADL-dependence nor ADL-help in this population.
138
What does an increase of ADL-help imply for resident and organization? At first, reception of
ADL-help implies loss of autonomy, also for residents. Second, ADL-ability is a determinant for
life satisfaction probably also in residents. Therefore, for the resident point of view, each in-
crease of ADL-help makes the difference between an autonomic or assisted performance of
ADL-activities, such as use of toilet. Thus, a resident will experience each increase of ADL-help
as loss of autonomy and life satisfaction. Each increase of ADL-help is therefore clinically most
relevant (11;12).
For the organization point of view, an increase of ADL-help means that the resident need one
or two additional care attendants. This affects the workforce planning. Thus, an increase of
ADL-help is most important for resident and organization.
Why are the six chronic diseases examined not associated with ADL-dependence and ADL-help
while some of them occur frequently? The disease category might be underestimated when
residents have more than one disease within the category. In such cases the disease merely
count as one chronic disease. Moreover, the categorization of chronic diseases used does not
represent the client’s disease burden. Generalization for the sake of categorization may have
led to the absence of significant associations of each of the six chronic diseases with ADL-
dependence and ADL-help.
How does the result that ADL-help is determined by CHF relate to literature? In his primary
care study on ADL and motor skills, Norberg finds that senior citizens with CHF are not de-
139
pendent on their personal hygiene but are in 75% of the cases dependent and get help with
putting on and taking off their compression stockings and shoes (21). Chen finds an increase in
ADL-help at 7 ADL-items from MDS, in institutionalized CHF residents (mean age 91 years), in
their final year of life (22). Scilley and Owsley prove the relation between impaired eyesight and
ADL-dependence in nursing home residents (23). Altogether, for the greater part, the results of
this study are supported by other studies. Is it possible that the etiological categorization of
chronic disorders influences its results? Is one of the chronic disorders related to CHF or are
they interrelated by a common pathophysiology such as vascular disorders? Kriegsman shows
indeed that, in the case of several chronic disorders, a common etiology leads to less loss of
function and a different etiology leads to more loss of function (9).This mono-centre study is
limited in its small population (# 103). However, when compared with two other Dutch nursing
home populations, our study population was representative in terms of distribution of age, sex,
hypertension and diabetes but not in terms of renal dysfunction (24;25). A bias on the part of
one physician-investigator who collected the data is possible. But this seems unlikely since she
did not assess electrocardiograms. Moreover, she was blinded for the final diagnoses made by
the cardiologist’ panel. Another possible limitation of the study might be that depression and
psychotropic drug use are left out of the analysis. The potential influence of these variables on
ADL-help has to be taken in consideration in further studies. The relevance of this study is that
CHF is associated to increase of ADL-help in this nursing home population. Therefore, the di-
agnosis of CHF is of importance both for resident (loss of autonomy and life satisfaction) and
organization (workforce planning). Further studies on CHF in relation to ADL are needed in lar-
140
ger NH populations. Also, subgroup analysis of CHF related to ADL are needful because it is
unknown whether only CHF with decreased LVEF is related to more ADL-help and not CHF
with preserved LVEF.
CONCLUSION
CHF is associated with increase of ADL-help given to nursing home residents. CHF is of impor-
tance for both residents (loss of autonomy and life satisfaction) and organization (workforce
planning).
ACKNOWLEDGEMENTS
The “Vereniging het Zonnehuis”, Bilthoven, The Netherlands granted the study. This study was
subsidised by the “Vereniging het Zonnehuis”, Bilthoven, The Netherlands. The authors have no
conflict of interest.
141
Table 1. Scores of ADL-dependency (ADL-D) and ADL-help (ADL-H) of MDS-items (Mini-
mum Data Set) from the Resident Assistant Instrument (RAI).
scores definition
Activities of daily living-
dependence 0 independent
1 care attendance, relatively independent
2 some help, mild restrictions
3 extensive help (with lifting) by 1 person
4 extensive help (with lifting) by 2 persons
5 dependent
6 total dependent
Activities of daily living-help 0 no help, no care needed
1 care attendance, verbal support
2 physical help by 1 person
3 physical help by 2 or more persons
Activities of daily living is scored from 0-6; Activities of daily living-help is scored from 0-3.
142
Table 2. Baseline characteristics of nursing home residents (n=103).
variables all % CHF+ % 103 CHF- % 103 P
number 103 (100) 24 (23) 79 (77)
age years, mean±SD
sex male (%)
Comorbidity COPD (%)
diabetes m. type 2(%)
neurological d. (%)
muscular-skeletal(%)
Renal dysfunction (%)
blind (%)
Physical examination tension systolic mn±SD
tension diastolic mn±SD
BMI kg/cm2, mean±SD
Blood tests Hb mmol/L, mean±SD
ADL scores ADL-D median, iqr
ADL-H median, iqr
78
39
25
26
52
44
77
3
141
80
25
7.7
2
5
(11)
(37)
(24)
(25)
(50)
(43)
(32)
(3)
(22)
(13)
(5)
(1.0)
(1-4)
(3-7)
80
11
6
9
15
7
12
0
143
78
26
7.8
4
6
(9)
(46)
(25)
(38)
(47)
(29)
(12)
(0)
(27)
(13)
(5)
(1.3)
(2-5)
(3-8)
78
18
19
17
37
37
21
3
140
81
25
7.7
2
4
(11)
(23)
(24)
(22)
(47)
(47)
(20)
(4)
(21)
(13)
(5)
(0.9)
(0-4)
(2-7)
0.351
0.358
0.925
0.114
0.181
0.096 0.032
0.083
0.534
0.590
0.897
0.834
0.005
0.009
Characteristics in numbers (percentage) unless otherwise indicated. COPD, chronic obstructive
pulmonary disorders; ND, neurological disorders; MD, musculoskeletal disorders; BMI, body
mass index; ADL, activities of daily living; ADL-D, ADL-dependence; ADL-H, ADL-help.
143
Table 3. Significant inter-variable correlations of age, sex, chronic disorders and CHF.
variable with variable correlation r p
chronic heart failure renal dysfunction 0.21 0.031
chronic heart failure ADL-dependence 0.28 0.004
chronic heart failure ADL-help 0.29 0.030
renal dysfunction age 0.42 0.000
neurological disorders ADL- dependence 0.21 0.032
neurological disorders musculoskeletal disorders 0.36 0.000
neurological disorders sex 0.25 0.010
ADL- dependence ADL-help 0.80 0.000
sex sex 0.23 0.020
ADL, activities of daily living.
144
Table 4. Associations of ADL-dependence (ADL-D) and age (univariate), sex (univariate),
CHF (age and sex adjusted) and each of the six chronic diseases (age and sex adjusted).
ADL-D
uni va-
riate OR
95% CI
P
age sex adj. OR
95% CI
P
multi varia-
te
OR
95% CI
P
age 1.00 0.96- 1.06 0.808 1.00 0.95-1.06 0.861
sex 0.72 0.26- 2.01 0.527 1.07 0.32-0.59 0.913
CHF 2.55 0.86- 7.54 0.092 2.45 0.82-7.35 0.110 2.43 0.73-8.14 0.149
COPD
0.87 0.26- 2.93 0.823 0.81 0.24-2.80 0.744 0.85 0.22-3.30 0.813
T2DM 1.63 0.54- 4.88 0.387 1.64 0.54-4.94 0.383 1.49 0.45-4.93 0.516
CRD 1.95 0.60-6.35 0.267 1.84 0.51-6.70 0.352 1.04 0.23-4.65 0.958
ND 0.93 0.32-2.75 0.897 1.12 0.32-3.87 0.862 1.93 0.47-7.93 0.361
MSd 0.32 0.10- 1.06 0.062 0.33 0.10-1.09 0.069 0.48 0.13-1.79 0.274
blind 10.50 0.90-122.81 0.061 9.72 0.82-115.67 0.072 10.73 0.73-158.83
0.084
CHF, chronic heart failure; COPD, chronic obstructive pulmonary disorders; T2DM, diabetes
mellitus; CRD, chronic renal dysfunction; ND, neurological disorders; MD, musculoskeletal dis-
orders; OR, odds ratio; CI, confidence interval; P, P-value.
145
Table 5. Associations of ADL-help (ADL-H) and age (univariate), sex (univariate), CHF (age and sex adjusted) and each of the six chronic diseases (age and sex adjusted).
ADL-H uni vari-
ate OR
95% CI
P
age sex adj. OR
95% CI
P
multi vari-
ate OR
CI
P
age 0.97 0.94-1.09 0.722 1.01 0.95-1.07 0.736 sex 1.07 0.23-4.51 0.982 0.88 0.24-3.21 0.848 CHF 4.44 1.45-13.60 0.009 4.46 1.44-13.88 0.010 4.68 1.35-16.17 0.015 COPD 0.68 0.18-2.62 0.577 0.65 0.17-2.53 0.534 0.60 0.14-2.62 0.497 T2DM 2.01 0.65-6.21 0.225 2.04 0.66-6.31 0.218 1.80 0.52-6.32 0.353 RD 1.60 0.45-5.65 0.465 1.52 0.39-6.00 0.548 0.97 0.21-4.56 0.968 ND 1.32 0.45-3.85 0.616 0.39 0.07-2.19 0.285 0.50 0.06-4.16 0.524 MS 0.56 0.18-1.75 0.317 0.56 0.78-1.75 0.316 0.75 0.20-2.83 0.673 blind 2.83 0.24-3.24 0.407 2.82 0.23-34.16 0.415 6.73 0.41-110.65 0.182 CHF, chronic heart failure; COPD, chronic obstructive pulmonary disorders; T2DM, diabetes
mellitus ; CRD, chronic renal dysfunction; ND, neurological disorders; MD, musculoskeletal dis-
orders; OR, odds ratio; CI, confidence interval; P, P-value.
146
Figure 1. ADL-dependence of residents with and without chronic heart failure.
M, median; IQR, interquartile range; CHF, chronic heart failure; ADL, activities of daily living.
.
Figure 2. ADL-help of residents with and without chronic heart failure.
M, median; IQR, interquartile range; CHF, chronic heart failure; ADL, activities of daily living.
147
References
1 Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA,
et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart
Failure 2008 of the European Society of Cardiology. Developed in collaboration with the
Heart Failure Association of the ESC (HFA) and endorsed by the European Society of
Intensive Care Medicine (ESICM). Eur Heart J 2008;29(19):2388-442.
2 Kelder JC, Cowie MR, McDonagh TA, Hardman SM, Grobbee DE, Cost B, et al.
Quantifying the added value of BNP in suspected heart failure in general practice: an
individual patient data meta-analysis. Heart 2011;97(12):959-63.
3 Wright SP, Doughty RN, Pearl A, Gamble GD, Whalley GA, Walsh HJ, et al. Plasma
amino-terminal pro-brain natriuretic peptide and accuracy of heart-failure diagnosis in
primary care: a randomized, controlled trial. J Am Coll Cardiol 2003;42(10):1793-800.
4 Cowie MR, Mosterd A, Wood DA, Deckers JW, Poole-Wilson PA, Sutton GC, et al. The
epidemiology of heart failure. Eur Heart J 1997 Feb;18(2):208-25.
5 Hobbs RE. Guidelines for the diagnosis and management of heart failure. Am J Ther
2004;11(6):467-72.
6 Zaphiriou A, Robb S, Murray-Thomas T, Mendez G, Fox K, McDonagh T, et al. The
diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary
care with suspected heart failure: results of the UK natriuretic peptide study. Eur J Heart
Fail 2005;7(4):537-41.
7 Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. JAMA
1999;281(18):1714-7.
148
8 Achterberg WP, Holtkamp CC, Kerkstra A, Pot AM, Ooms ME, Ribbe MW.
Improvements in the quality of co-ordination of nursing care following implementation of
the Resident Assessment Instrument in Dutch nursing homes. J Adv Nurs
2001;35(2):268-75.
9 Holtkamp CC, Kerkstra A, Ooms ME, van CC, Ribbe MW. Effects of the implementation
of the Resident Assessment Instrument on gaps between perceived needs and nursing
care supply for nursing home residents in The Netherlands. Int J Nurs Stud
2001;38(6):619-28.
10 Morris JN, Murphy K, Nonemaker S. Interrai resident assesment instrument versie 2.0
gebruikershandleiding. Utrecht: SIG zorginformatie Mailiebaan 50 3508 SC Utrecht The
Netherlands; 96 A.D.
11 Mutasingwa DR, Ge H, Upshur RE. How applicable are clinical practice guidelines to
elderly patients with comorbidities? Can Fam Physician 2011;57(7):e253-e262.
12 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al.
Diagnosis and management of the metabolic syndrome: an American Heart
Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation
2005;112(17):2735-52.
13 Barents M, van der Horst IC, Voors AA, Hillege JL, Muskiet FA, de Jongste MJ.
Prevalence and misdiagnosis of chronic heart failure in nursing home residents: the role
of B-type natriuretic peptides. Neth Heart J 2008;16(4):123-8.
14 Voors AA, Walma EP, Twickler TB, Rutten FH, Hoes AW. [Multidisciplinary guideline
'Heart failure 2010']. Ned Tijdschr Geneeskd 2011;155:A2957.
149
15 Barents M, van der Horst IC, Voors AA, Hillege JL, Muskiet FA, de Jongste MJ.
Prevalence and misdiagnosis of chronic heart failure in nursing home residents: the role
of B-type natriuretic peptides. Neth Heart J 200;16(4):123-8.
16 Mason JM, Hancock HC, Close H, Murphy JJ, Fuat A, de BM, et al. Utility of biomarkers
in the differential diagnosis of heart failure in older people: findings from the heart failure
in care homes (HFinCH) diagnostic accuracy study. PLoS One 2013;8(1):e53560.
17 Oudejans I, Mosterd A, Bloemen JA, Valk MJ, van VE, Wielders JP, et al. Clinical
evaluation of geriatric outpatients with suspected heart failure: value of symptoms, signs,
and additional tests. Eur J Heart Fail 2011;13(5):518-27.
18 Fernhall B. Long-term aerobic exercise maintains peak VO(2), improves quality of life,
and reduces hospitalisations and mortality in patients with heart failure. J Physiother
2013 ;59(1):56.
19 Dontje ML, van der Wal MH, Stolk RP, Brugemann J, Jaarsma T, Wijtvliet PE, et al.
Daily Physical Activity in Stable Heart Failure Patients. J Cardiovasc Nurs 2013 Feb 14.
150
151
Chapter 5
PHYSICAL EXERCISE PERFORMED BY RESIDENTIAL ELDERLY OF
HIGH AGE, IS SAFE HOWEVER DOES NOT AFFECT HEART FAIL-
URE SYMPTOMS, NT-PROBNP AND CARDIOVASCULAR-
METABOLIC INDICES; A PILOT, SINGLE-BLINDED RCT. Barents M, Weening B, de Greef MH, Muskiet FAJ, Hillege HL, DeJongste MJ.
Submitted.
152
ABSTRACT
Does exercise benefit care-home residents afflicted with cardiovascular-metabolic diseases who
are leading a sedentary life? Exercise effects were investigated on chronic heart failure (CHF)
and the metabolic syndrome. METHODS. For 16 weeks a twice weekly exercise was performed by the exercise group and a
non-physical program by the control group. Cardiovascular-metabolic markers were measured
[(N-terminal-pro B-type-natriuretic peptides(NT-proBNP), waist, HbA1c, diabetes mellitus type
2 (T2DM), plasma lipids and blood pressure]. RESULTS. Analysis of aged 85 years showed neither significant changes in exercise groups
(24) compared to controls (22) nor lasting injury from falls. Only exercise group attendance is
inversely related to non-fasting triglycerides (p=0.024). CONCLUSION. In care-home residents, guided physical exercise is safe in the short term but
may be less effective in reducing chronic heart failure symptoms, NT-proBNP concentrations
and the metabolic syndrome. We have explained the neutral results by the high age (85 year
on average) accompanied by low muscle endurance, and by a training schedule that might be
not enough personalized.
153
INTRODUCTION
The Dutch guideline for cardiovascular risk management (CVRM) states that the 10-year risk of
cardiovascular diseases (CVD) of 70+ elderly should exceed 20% and that the elderly should
be eligible for medication when lifestyle changes fail (1).
Care home elderly (residents) are even more at cardiovascular (CV) risk when compared to
70+ elderly because the first group (of elderly) are sedentary most often and they are suffering
from multimorbidity. Examples of multimorbidity are diabetes mellitus type 2 (T2DM), CV dis-
eases, notably heart failure (CHF), cerebrovascular ischemic attack (CVA) (2). In the daily practice of geriatric medicine, these risks are addressed pharmacologically rather
than by a change of life style such as physical activity (1;3;4). Changes of lifestyle require mo-
tivation to adjust behaviour while drug intake barely takes extra effort. This is one of the reasons
why residential elderly remain sedentary. Their daily physical activity is three to eleven minutes.
However, this inactivity of residents is inconsistent with the recommendations of the CVRM
guideline (5-9). This inconsistency is also based on perspectives of a limited lifespan and fear
of falling. These anxieties prevent residents from becoming physically active. Chronic heart
failure (CHF) is defined as a syndrome resulting from myocardial muscle dysfunction with usual
exposure of characteristic symptoms (10). Natriuretic peptides, notably B-type natriuretic pep-
tide (BNP) and amino-terminal pro-B-type NP (NT-proBNP) are well established CHF bio-
markers. They are widely used for CHF diagnosis, follow-up and prognosis (11), while they also
provide opportunities for biomarker-guided treatment optimization (12).
The metabolic syndrome was defined as the presence of at least three out of five of the follow-
ing symptoms (13): central obesity, compromised glucose homeostasis or diagnosed T2DM,
atherogenic dyslipidemia and hypertension (14;15). Both CV and metabolic derailments have
atherosclerosis as a central pathophysiological phenomenon that is eligible for lifestyle changes
as physical exercise.
In the present study we sought to investigate two aspects of physical exercise with/in residents,
its safety and changes of CHF symptoms and a marker, and markers of the metabolic syn-
154
drome. We aimed to study whether participation in a predefined exercise program is safe and
whether symptoms and a marker of CHF and markers of the metabolic syndrome, will change
after such a program. x
METHODS
This pilot study was designed as a multicenter single-blinded randomized controlled trial. The
end points were CHF symptoms, a marker, and the metabolic syndrome. This study was part of
the Benefit study (). The Benefit study took place in 14 care homes. The care home residents
in the present study participated in the same intervention program as those in the Benefit study.
This program consisted of either physical exercise or a program without exercise. The Benefit
and present study differed in size (Benefit: 14 care homes, present study: 4 care homes) and
end points. The Benefit study end points consisted of physical fitness, functional performance,
activities of daily life and quality of life (16).
Subject selection. From March 2010 to December 2011, we invited all elderly of four residential homes in Gronin-
gen to participate in the study. The inclusion criteria were: no dementia, the ability to walk at
least ten meters, understanding the impact of the study. Potential participants had to sign an
informed consent. Exclusion criteria were age <70 years, disturbed cognition (Mini-Mental
State Examination test <20; range 0-30), serious aphasia, heart failure New York Heart Asso-
ciation (NYHA)-class IV, terminal phase, and metastatic cancer. To the best of our knowledge
there was no literature available about effects of exercise programs on patients with CHF and
CV-metabolic indices among the elderly with multimorbidities. Since a meaningful estimation of
the number of participants needed for a power analysis was debatable we decided to perform a
pilot study.
155
Endpoint definitions (Table 1) Chronic heart failure was defined as a syndrome resulting from myocardial muscle dysfunction
with the usual exposure of characteristic symptoms such as shortness of breath (dyspnoea) and
fatigue, both in rest, during activity and during exertion (in three conditions)(10). Symptoms of
CHF were estimated as changed if dyspnea (scores 0-3) and or fatigue (scores 0-3) de-
crease with at least one score point. The metabolic syndrome was defined as the presence of at
least three out of five of the following symptoms (17): central obesity (waist circumference ≥102
males or ≥88 females, compromised glucose homeostasis (increased glycated hemoglobin >41
mmol/mol or the diagnosis T2DM), atherogenic dyslipidemia (high triglycerides >150 mg/dL,
low HDL-cholesterol <40 mg/dL for males or <50 for females) and increased systolic blood
pressure (>130 mm Hg) (14;15). Smoking is not included in this enumeration. Participation in
the exercise program was defined as safe if falls or unfavourable events during exercise ses-
sions occurred in <4% [16 out of 32 followed sessions x 24 (number of) exercising resi-
dents=384 occasions/100%=around 4% accidents]. The chosen changes of endpoint variables
are represented in Table 1.
Motives for non-participation. As expected (17), a relatively low participation was taken into
account. Participants were randomly assigned to the two groups at each location. Intending to
analyse motives for not participating, we inquired those who refused participation about their
reasons. In order to compare characteristics of non-participants to those of participants, biomet-
ric data of the first group (age, weight, height, heart rate and blood pressure) were collected by
the investigator. Medical history and medication were obtained from general practitioners. The
reasons for refusal were grouped into intrinsic motives (‘no realization of benefits of exercise’
and ‘does not want to adhere to the program’) and extrinsic motives. The latter were defined as
‘too busy with other activities’, illness, hospital admission, moving and impending death.
156
Subjects
During two visits before and after the intervention, all participants were subjected to a structured
interview, specific physical examination and biometric measurements. Blood samples were
taken within two hours after breakfast and lunch. Participants were physically examined for car-
diopulmonary symptoms, blood pressure (Heine gamma-G5®; www.Heine.com), symptoms or
complaints of the abdomen, joints, back, visual ability and hearing. Multimorbidity was scored
using the Charlson Comorbidity Index (18;19). Blood samples were taken two hours after
breakfast or lunch. For logistic reasons, it was not feasible to collect fasting blood samples. The
Medical Ethical Committee of the UMCG approved of the study (number 2010.178).
Interventions
The exercise program included moderate to high-intensity training sessions (16).
In each session, the participants performed progressive resistance training of upper and lower
extremities and trunk, static and dynamic balance training, and functional training. Elastic bands
(20) were used for resistance training. The following muscle groups were trained: biceps, tri-
ceps, shoulder, back, abdominal and hip muscles, quadriceps femoris, gastrocnemic, peroneus
and tibialis as well as foot muscles. The volume of resistance training was gradually increased
from one set of eight repetitions in the first five weeks to two sets of eight repetitions in weeks
six to ten and finally to three sets of eight repetitions in weeks eleven to sixteen. Balance train-
ing was adjusted to individual abilities. The level of difficulty was established by observing the
participants performing a balance task, e.g. walking on a fitness mat. The participants’ balance
was progressively challenged by increasing the level of difficulty every two weeks. Functional
training comprised exercises like chair stands, walking, turning, walking on a course with obsta-
cles. Frequency and duration of both group sessions were one hour twice weekly/two times a
week during sixteen weeks, 32 in total. The controls followed a non-physical social program
with information, games and videos in the same weeks. The participants were not allowed to
participate in other physical activity programs except current physiotherapy.
157
Clinical chemical analyses
Hemoglobin, estimated glomerular filtration rate (eGFR), HDL-cholesterol, triglycerides and
HbA1c were measured by standard procedures. NT-proBNP was measured by immune-assay
(www.roche-diagnostics.com).
Statistics All statistical analyses were performed with SPSS version 18.0 for Windows. Results were ex-
pressed as means ± SD or medians [interquartile range (IQR)] for parametric and non-
parametric data, respectively. Available data of non-participants were compared to data of par-
ticipants. Characteristics of exercise and control groups were compared at baseline. Differences
within groups between end-point minus baseline of each variable were tested by a paired t-test
or Wilcoxon-signed-ranks-test. Differences across both groups were tested by unpaired tests (t-test or Mann-Whitney U test). A sub-analysis was made, aimed at those participants who com-
pleted 16 or more (≥50%) of all sessions, who were defined as ‘as treated’. In case of insignifi-
cant differences in the outcomes of the ‘intention-to-treat’ and ‘as treated’ statistical analyses,
we only report outcomes of the ‘intention-to-treat’ analysis. All statistical comparisons were two-
tailed. A p<0.05 was considered statistically significant.
RESULTS Subjects’ characteristics
The number of subjects in four care homes consisted of 434 residents. Of these, 163 (38%)
were eligible to participate. There were 52/434 (12%) subjects willing to join the study who
were included (participants), and 111/434 (26%) who refused to take part (non-participants).
Of the non-participants, 47/111 (42%) were willing to provide us some biometric data only
once. They also explained their motives not to take part in the study:23/47 repulsed participa-
tion because of intrinsic and 24/47 because of extrinsic motives. Fifty-two participants were
158
assessed at baseline, of which 28/52 were randomized to the exercise group and 24/52 to
the controls. During the study, 6/434 (1%) participants dropped out because of not exercise-
related reasons: one died after a CVA, two moved to other institutions and three discontinued
their participation for intrinsic reasons. Their data were excluded from the final analysis. Out of
52 participants, 46 completed the program, 24/28 of the exercise group and 22/24 of the
controls. No differences were observed between characteristics of the interviewed non-participants
(n=47) and participants (n=46), except that the non-participants had a more disturbed cogni-
tion compared to the participants (MMSE 30 22 vs. 25; p=0.011). The participants were 85 years on average and 65% of them were female (Table 1). T2DM
occurred in 17% with a mean HbA1c of 43 ± 8 mmol/mol. Half of them used antihyperten-
sives. Nine (20%) had CHF. More females than males and more residents with CHF than without CHF were enrolled in the
exercise group compared to controls, respectively (79% vs. 50%; p=0.041 and 8 vs. 1;
p=0.028). In the exercise group, median NT-proBNP (446 vs. 251 pg/mL), systolic blood
pressure (143 versus 127 mm Hg) and antihypertensive use (83% versus 55%) respectively,
were significantly higher compared to controls. The exercise group differed from the control
group neither in fatigue nor in dyspnea. One fall without permanent injury was reported during an exercise session (Table 3). The usual physical activity consisted of one walk a day to an
indoor restaurant. Residents seldom visited the garden outside. For distances longer than 50-
150 m a wheelchair was used.
Comparison of exercise and control groups before and after intervention Within the exercise group, the female waist changed significantly [-8(-15- -2) cm]. The triglyc-
erides changed insignificantly [-6(-19-8)] within the exercise group and significantly [-8(-17-
0)] in the controls. Between-group comparison revealed relevant changes in female waist and
159
systolic BLOOD PRESSURE, though the findings were not statistically significant. The other variables did show neither significant within-group nor between-group differences (Table 4).
Sub-analysis. In the sub-analysis of participants who attended ≥16 of the sessions (‘as treated’)
we found a decrease of female waist within the controls [-11(-22-0)cm, p=0.049)], and within
the exercise group a decrease of triglycerides [-11(-19--1) mg/dL, p=0.032] and an increase
of NT-proBNP 81(8-155), p=0.33], both insignificant when compared between exercise and control group (supplemental Table 4a). There were no other significant or worthwhile between-
group differences detected in this ‘as treated’ sub-analysis. Attendance and endpoints. The
number of attended sessions was not associated with age, gender and comorbidity. However, it
was inversely related with changes of triglycerides (p=0.024) in the exercise group only.
DISCUSSION
In this study, we questioned whether participation in a predefined exercise program was safe
and effective to change symptoms, a marker of CHF, and markers of the metabolic syndrome.
Besides, we regarded participation rates in the interventions. In this pilot study, we found the
applied exercise program to be safe for residents (1 fall, no lasting injuries). We observed that
neither metabolic markers nor a marker and symptoms of CHF changed after completing a one
hour moderate-to-high intensity exercise program, followed twice weekly over a period of 16-
weeks, when compared to controls. It was found that the number of attended sessions in the
exercise group was inversely related to the change of non-fasting triglycerides from baseline to
study end. This relation was however not confirmed by a triglycerides decrease after exercise.
The change in triglycerides suggest that some metabolic change occurred, but this was at most
genuinely minor. Of the eligible residents, we found one-third (32%) motivated, one-third not
willing for intrinsic and extrinsic reasons and one-third unmotivated to participate with unknown
motives .
160
To explain the results, we assessed population characteristics, exercise frequency, safety, par-
ticipation and attendance. At last, the results of the Benefit study were added to our outcome.
Firstly, plasma levels of Hb, HbA1c, triglycerides, HDL-cholesterol, and systolic blood pressure
were all within reference limits before the intervention. The renal function was only slightly af-
fected. Therefore, it was estimated that participants were properly set up on medications for CVD, CHF and metabolic syndrome (e.g. the majority used antihypertensives (Table 3). It was
noted that doses of antidiabetics, antihypertensives and digitalis remained unchanged during the
study period. Secondly, we also found that participants had fewer complaints. Only 27% of the
exercise and 41% of the control group complained of fatigue and or dyspnea. Thirdly, the high
age of participants might explain partly why symptom and marker changes did not occur. In
general, people aged 50 yrs and older, lose muscle strength (mass) and muscle endurance
(mitochondria), especially when they lead a sedentary life (21). Endurance training, which is
the best exercise to increase or maintain mitochondrial concentration when aging, has generally
resulted in relatively small functional benefits for care home residents (22;23). This implies that
the high-age related changes in muscular and CV physiology, augmented by the CHF disease
state in some of our participants, limited the exercise capacity and its corresponding benefits.
Surprisingly, the studied population was stable thanks to medication. Fourthly, the high intra-
individual variation of NT-proBNP (24) explained the lack of results, which precluded the detec-
tion of minor changes, if any, in a small study group.
Although the exercise program used was specifically developed for our study population (16), it
was questioned whether a (three-times weekly) frequency of three times a week might have
provided more changes. However, we preferred a twice weekly frequency for fear of more drop-
outs and based on promising results of others (25).
Measures taken to ensure safety consisted not only of the individual exertion level but also of
guidance of the training and the own environment where the training sessions were held. Till
now, effective management of (the) fear of falling is lacking (26).
161
The participation rate of our study consisting of 32% inclusion and 68% refusal, was compared
with that of another group of 65 years old residents with 49% inclusion and 6% refusal (17).
This comparison suggested that the higher age of our participants was due to the lower partici-
pation rate. Another reason for the found lower participation rate might be interference of other
social activities with our interventions. In addition, the reported non-participants were related to
those with a lower cognition. This suggested that a certain level of cognition may be required to
participate in a study design as is applied in our study.
One positive aspect was noted. Most participants remained in the program. Their motivation
appeared from fewer drop-outs (12%) compared to the number of drop-outs (>20%) found in
another group of 72 year old exercising residents (17).
In this study, the attendance (up to 60%) was lower compared to that reported by others (31).
Accordingly, we analyzed the relations between attendance and all outcome variables in a sub-
group of participants with the best attendance ( ≥50% attendance). Compared to the entire
group, this subgroup did not exhibit more changes in metabolic markers and symptoms and a marker of CHF (supplemental Table 4a). It is therefore unlikely that our results are based on
lower attendance. Other reasons must account for this.
Using the same exercise program in comparable cohorts, it is rational to summarize the conclu-
sions of the present study and the Benefit study (20). Both studies conclude that the exercise
program is ineffective in reducing disability, care-dependency and cardiovascular-metabolic
endpoints in care home residents. However, on the basis of these two studies, the question
whether we should advise physical exercise to residents in order to promote health and func-
tionality or not, cannot be answered. As a consequence, we still do not know whether the
CVRM recommendations on physical exercise are applicable to care home residents. Subse-
quently, studies in care home residents are warranted. The limitations of the present study were
the skewed distribution of CHF and gender following randomization and the non-fasting triglyc-
erides measurement, which could, unfortunately, not be avoided because of logistical reasons.
162
CONCLUSION
In care-home residents, guided physical exercise is safe in the short term but may be less ef-
fective in reducing chronic heart failure symptoms, NT-proBNP concentrations and the metabolic
syndrome. We have explained the neutral results by the high age (85 year on average) accom-
panied by low muscle endurance and by a training schedule that might be not enough personal-
ized.
ACKNOWLEDGEMENTS
The “Hanze University of Applied Sciences” and “Stichting de Hoven”, both in Groningen, The Netherlands, granted the study. Conflict of interest statement: none.
163
References
1 Wiersma T, Smulders YM, Stehouwer CD, Konings KT, Lanphen J. [Summary of the
multidisciplinary guideline on cardiovascular risk management (revision 2011)]. Ned
Tijdschr Geneeskd 2012;156(36):A5104.
2 Marengoni A, Rizzuto D, Wang HX, Winblad B, Fratiglioni L. Patterns of chronic
multimorbidity in the elderly population. J Am Geriatr Soc 2009;57(2):225-30.
3 Mancia G, De BG, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 ESH-
ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task
Force on the Management of Arterial Hypertension. J Hypertens 2007;25(9):1751-62.
4 Kroon AA. [Dutch guideline for cardiovascular risk management: a consensus model].
Ned Tijdschr Geneeskd 2012;156(36):A5196.
5 Nelson ME, Rejeski WJ, Blair SN, Duncan PW, Judge JO, King AC, et al. Physical
activity and public health in older adults: recommendation from the American College of
Sports Medicine and the American Heart Association. Med Sci Sports Exerc
2007;39(8):1435-45.
6 Jans M.P. De ontwikkeling van een beweegnorm voor ouderen in verpleeg- en
verzorgingshuizen. Vreede de P., Tak E.C.P.M., Meeteren van N.L.U., editors. TNO
kwaliteit van leven. 046[KvL/B&G], 9-15. 1-9-2008. www.tno.nl, TNO.
7 Christmas C, Andersen RA. Exercise and older patients: guidelines for the clinician. J
Am Geriatr Soc 2000;48(3):318-24.
8 Taylor AH, Cable NT, Faulkner G, Hillsdon M, Narici M, Van Der Bij AK. Physical activity
and older adults: a review of health benefits and the effectiveness of interventions. J
Sports Sci 2004;22(8):703-25.
164
9 Mutasingwa DR, Ge H, Upshur RE. How applicable are clinical practice guidelines to
elderly patients with comorbidities? Can Fam Physician 2011;57(7):e253-e262.
10 Mosterd WL, Rosier PF. [Guideline 'Chronic heart failure']. Ned Tijdschr Geneeskd
2004;148(13):609-14.
11 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC
Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The
Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of
the European Society of Cardiology. Developed in collaboration with the Heart Failure
Association (HFA) of the ESC. Eur Heart J 2012;33(14):1787-847.
12 Morello AM, Januzzi JL. Amino-terminal pro-brain natriuretic peptide: a biomarker for
diagnosis, prognosis and management of heart failure. Expert Rev Mol Diagn
2006;6(5):649-62.
13 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al.
Diagnosis and management of the metabolic syndrome: an American Heart
Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation
2005;112(17):2735-52.
14 Executive Summary of The Third Report of The National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood
Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-97.
15 Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, et al.
Lipoprotein management in patients with cardiometabolic risk: consensus statement from
the American Diabetes Association and the American College of Cardiology Foundation.
Diabetes Care 2008;31(4):811-22.
165
16 Weening-Dijksterhuis E, de Greef MH, Scherder EJ, Slaets JP, van der Schans CP. Frail
institutionalized older persons: A comprehensive review on physical exercise, physical
fitness, activities of daily living, and quality-of-life. Am J Phys Med Rehabil
2011;90(2):156-68.
17 Nyman SR, Victor CR. Older people's recruitment, sustained participation, and
adherence to falls prevention interventions in institutional settings: a supplement to the
Cochrane systematic review. Age Ageing 2011;40(4):430-6.
18 Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity
index. J Clin Epidemiol 1994;47(11):1245-51.
19 Charlson ME, Charlson RE, Peterson JC, Marinopoulos SS, Briggs WM, Hollenberg JP.
The Charlson comorbidity index is adapted to predict costs of chronic disease in primary
care patients. J Clin Epidemiol 2008;61(12):1234-40.
20 Baum EE, Jarjoura D, Polen AE, Faur D, Rutecki G. Effectiveness of a group exercise
program in a long-term care facility: a randomized pilot trial. J Am Med Dir Assoc
2003;4(2):74-80.
21 Rogers MA, Evans WJ. Changes in skeletal muscle with aging: effects of exercise train-
ing. Exerc Sport Sci Rev 1993;21:65-102.
22 Fiatarone MA, O'Neill EF, Ryan ND, Clements KM, Solares GR et al. Exercise training
and nutritional supplementation for physical frailty in very elderly people. N Engl J Med
1994;330(25):1769-1775.
23 Tseng BS, Marsh DR, Hamilton MT, Booth FW. Strength and aerobic training attenuate
muscle wasting and improve resistance to the development of disability with aging. J
Gerontol A Biol Sci Med Sci 1995;50 Spec No:113-9.
166
24 Bruins S, Fokkema MR, Romer JW, Dejongste MJ, van der Dijs FP, van den Ouweland
JM, et al. High intraindividual variation of B-type natriuretic peptide (BNP) and amino-
terminal proBNP in patients with stable chronic heart failure. Clin Chem
2004;50(11):2052-8.
25 Chin APM, van Poppel MN, Twisk JW, van MW. Effects of resistance and all-round,
functional training on quality of life, vitality and depression of older adults living in long-
term care facilities: a 'randomized' controlled trial [ISRCTN87177281]. BMC Geriatr
2004;4:5.
26 Parry SW, Deary V, Finch T, Bamford C, Sabin N, McMeekin P, et al. The STRIDE
(Strategies to Increase confidence, InDependence and Energy) study: cognitive
behavioural therapy-based intervention to reduce fear of falling in older fallers living in
the community - study protocol for a randomised controlled trial. Trials 2014;15:210.
27 Rydwik E, Gustafsson T, Frandin K, Akner G. Effects of physical training on aerobic
capacity in frail elderly people (75+ years). Influence of lung capacity, cardiovascular
disease and medical drug treatment: a randomized controlled pilot trial. Aging Clin Exp
Res 2010;22(1):85-94.
167
Table 1. Endpoints
Primary endpoints At risk for
all Male Female
waist circumference (cm)a >102 >88 triglycerides (mg/dL)a >150 high-Density Lipoprotein-cholesterol (mg/dL)a <40 <50 systolic blood pressure (mm Hg)a >130 diastolic blood pressure (mm Hg)a >95 non-fasting glucose (mg/dL)a <140 glycated Hemoglobin (mmol/mol) >41 Secondary endpoints fatigue in 3 activity levels (1 – 3)
>1
dyspnea in 3 activity levels (1 – 3) >1 N-terminal pro B-type natriuretic peptide( pg/mL)b
>450
a Based on definition of the metabolic syndrome. The severity of fatigue and dyspnea are based on the definition of the NYHA classification: class 1: no symptoms; class 2: symptoms occur at ordinary activity; class 3: symptoms occur ordinary activity. b NT-proBNP cut-off value for the diagnosis of heart failure (11).
168
Table 2. Sample description. Participants are compared to non-participants at baseline.
Variable Participants
N = 46
Non-participants
N=47
P
male/female 16/30 9/38 0.151
age (years) 85 ± 6 84 ± 8 0.658
body mass index kg/m2 27 ± 5 25 ± 65 0.258
mini-mental state estimation 30 25 ± 4 22 ± 4 0.011
heart rate (beats/min) 73 ± 11 71 ± 25 0.522
smoking median (interquartile range) 3 (1-4)
heart failure n (%) 9 (%)
Cerebro-vascular accident n (%) 16 (%)
comorbidity 11 (%)
residents with antidiabetics n (%) 6 (13)
residents with antihypertensives n(%) 32 (70)
Data are presented as means ± SD. Comorbidity, Charlson Comorbidity Index (sum of current
chronic diseases out of 17 chronic diseases).
169
Table 3. Characteristics of exercise and control groups of care home residents. Variable Exercise group
(Ex) n=24 Controls (C) n=22
Ex vs. C P-value
age years mn SD 85±5 84±6 0.298 male/female number/number 5/19 11/11 0.041 waistm cm mn SD 107±15 113±28 0.692 waistf cm mn SD 105±21 97±12 0.690 mini-mental state examination mn SD 26±3 25±4 0.421 smoking number 4 7 0.273 fatigue n (range 0-3) 1±1 1±1 0.757 dyspnea n (range 0-3) 1±1 1±1 0.859 heart rate (beats/min) 71±12 76±9 0.154 diastolic blood pressure (mm Hg) mn SD 85±12 81±12 0.263 systolic blood pressure (mm Hg) mn SD 143±9 127±18 0.005 comorbidity number md IQR 3(0-4) 3(1-4) 0.705 cerebrovascular accidents number 7 9 0.353 diabetes mellitus type 2 number 6 2 0.183 % residents using antidiabetics 21 1 0.099 chronic heart failure number 8 1 0.028 % residents using antihypertensives 83 55 0.037 digoxin % 8 5 0.671 NT-proBNP pg/mL median IQR 446 (260-967) 251 (93-664) 0.024 eGFR mL/min/1.73 m2 mn SD 58±22 70±27 0.098 hemoglobin mg/dL mn SD 13±2 13±2 0.871 glucose mg/dL mn SD 118±38 101±20 0.061 HbA1c mmol/mol mn SD 43±10 43±6 0.844 triglycerides mg/dL mn SD 122±56 131±66 0.633 HDL-cholesterol male mg/dL mn SD 40±6 51±16 0.139 HDL-cholesterol female mg/dL mn SD 51±11 54±22 0.690 attended sessions% 60±37 58±34 0.840 fall without injury number 1 0 0.852 IQR, interquartile range; NT-proBNP, amino-terminal proBNP; eGFR, estimated glomerular fil-tration rate.
170
Table 4. Changes (Dif) in the exercise and control groups from baseline to the study end,
together with between-group differences of these changes.
Variable Difference
Exercise (Ex)
Within group
Control (C)
Within group
Ex vs. C Between
group adjusted
Dif Mn (95%CI) P Mn (95%CI)
P Mn (95%CI)
P
Dif waist male cm -1 (-4 – 1) 0.135 -3 (-1 – 2) 0.155 -2 (-6 – 2) 0.381
Dif waist female cm -8 (-15- -2) 0.018 -2 (-6 – 3) 0.405 -4 (-10 – 1) 0.076
Dif triglycerides mg/dL -6 (-19 – 8) 0.394 -8 (-17- 0) 0.033 -6 (-11- -1) 0.271
Dif HDL-C male mg/dL 0 (-3 – 3) 0.951 -6 (-18– 6) 0.274 -3 (-11- 5) 0.773
Dif HDL-C female mg/dL 1 (-3 – 5) 0.577 2 (0 – 5) 0.086 2 (-1- 4) 0.948
Dif DBP mm Hg -4 (-7 – 0) 0.029 -3 (-10– 4) 0.378 -4 (-8 – 1) 0.935
Dif SBP mm Hg -1 (-14 – 11) 0.830 2 (-7 – 11) 0.681 -4 (-7- 6) 0.059
Dif glucose mg/dL -13 (-27–2) 0.078 7 (-5 – 20) 0.228 -7(-26– 13) 0.127
Dif HbA1c mmol/mol 3 (0 – 6) 0.086 1 (-1 – 3) 0.329 0 (0 – 0) 0.579
Dif fatigue n 0 (-1 – 0) 0.137 0 (-1 – 0) 0.261 0 (-1- 0) 0.930
Dif dyspnea n 0 (-1 – 0) 0.328 0 (0 – 0) 0.162 0 (-1- 0) 0.696
Dif NT-proBNP
pg/mL*(md IQR)
334(-117– 785) 0.139 67(7–126) 0.030 22(-9– 140) 0.948
mn, means; SD, standard deviation; * md, median with IQR, interquartile range; MMSE30,
mini-mental state examination 30; comorbidity, Charlson Comorbidity Index (sum of current
chronic diseases out of 17 chronic diseases); CVA , cerebrovascular accidents; DBP, diastolic
blood pressure; SBP, systolic blood pressure; HDL-C, HDL–cholesterol; n, number; NT-
proBNP, amino-terminal proBNP, this variable is tested non-parametrically; eGFR, estimated
glomerular filtration rate; attendance, percentage attended sessions.
171
Supplemental Table 4a. Subgroup of attendance ≥16 sessions: changes (Dif) in exercise
and control groups from baseline to the study end, together with between-group differences
of these changes.
Variable Differences
Exercise Within-group
Control Withingroup
Ex vs. C Between-
group adjusted
(Dif) Mn(95%CI) P Mn(95%CI) P Mn(95%CI) P Dif waist m cm -4(-10-3) 0.270 -1(-4-1) 0.135 2(-6-10) 0.601 Dif waist f cm -2(-7-3) 0.408 -11(-22-0) 0.049 -9(-22-5) 0.190 Dif triglycerides -11(-19--1) 0.032 -5(-12-2) 0.134 5(-6-17) 0.563 Dif HDL-C m -7(-20-7) 0.277 0(-3-3) 1.00 8(-10-25) 0.351 Dif HDL-C f 25(-29-78) 0.321 2(-1-4) 0.2100 0(-6-6) 0.986 Dif SBP 2(-10-13) 0.762 0(-14(-14) 0.993 -2(-19-16) 0.540 Dif HbA1c % 0.1(-0.1-0.2) 0.332 0.1(0.1-1.0) 0.281 0.1(-0.2-0.3) 0.736 Dif fatigue n 0(0-0) 0.543 0(0-0) 0.136 0(-1-0) 0.543 Dif dyspnea n 0(0-0) 0.332 0(0-0) 0.229 0(-1-0) 0.670 Dif NT-proBNP 81(8-155) 0.033 367(-245-981) 0.222 280(-354-914) 0.852 Data are means ±SD; *median with interquartile range (md, iqr); m, male; f, female; DBP, dia-
stolic blood pressure; SBP, systolic blood pressure; HDL-C, HDL–cholesterol; n, number; NT-
proBNP, amino-terminal proBNP this variable is tested non-parametrically.
172
173
Chapter 6
SUMMARY, DISCUSSION, RECOMMENDATIONS AND FUTURE
PERSPECTIVES
174
Chapter 6.1
SUMMARY
A drawback of the improved survival from cardiovascular diseases (CVD) (1) is that cardiovas-
cular morbidities have grown. As we have emphasized in the introduction of this thesis, the
number of people living with heart failure (HF) has increased impressively in conjunction with a
tremendously improved life expectancy of the Dutch population (www.cbs.nl;
www.nationaalkompas.nl), during the last century. Since HF is mainly a problem of advanced
age, subjects diagnosed with chronic HF (CHF) often concern elderly. However, there is a wide
lack of knowledge with regard to data on HF when age progresses and elderly become frail and
more care dependent. The most care dependent elderly are committed to a care or nursing
home. In this thesis, those elderly persons are indicated as residential elderly. The shortage of
(research) data is mainly caused by excluding residential elderly from studies because of high
age and multimorbidities, such as CVD. Since there is a deficiency of data, no specific guidelines are available to diagnose and to treat
HF in residential elderly. From this perspective, there is debate on the applicability of existing
HF guidelines developed for CHF patients in general, to residential elderly with CHF. However,
guidelines for residential elderly with CHF are sorely missing because diagnosing CHF is notori-
ously difficult: elderly tend to subscribe complaints to aging instead of CHF or other diseases.
Subsequently, CHF treatments are often incorrectly applied, or not applied at all. The conse-
quences of these caveats may be loss of quality of life and increase of costs.
Therefore, we sought to study CHF in the residential elderly.
In Chapter 2.1 we have explored the epidemiological scale of CHF, by determining the preva-
lence of CHF in residential elderly. Based on the recent literature, when general guidelines on
CHF (2;3;4) were applied to residential elderly, diagnosing CHF was less accurate due to poor
predictive values of signs and symptoms, medical history, and electrocardiogram (ECG).
175
From medical files of residential elderly in a single nursing home in Groningen, we inventoried
signs, symptoms, medical history and registered the number of subjects with CHF. Then we
performed a physical examination and an ECG of all residents. Next we estimated the accuracy
of both, former CHF diagnostic (natriuretic peptides (NPs) not used) and current CHF diagnos-
tic procedures (including NPs), since, in contrast to the broad recognition of NPs as a screening
test for CHF, their use as biomarkers in residential elderly has remained limited. The restricted
use in elderly is caused by lack of validation of cut-off values for NPs in this group of subjects.
Finally, we studied ECGs of all residents.
A panel of cardiologists decided on the presence or absence of CHF by assessment of NPs and
the result of echocardiography, successively. Echocardiographic investigations were feasible in
98%. As a result of the present study, CHF was established in 24/103 (23%) residential eld-
erly. Fifteen (15/24) residents were not previously detected with CHF. Before the study, 22
were identified with CHF. Out of the 22 residents with CHF before the study, in only 9 residents
CHF was confirmed and of 13 residents with CHF the diagnosis was rejected.
The diagnostic accuracy of NT-proBNP at 450 pg/mL was 0.71 sensitivity, 0.67 specificity,
0.42 positive predictive value (PPV) and 0.91 negative predictive value (NPV). The diagnostic
accuracy of BNP at 100 pg/mL was: 0.71 sensitivity, 0.70 specificity, 0.41 PPV and 0.88
NPV.
In brief, the most striking results of the present study were that more than half the CHF diagno-
ses were missed (i.e. 15/24) or incorrectly made (i.e. 13/22). Hence we concluded that the
overall accuracy of identifying CHF is limited. However, given the high NPVs, the use of natri-
uretic peptides as additional diagnostic instrument seems promising, even in nursing home resi-
dents but requires further evaluation. The CHF prevalence in residential elderly was estimated
at 23%. In Chapter 2.2 we studied whether the outcomes of chapter 2.1 were consistent with the CHF
prevalence in Aruban nursing homes. Aruban nursing homes were chosen since we were inter-
ested in a comparable population with Dutch nationality living in a different environment and
176
having another lifestyle. The same design as in Chapter 2.1 was utilized to study the prevalence
of CHF in Aruban residential elderly. The other aim was to validate whether employment of na-
triuretic peptides could improve identification of CHF in residential elderly in another part of the
Dutch Kingdom. The main difference with the chapter 2.1 study was that we were unable to
obtain echocardiograms of all residential elderly, due to logistic reasons. Therefore, we could
not meet the diagnostic standards for CHF (2-4).
As a result, 51 out of 235 elderly Aruban residents were included with a mean age of 78±8
years. According to the medical files 7/51 residents were acknowledged with CHF. However,
two out of the 7 residents did not have CHF. Furthermore, CHF was established in 16 out of 51
(31%) residents. Out of the 16 residents with CHF, 11 were not previously diagnosed with CHF
and of 5/16 residents identified with CHF, the diagnosis was confirmed.
In brief, the general guidelines for HF are applied to Aruban residential elderly, infrequently.
When compared to residential elderly in Groningen, the prevalence of CHF may be at least as
high in Aruban residential elderly. In conclusion, recognition of CHF appears to be severely un-
derestimated in Aruban residential elderly. The detection of CHF will be improved by implement-
ing an appropriate guideline, including the determination of BNP.
In Chapter 2.3 we addressed the problem of the large intra-individual variations [individual co-
efficient of variation (CVi)] of NT-proBNP in plasma, since large CVis limit the applicability of
NT-proBNP for among others, guided therapy optimization in individual patients with CHF (5).
In search of more reliable CVis we compared concentrations of urine NT-proBNP (NT-proBNPu)
to concentrations of plasma NT-proBNP (NT-proBNPp), in HF patients living in Curaçao.
Urine and blood samples were taken on a single day (“within-day”): six blood samples every 2
hours and spontaneously voided urines during 24-hours. On five consecutive days (“day-to-
day”): five blood samples, five enforced urine samples, and five full 24-h urines were taken. On
the same day of six consecutive weeks (“week-to-week”): one blood sample, one enforced
177
urine sample and one full 24-h urine was collected. Out of these blood and urine samples the
total CVs (CVts), CVis and reference change values (RCVs) were calculated.
In this study 25 CHF patients were included with a mean age of 61 (range 36-80) years, 60%
was male and the average left ventricular ejection fraction was 36±15%. Median CV is for NT-
proBNPp were 9% (within-day), 18% (day-to-day) and 30% (week-to-week). For NT-proBNPu
the CVis were 34%, 21% and 28%, respectively. The reference change value (RCV) of NT-
proBNPu was higher than, or equal to, the RCV for NT-proBNPp, even after correction for
creatinine and the time period (in hours) in which the urine accumulated in the bladder.
Our data of day-to-day and week-to-week samples suggest that (immunoreactive) concentra-
tions of NT-proBNP in urine do not unequivocally correlate with (immunoreactive) NT-proBNP
concentrations in plasma, up to an NT-proBNPp threshold of about 310 pg/mL (Figure 1). In
addition, we found that beyond this threshold the higher NT-proBNP concentrations, as ex-
pressed in Figure 1, are not explained by an increase in blood pressure, during the day (results
not shown). We hypothesise that filtration of natriuretic peptides may be considered as the
dominant factor beyond the threshold and that at lower NT-proBNP levels filtration and reab-
sorption are more dynamically interacting.
In conclusion, measurements of NT-proBNP in urine have no advantages in stable patients with
chronic heart failure.
178
Figure 1. Relation between NT-proBNP in plasma and NT-proBNP in the enforced urine
voidings collected in the day-to-day and week-to-week protocols.
Data derive from 22 patients and in total 182 comparisons of NT-proBNP in plasma and urine.
Day-to-day and week-to-week samples were used. For urine we have used the enforced void-
ings.
In Chapter 3 we have investigated the prognostic value of natriuretic peptides on one-year mor-
tality in the same cohort of residential elderly as studied in chapter 2.1. The clinical relevance is
that if natriuretic peptides are related to prognosis of residential elderly with CHF, these bio-
markers may be exploited for advance care planning. Advance care planning is related to qual-
ity of life and becomes important when life expectancy is restricted (www.Verenso.nl).
To investigate one-year mortality, survival and death of residential elderly was tracked, during
one year. Since ten residential elderly could not be followed up, because they moved to un-
known destinations, we studied the remaining 93 residential elderly.
179
Eighteen out of 93 residents (mean age 81 ± 3 years, 66% female) died within one year (non-
survivors).
A mutually adjusted Cox proportional hazard regression analysis was performed. Adjustments
were made for six predefined chronic diseases, immobilization, age, sex, NT-proBNP and BNP.
The results found were that both natriuretic peptides (NT-proBNP and BNP) significantly pre-
dicted one-year mortality (HR 1.02 and p=0.001, and HR 1.16 and p=0.003, respectively). In
addition, the one-year mortality risk increases exponentially in concert with higher BNP and NT-
proBNP levels. For instance, an NT-proBNP increase up to 2,000 pg/mL was associated with
a 60% higher risk of dying, within one year.
In conclusion, both BNP and NT-proBNP are independent predictors of one-year mortality for
residential elderly with CHF. In addition, the mortality risk increases at natriuretic peptide con-
centrations elevated far beyond the diagnostic cut-off values of the guidelines (2;3;4).
In Chapter 4 we studied the relation between CHF and the support that is needed for residential
elderly with CHF during their activities of daily life (ADL). To this end, the same cohort of resi-
dential elderly was examined as in chapter 2.1. The rationale for this study question was to
draw attention of care teams to the need of support among those residents with CHF.
For this study the same group of residential elderly was assessed as in chapter 2.1. To collect
data on ADL the Minimal Data Set (MDS)-items of the Resident Assistant Instrument was used.
The MDS consists of systematic observations on dependency and delivered support and aims to
quantify dependence and aid (6). The MDS instrument consists of a software program for en-
tering the observations of the individual residential elderly, during predefined activities of daily
living (ADL). An example of such an activity is walking. The care taker observes and scores
(quantifies) whether the individual is able to walk predefined distances independently and needs
help during walking. Of 103 residents with and without CHF, the ADL-dependence and ADL-
help scores were compared and adjusted for differences between the two groups by means of
180
logistic multivariate regression. CHF was associated with ADL-help (OR 4.68 and p=0.015)
however, CHF was not related to ADL-dependence.
In conclusion, CHF is associated with a necessary increase of ADL-help for nursing home resi-
dents. In this regard, CHF is of importance for both residents (loss of autonomy and life satis-
faction) and organization (workforce planning).
In Chapter 5 we assessed a physical exercise program in residential elderly with CHF. The ra-
tionale for this study was the discrepancy between the sedentary lifestyle adhered to by resi-
dential elderly and the recommendations for physical activity from HF guidelines (2;3;4). Also
family members are stimulating their parents in care homes to become physically active. How-
ever, for a variety of reasons, residential elderly prefer to remain sedentary. Furthermore, be-
cause of fear of falling, also caretakers prefer residential elderly to maintain their sedentary life-
style. On the other hand, a sedentary life style is related to an increased risk on (progression
of) atherosclerosis and CV-metabolic diseases, such as CHF and metabolic syndrome (7).
To investigate whether regular exercise is safe and has beneficial effects on CV-metabolic indi-
ces for residential elderly, we evaluated effects of exercise on CHF symptoms, NT-proBNP and
metabolic syndrome.
A pilot single-blinded, randomized controlled feasibility trial in four care homes was performed.
In collaboration with other investigators (8), we studied whether a standardized exercise pro-
gram affects CHF symptoms, NT-proBNP and the metabolic syndrome. The other investigators
(8) studied whether the same standardized exercise program affects functional endpoints in
comparable groups.
The exercise intervention included a guided moderate-to-high intensity training of one hour
twice weekly, during 16 consecutive weeks. Exercise consisted of progressive resistance train-
ing of upper and lower extremities, and of the trunk, static and dynamic balance training, and
functional training. The control group intervention contained a guided non-physical social pro-
gram of similar frequency, duration, length and location. The study endpoints consisted of
181
symptoms of CHF (fatigue, dyspnea), NT-proBNP, and body measurements and laboratory
results, together known as parameters of the “metabolic syndrome”. The syndrome is defined as
the presence of three out of five measurements and laboratory results. These measurements
include waist, blood pressure, fasting glucose, triglycerides and high-density lipoprotein (HDL)-
cholesterol. We substituted glucose for glycated hemoglobin (HbA1c), since fasting blood col-
lection was not feasible for logistic reasons.
As a result, out of 434 residential elderly 163 were eligible. Unfortunately, only 52 (12%) were
willing to participate in the study. Of these 52, six dropped out during the study for reasons not
related to the exercise. The remaining 46 participants were 85±6 years, 65% females and all
had been randomized to exercise (n=24) or control groups (n=22). The intention-to-treat
analysis showed no significant change of any of a variable in the exercise groups compared to
controls. The as-treated group completed half or more of the 32 training sessions. The females
of the latter group had a significant reduction in waist size [-8 (range -15 - -2) cm]. The con-
trols showed a significant triglycerides decrease [-8 (-17-0) mg/dL] and an NT-proBNP in-
crease [67 (7-126) pg/mL]. The attendance of the residents was inversely related to the non-
fasting triglycerides in the exercise group (p=0.024).
We concluded that over a short period of time guided physical exercise, performed by residen-
tial elderly, had neither beneficial effects on symptoms and a biomarker of CHF, nor on cardio-
vascular-metabolic indices. We have explained the neutral results with the high age (85 years
on average) accompanied by loss of muscle endurance, and with a training offer that is not
enough personalized.
182
In brief, the outcomes of this thesis are: the prevalences of CHF in residential elderly are 23% in Groningen, which is consistent
with literature (9), and >30% in Aruba (chapters 2.1 and 2.2).
in Dutch residential elderly, undetected diagnoses of CHF often occur. The use of natri-
uretic peptides, as an additional test for CHF, needs to be further studied. In residential
elderly in Groningen, the incorrect diagnoses of CHF can be reduced by applying natri-
uretic peptides (chapter 2.1 and 2.2).
determination of NT-proBNP concentrations in the urine of CHF patients is not more fa-
vourable compared to NT-proBNP plasma levels. This finding results from the large in-
traindividual variabilities of urine NT-proBNP which is comparable to that in plasma NT-
proBNP (chapter 2.3).
in residential elderly, natriuretic peptide testing has prognostic values [HR of NT-proBNP
1.02 and BNP 1.16 (vs. HR (10) of BNP is 2.2)], of which the outcome of BNP is con-
sistent with the literature (10) (chapter 3).
residential elderly with CHF need more ADL-help, when compared to those without CHF
(chapter 4).
a short-term period of guided exercise performed by residential elderly has neither effect
on CHF nor on cardiovascular indices (i.e. the metabolic syndrome). There are no stud-
ies to compare with (chapter 5).
183
184
185
Chapter 6.2
DISCUSSION
186
We assessed our hypothesis (Introduction) according to which general HF guidelines (2-4) are
not applicable to residential elderly with regard to diagnostics. Therefore, we applied natriuretic
peptides (NPs) threshold values, derived from HF guidelines (2-4) to the residential elderly
cohort in Groningen (chapter 2.1). It should be noticed that both, the ESC and Multidisciplinary
HF guidelines (2;3) advise to use the same cut-off values (NT-proBNP 125 and BNP 35
pg/mL), which values are lower compared to the NICE HF guideline (i.e. NT-proBNP 400 and
BNP 100 pg/mL) (4). Using these cut-off values from the guidelines, we calculated the pre-
dictive values for the CHF diagnosis in residential elderly of a single nursing home in Groningen (Table 1). We also calculated the predictive values at higher thresholds such as at NT-pro BNP
900 pg/mL and BNP 100 pg/mL. Years after our study, Mason et al. (11) published a paper
on predictive values of NPs for CHF. The cut-off values of their study in British residential eld-
erly were slightly different from those chosen in our study. In accordance with the NICE HF guideline (4) Mason et al. validated their findings for NT-proBNP and BNP cut-off points (Table
1).
The Mason group (11) and we not only evaluated isolated natriuretic peptides but also combina-
tions of medical history, symptoms and signs, ECG, and natriuretic peptides to predict the pres-
ence of CHF. We both found that any combination of studied parameters did not improve the predictive values, as determined by natriuretic peptides either (Table 1). The outcomes of Ma-
son’s study, specifically with regard to PPV, correspond well with our findings.
187
Table 1. Predictive values of NT-proBNP and BNP for the heart failure diagnosis in two
populations of residential elderly (RE): the Groningen (NL) (Chapter 2.1) and the British
population (11).
Cut-off value
pg/mL sensitivity specificity PPV NPV
Groningen (NL) RE
NT-proBNP1 125 1.00 0.28 0.29 1.00
NT-proBNP 450 0.71 0.67 0.42 0.91
NT-proBNP 900 0.67 0.85 0.56 0.89
BNP1 35 0.88 0.39 0.30 0.91
BNP 50 0.88 0.63 0.31 0.89
BNP2 100 0.71 0.70 0.41 0.88
British RE (11)
NT-proBNP2 400 0.56 0.69 0.35 0.84
NT-proBNP 760 0.62 0.75 0.42 0.87
BNP 115 0.67 0.68 0.38 0.88
Residential elderly, RE; PPV, positive predictive value; NPV, negative predictive value; NT-
proBNP, N-terminal amino pro B-type natriuretic peptide; B-type natriuretic peptide.
1 ESC HF guideline (2) and multidisciplinary HF guideline (3)
2 NICE HF guideline (4).
In addition, both groups report that when applying HF guidelines (2-4) to Dutch and British
residential elderly (11), more than half of the initial CHF diagnoses are missed (too many false
negatives). Also lowering the threshold values (2;3), when compared to the NICE (4) HF
guideline, does not provide any substantial improvements. We and Mason et al. further estab-
188
lished that in residential elderly, the calculated predictive values are not reliable for ruling-in but
only for ruling out CHF.
In this thesis, we thus adapt the algorithm of the Multidisciplinary HF guideline (3) to residential elderly (Figure 1). These modifications include the use of NPs for excluding CHF only, the use
of echocardiography for ruling in CHF, the use of NICE cut-off values (4), and utilization of
echocardiography in primary care laboratories (www.Certe.nl).
However, Oudejans et al. (12) demonstrated in geriatric outpatients with a prevalence of >40%
CHF, that natriuretic peptide testing in combination with other diagnostic tests, are very accurate
for both, ruling out and ruling in CHF. Therefore, the PPV of CHF in our group might have been
lower due to a lower a priori chance on having CHF based on the lower CHF prevalence (23%)
when compared to the a priori chance of CHF in outpatients (CHF prevalence >40%). In con-
trast to the results of the Oudejans group, but in concert with those of Mason and our study
group [Chapter 1.2 and reference (11)], we have revised our recommendations for residential
elderly.
We had to reject our hypothesis in part, since CHF cannot be diagnosed in residential elderly by
making use of HF guidelines. In addition, our hypothesis was fair in part because CHF can be
ruled out using natriuretic peptides according to the HF guidelines.
Based on our new insights, we advise to make an echocardiogram for diagnosing CHF in resi-
dential elderly. Theoretically, NPs are recommended to rule out CHF although we realize that
excluding CHF does not comply with daily practice. Further, We processed these recommenda-tions into an algorithm for CHF diagnostics (i.e. non-acute HF) for residential elderly (Figure
1).
189
190
191
Chapter 6.3
RECOMMENDATIONS AND FUTURE PERSPECTIVES
192
In the discussion, we have concluded that general HF guidelines cannot be used for diagnosing
CHF in residential elderly. Furthermore, echocardiography is warranted to establish the diagno-
sis of CHF in the individual residential elderly.
To that end, we have customized the Dutch diagnostic algorithm for CHF (3) to that particular group (Figure 1). In the future, it is crucial to assess this adjusted CHF diagnostic algorithm on
accuracy and costs. We therefore recommend to validate the customized CHF diagnostic algo-
rithm in new populations of residential elderly.
In the introduction, the paragraph on HF diagnostics, we emphasized that access to echocardi-
ography was limited. Since recently, echocardiography has become available for primary care
patients in The Netherlands, that barrier to accurately diagnose CHF seems to be removed. We
subsequently argue for the option of on-site echocardiography for those (residential) elderly
who are immobile.
To editors of the Multidisciplinary HF guideline (3), we give in consideration to adapt the algo-
rithm (3) to residential elderly. The adaptations concern non-acute HF exclusively. They include
the use of echocardiography for ruling in CHF, the use of NPs only for excluding CHF, and
referral for echocardiography also in primary care laboratories (www.Certe.nl).
In Chapter 3, we showed the prognostic values of NPs for one-year mortality of residential eld-
erly with an established diagnosis of CHF. We therefore advise to add natriuretic peptide testing
to “advance care planning” for those (residential) elderly facing a limited life expectancy. In Chapter 4, we demonstrated the relation between CHF and the needs for more ADL-help,
compared to residential elderly without CHF. This relation made us to advise care teams to rec-
ognise higher requirements for ADL-help, in residential elderly with CHF. In Chapter 5, we observed that residential elderly who performed exercise during four months,
changed neither their CHF nor their CV-metabolic indices. We have explained the absence of
improvements to the high age and subsequent loss of muscular endurance. In addition, the
193
training frequency and duration were too modest contributing to the absence of improvements
as well. Based on these findings, we recommend in future to study residential elderly with CHF
during and after a personalized exercise program of three times a week in the long-run. An ex-
ample of a personalized program is the option for the aged to select his type of training himself.
Such programs may be more effective compared to programs imposed (13). Besides, we em-
phasize to pay attention regularly to the motivation of residential elderly to exercise, since we
found low participation rates in our study.
As a consequence of our results partly processed in the diagnostic CHF algorithm specific for residential elderly (Chapter 6.2), we recommend the following:
To editors of continuing medical education (e.g. www.CME-scholing.nl), we suggest to record
our new insights into CHF in education programs for physicians elderly medicine (SO). The
insights include the found CHF prevalence of at least 23% in residential elderly. Those also
include that CHF can be better diagnosed according to the diagnostic CHF algorithm that we customized to residential elderly (Figure 1). Furthermore, that advance care for residential eld-
erly, can be improved by the determination of natriuretic peptides also. Importantly, neither CHF
symptoms and a marker nor CV-metabolic indices may not improve in residential elderly, after
exercise during a four months period. However, in the long-run, beneficial effects of exercise in
residential elderly may not be impossible, when using personalized conditions. This includes
that the resident chooses himself whether he starts walking, home-training, swimming or visits
the fitness club.
194
elderly medicine in primary care
HF outpatients’ clinic
Figure 1. Diagnostic algorithm for non-acute heart failure in residential elderly.
Residential elderly with complaints and symptoms suspected for non-acute heart failure (HF) in a long-term care facility or primary care medicine
Physical examination, ecg, lab. consider comorbidity or HF de-cline consider further steps
NT-proBNP<400 pg/mL or BNP <100 pg/mL, ecg undisturbed
HF is unlikely. Consider other causes
Patient not diagnosed with HF
Physical examination, ecg, NT-proBNP or BNP (Hb, eGFR, TSH, K+, glucose)
Patient diagnosed with HF
Echocardiography
HFrEF and or HFpEF is likely.
Cause analysis/ treatable HF cause.
Cause analysis /no treatable cause for HF.
Consultation with SO /GP Treatment
Referral back to SO/GP with treatment advice.
Further diagnostics by the SO/GP
Yess
No
Neg.
Pos.
195
BNP, B-type natriuretic peptide; NT-proBNP, nitrogen-terminal-proBNP; SO, specialist ouder-
engeneeskunde; GP, general practitioner. References
1 Leening MJ, Siregar S, Vaartjes I, Bots ML, Versteegh MI, van Geuns RJ, et al. Heart
disease in The Netherlands: a quantitative update. Neth Heart J 2014;22(1):3-10.
2 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart
Failure 2012 of the European Society of Cardiology. Developed in collaboration with the
Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33(14):1787-1847.
3 Voors AA, Walma EP, Twickler TB, Rutten FH, Hoes AW. [Multidisciplinary guideline
'Heart failure 2010']. Ned Tijdschr Geneeskd 2011;155:A2957.
4 Mant J, Al-Mohammad A, Swain S, Laramee P. Management of chronic heart failure in
adults: synopsis of the National Institute For Health and clinical excellence guideline.
Ann Intern Med 2011;155(4):252-259.
5 Bruins S, Fokkema MR, Römer JW, DeJongste MJ, van der Dijs FP, van Ouweland
JM, et al. High intraindividual variation of B-type natriuretic peptide (BNP) and amino-
terminal proBNP in patients with stable chronic heart failure. Clin Chem
2004;50(11):2052-8.
196
6 Grebe C, Brandenburg H. [Resident assessment instrument. Application options and
relevance for Germany]. Z Gerontol Geriatr 2015;48(2):105-13.
7 Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Sr, Gibbons, et al.
2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the
American College of Cardiology/American Heart Association Task Force on Practice
Guidelines. J Am Coll Cardiol 2014 ;63(25 Pt B):2935-2959.
8 Weening-Dijksterhuis E, de Greef MH, Krijnen W, van der Schans CP. Group exercise
has little effect on ADL, physical fitness, and care dependency in frail institutionalised
elderly people: a randomized controlled trial. Thesis 2014; www.Hanze.nl.
9 Hancock C, Close H, Mason JM, Murphy JJ, Fuat A, Singh R, et al. High prevalence
of undetected heart failure in long-term care residents: findings from the Heart Failure
in Care Homes (HFinCH) study. Eur J Heart Fail 2012;15(2):158-65.
10 Bibbins-Domingo K, Gupta R, Na B, Wu AH, Schiller NB, Whooley MA. N-terminal
fragment of the prohormone brain-type natriuretic peptide (NT-proBNP), cardiovas
cular events, and mortality in patients with stable coronary heart disease. JAMA
2007;297:169–176.
11 Mason JM, Hancock HC, Close H, Murphy JJ, Fuat A, de Belder M, et al. Utility of
biomarkers in the differential diagnosis of heart failure in older people: findings from the
heart failure in care homes (HFinCH) diagnostic accuracy study. PLoS.One 2013;8(1);
e53560.
197
12 Oudejans I, Mosterd A, Bloemen JA, Valk MJ, van Velzen E, Wielders JP, et al. Clini-
cal evaluation of geriatric outpatients with suspected heart failure: value of symptoms,
signs, and additional tests. Eur J Heart Fail 2011;13(5):518-27.
13 Beckers PJ, Denollet J, Possemiers NM, Wuyts K, Vrints CJ, Conraads VM. Maintaining
physical fitness of patients with chronic heart failure: a randomized controlled trial. Eur J
Cardiovasc Prev Rehabil 2010;17(6):660-7.
198
199
Chapter 7
SAMENVATTING, DISCUSSIE, AANBEVELINGEN EN TOEKOMST-
PERSPECTIEVEN
200
Chapter 7.1
SAMENVATTING Een nadelig gevolg van de verbeterde overleving van cardiovasculaire ziektes (CVD) (1) is dat
de cardiovasculaire morbiditeit is toegenomen. Zoals in de introductie van dit proefschrift wordt
benadrukt, is het aantal mensen met hartfalen (HF) aanzienlijk toegenomen, terwijl tegelijkertijd
de levensverwachting in de Nederlandse populatie sterk is verbeterd gedurende de laatste eeuw
(www.cbs.nl; www.nationaalkompas.nl). Omdat HF zich veelal op hogere leeftijd manifesteert,
behoren patiënten met chronisch hartfalen (CHF) meestal tot de categorie ouderen.
Er bestaat echter een groot tekort aan kennis over HF bij toenemende leeftijd en bij kwetsbare
ouderen die afhankelijker worden van zorg. Ouderen die het meest afhankelijk zijn van zorg,
worden opgenomen in een verzorgings- of verpleeghuis. Deze ouderen worden in deze thesis
aangeduid als residentiële ouderen. Het gebrek aan onderzoeksgegevens en resultaten is voor-
namelijk ontstaan doordat residentiële ouderen geweerd worden uit studies vanwege hun hoge
leeftijd en multimorbiditeit, zoals CVD. Vanwege een gebrek aan gegevens zijn er geen richtlij-
nen beschikbaar om HF bij residentiële ouderen te diagnostiseren en te behandelen. Vanuit dit
gezichtspunt bestaat er discussie over de toepasbaarheid van bestaande HF-richtlijnen bij resi-
dentiële ouderen die ontwikkeld zijn voor CHF patiënten in het algemeen. Richtlijnen voor resi-
dentiële ouderen met CHF worden node gemist omdat de CHF diagnose lastig te stellen is: ou-
deren neigen ertoe om klachten toe te schrijven aan het ouder worden in plaats van CHF of
andere ziektes. Daardoor wordt de behandeling van CHF vaak ten onrechte of helemaal niet
uitgevoerd. Als gevolg van deze ongewenste situatie gaat er kwaliteit van leven verloren en
nemen de kosten toe. Deze bevindingen vormen de aanleiding om CHF bij residentiële ouderen
aan nader onderzoek te onderwerpen. In Hoofdstuk 2.1 wordt de schaalgrootte van CHF verkend door de prevalentie van CHF onder
residentiële ouderen te bepalen. Wanneer de algemene HF richtlijnen (2-4) worden toegepast,
blijkt uit recente literatuur de HF diagnostiek minder accuraat te zijn ten gevolge van de laag-
voorspellende waarden van klachten en symptomen, medische voorgeschiedenis en elektrocar-
201
diogram (ECG). Uit de medische gegevens van residentiële ouderen van één verpleeghuis in
Groningen werden de klachten, de symptomen en de medische voorgeschiedenis verzameld en
werd het aantal ouderen met CHF geïnventariseerd. Vervolgens werden alle ouderen onderwor-
pen aan een lichamelijk onderzoek en maakten we een ECG van elk van hen. Daarna bepaal-
den we hoe accuraat de eerdere CHF diagnostiek [zonder gebruik van natriuretische peptiden
(NP’s)] en de huidige CHF diagnostiek (met NP’s) waren, omdat in tegenstelling tot de brede
erkenning van NP’s als screening test van CHF, deze NP’s nog steeds weinig gebruikt worden
als biomarker bij residentiële ouderen. Het beperkte gebruik bij ouderen wordt veroorzaakt
doordat de afkapwaarden van NP’s in deze groep onvoldoende gevalideerd zijn. Tot slot werden
de ECG’s van alle residentiële ouderen beoordeeld.
Een cardiologenpanel stelde de diagnose CHF vast of sloot deze uit door, achtereenvolgens de
uitslagen van de NP’s en resultaten van echocardiografie te beoordelen. Echocardiografisch
onderzoek bleek mogelijk in 98% van de ouderen. Het resultaat van de huidige studie was dat
CHF werd bevestigd in 24/103 (23%) van de residentiële ouderen. Voorafgaand aan de stu-
die, werden 22 ouderen geïdentificeerd met CHF. Bij deze 22 ouderen met CHF, vastgesteld
voorafgaand aan de studie, werd CHF bevestigd bij 9 ouderen en bij 13 ouderen werd de dia-
gnose CHF verworpen. De diagnostische accuratesse van NT-proBNP bij 450 pg/mL bestond
uit een sensitiviteit van 0,71, specificiteit van 0,67, positief voorspellende waarde (PPV) van
0,42 en negatief voorspellende waarde (NPV) van 0,91. De diagnostische accuratesse van
BNP bij 100 pg/mL toonde een 0,71 sensitiviteit, 0,70 specificiteit, 0,41 PPV en 0,88 NPV.
In het kort waren de meest opvallende resultaten van de huidige studie dat meer dan de helft
van de CHF diagnoses werd gemist (namelijk 15/24) of onjuist werd gesteld (namelijk 13/22).
Daarom kan worden geconcludeerd dat het identificeren van CHF inaccuraat is. Maar uitgaande
van de hoge NPV, lijkt het gebruik van NP’s als additionele diagnostische test veelbelovend,
zelfs bij residentiële ouderen. Het laatste moet echter nog nader worden geëvalueerd. De CHF-
prevalentie onder residentiële ouderen werd vastgesteld op 23%.
202
In Hoofdstuk 2.2 is onderzocht of de uitkomsten van hoofdstuk 2.1 consistent zijn met de CHF-
prevalentie in Arubaanse verpleeghuizen. Er werd voor Arubaanse verpleeghuizen gekozen
vanwege onze interesse in een vergelijkbare onderzoekspopulatie met die in Nederland, die
echter woont in een andere omgeving en er een andere levensstijl op na houdt. Er werd gebruik
gemaakt van hetzelfde studieontwerp zoals gehanteerd in hoofdstuk 2.1 om de prevalentie van
CHF bij Arubaanse residentiële ouderen te berekenen.
Een ander doel was het maken van een inschatting of de toepassing van NP’s voor het opspo-
ren van CHF bij residentiële ouderen in een ander deel van het Nederlands Koninkrijk verbeterd
kan worden. Het belangrijkste verschil met de studie uit hoofdstuk 2.1 was dat er geen echocar-
diogram van alle residentiële ouderen kon worden verkregen vanwege logistieke belemmerin-
gen. Daarom kon niet worden voldaan aan de diagnostische standaard voor CHF (2-4). Als
resultaat werden 51 van de 235 Arubaanse ouderen met een gemiddelde leeftijd van 78±8 jaar
in de studie opgenomen. Afgaand op de medische gegevens, werd CHF vastgesteld bij 7/51
ouderen. Echter twee van de zeven ouderen hadden geen CHF. Verder werd CHF bevestigd bij
16 van de 51 (31%) ouderen. Van de 16 ouderen met CHF, waren 11 niet eerder gediagnosti-
seerd met CHF en van 5/16 ouderen bij wie CHF eerder was vastgesteld, werd de diagnose
bevestigd.
Kort gezegd, de algemene richtlijnen voor HF worden laagfrequent toegepast bij Arubaanse
residentiële ouderen. Vergeleken met residentiële ouderen uit Groningen, is de prevalentie van
CHF waarschijnlijk minstens zo hoog onder de Arubaanse residentiële ouderen. Als conclusie
blijkt de herkenning van CHF ernstig onderschat te worden onder Arubaanse residentiële oude-
ren. De opsporing van CHF kan worden verbeterd door een geschikte richtlijn te implementeren,
inclusief de bepaling van BNP.
Hoofdstuk 2.3 behandelt het probleem van de grote intra-individuele variaties [individuele va-
riatie coëfficiënt (CVi)] van NT-proBNP in plasma, aangezien grote CVis de toepasbaarheid van
NT-proBNP beperken voor o.a. de NT-proBNP-geleide therapieoptimalisatie bij individuele pati-
203
enten met CHF (5). Op zoek naar meer betrouwbare CVis werden de concentraties van urine-
NT-proBNP (NT-proBNPu) vergeleken met die van plasma-NT-proBNP (NT-proBNPp) bij pati-
enten met CHF woonachtig op Curaçao. Op één enkele dag ("op-1-dag") werden urine en
bloed monsters afgenomen: zes bloedmonsters elke 2 uur en de spontaan uitgeplaste urines
gedurende 24 uur. Op vijf opeenvolgende dagen ("dag-tot-dag") werden verzameld: vijf
bloedmonsters, vijf geforceerd uitgeplaste urine monsters en vijf volledige 24-uurs urines. Op
dezelfde dag van zes opeenvolgende weken ("week-tot-week") werden verzameld: één
bloedmonster, één geforceerd uitgeplast urinemonster en een volledige 24-uurs urine.
Uit deze bloed- en urinemonsters werden de totale CVs (CVts), de CVis en de coëfficiënten van
het percentage verandering van de referentiewaarden (RCV) berekend. In de studie werden 25
patiënten met CHF opgenomen met een gemiddelde leeftijd van 61 jaar (spreiding 36-80),
60% was man en de gemiddelde linker ventrikel ejectiefractie (LVEF) was 36±15%. De media-
ne CVis voor NT-proBNPp waren 9% (“op-1-dag”), 18% (“dag-tot-dag”) en 30% (“week-tot-
week”).
De CVis van NT-proBNPu waren respectievelijk 34%, 21% en 28%. De RCV van NT-proBNPu
was hoger dan of gelijk aan de RCV van NT-proBNPp, zelfs na correctie voor creatinine en de
periode (in uren) waarin de urine zich in de blaas had verzameld. De gegevens van de “dag-
tot-dag” en “week-tot-week” monsters doen vermoeden dat (immunoreactive) concentraties van
NT-proBNPu in de urine niet ondubbelzinnig correleren met de (immunoreactive) NT-proBNP concentraties in plasma, tot aan de NT-proBNPp drempel van ongeveer 310 pg/mL (Figuur 1).
Daarnaast werd opgemerkt dat boven deze drempel de hogere NT-proBNP concentraties, zoals
weergegeven in Figuur 1, niet verklaard kunnen worden door een verhoging van de bloeddruk
gedurende de dag (resultaten niet weergegeven).
Veronderstelt kan worden dat filtratie van natriuretische peptiden kan worden beschouwd als
dominante factor voorbij de drempelwaarde en dat bij lagere NT-proBNP-waarden, filtratie en
terugresorptie meer dynamisch interacteren. Geconcludeerd kan worden dat het bepalen van
NT-proBNP in urine geen voordelen biedt bij patiënten met stabiel chronisch hartfalen.
204
Figuur 1. De relatie tussen NT-proBNP in plasma and NT-proBNP in geforceerd uitgeplaste
urines verzameld volgens de “dag-tot-dag” en “week-tot-week” protocollen.
De data zijn afkomstig van 22 patiënten en in totaal 182 corresponderende plasma en
urine monsters. De “dag-tot-dag”- en week-tot-week”-bloedmonsters werden gebruikt. Voor de
urine werden de geforceerd uitgeplaste urinemonsters gebruikt.
In hoofdstuk 3 werd de prognostische waarde onderzocht van NP’s op de sterfte in één jaar bij
hetzelfde cohort residentiële ouderen dat werd bestudeerd in hoofdstuk 2.1. De klinische rele-
vantie hiervan is dat als NP’s gerelateerd worden aan de prognose van residentiële ouderen
met CHF, deze biomarkers kunnen worden benut voor “advance care planning”. Deze vorm van
205
zorgplanning is gerelateerd aan de kwaliteit van leven en wordt belangrijk wanneer de levens-
verwachting beperkt is (www.Verenso.nl). Om de sterfte in één jaar te onderzoeken, werden
gedurende één jaar de overleving en het overlijden van residentiële ouderen bijgehouden. Om-
dat tien residentiële ouderen niet konden worden vervolgd doordat zij naar onbekende bestem-
mingen verhuisden onderzochten we de resterende 93 residentiële ouderen.
Achttien uit 93 bewoners (gemiddelde leeftijd 81 ± 3 jaar, 66% vrouw) stierven binnen één
jaar(niet-overlevenden).
Een wederzijds aangepaste Cox proportionele risico regressieanalyse werd uitgevoerd. Er von-
den correcties plaats voor zes vooraf gedefinieerde chronische ziekten, immobilisatie, leeftijd,
geslacht, NT-proBNP en BNP.
De gevonden resultaten lieten zien dat beide NP’s (NT-proBNP en BNP) de één-jaars sterfte
significant voorspelden (respectievelijk, HR 1,02 en p = 0,001 en HR 1,16 en p = 0,003). Bo-
vendien nam het risico op overlijden in één jaar exponentieel toe parallel aan de stijging van
BNP en NT-proBNP in de hogere concentraties. Bijvoorbeeld, een toename van NT-proBNP tot
2.000 pg/mL was geassocieerd met een 60% hoger risico op overlijden binnen één jaar.
Concluderend zijn zowel BNP als NT-proBNP onafhankelijke voorspellers van de één-jaars
mortaliteit onder residentiële ouderen met CHF. Daarbij neemt het sterfterisico toe bij NP con-
centraties die verhoogd zijn tot ver boven de diagnostische afkapwaarden van de richtlijnen (2-
4). In hoofdstuk 4 is de relatie bestudeerd tussen CHF en de steun die nodig is voor residentiële
ouderen met CHF tijdens hun activiteiten van het dagelijks leven (ADL). Daarvoor werd hetzelf-
de cohort residentiële ouderen onderzocht als in hoofdstuk 2.1. Het doel van deze studievraag
was aandacht te trekken van zorgteams voor de behoefte aan steun onder residentiële ouderen
met CHF.
Voor deze studie werd dezelfde groep residentiële ouderen onderzocht als in hoofdstuk 2.1. Om
gegevens over ADL te verzamelen, werden de “Minimal Data Set (MDS)” items van het “Resi-
dent-Assistant Instrument” gebruikt. De MDS bestaat uit systematische observaties van de af-
206
hankelijkheid en van de geboden ondersteuning en heeft als doel om de afhankelijkheid en de
hulp te kwantificeren (6). Het MDS instrument is in feite een softwareprogramma voor de invoer
van observaties van individuele residentiële ouderen tijdens vast omschreven ADL. Een voor-
beeld van een dergelijke activiteit is lopen. De verzorgende observeert en scoort (kwantificeert)
of het individu in staat is om bepaalde afstanden onafhankelijk te lopen en of hij hulp nodig
heeft bij het lopen. Van de 103 residentiële ouderen met en zonder CHF, werden de scores van
ADL-afhankelijkheid en ADL-hulp vergeleken en gecorrigeerd voor de verschillen tussen beide
groepen door middel van multivariabele logistische regressieanalyse. CHF was geassocieerd
met ADL-hulp (OR 4,68 en p=0,015) echter, CHF was niet gerelateerd aan de ADL-
afhankelijkheid.
Geconcludeerd kan worden dat CHF bij residentiële ouderen geassocieerd is met de behoefte
aan meer ADL-hulp. In dit verband is CHF van belang voor zowel de residentiële ouderen (ver-
lies van autonomie en levenssatisfactie) als ook voor de organisatie (personele inzet).
In hoofdstuk 5 wordt een fysiek oefenprogramma onderzocht onder residentiële ouderen met
CHF. De reden voor deze studie is inzicht te verkrijgen in de gevonden discrepantie tussen de
sedentaire levensstijl van residentiële ouderen en de gedane aanbevelingen voor fysieke activi-
teit van de HF-richtlijnen (2-4). Ook stimuleren familieleden hun ouders in verzorgingshuizen
om lichamelijk actief te worden. Echter, om diverse redenen blijven residentiële ouderen liever
sedentair. Bovendien, uit angst voor vallen, geven ook verzorgers er de voorkeur aan dat resi-
dentiële ouderen zoveel mogelijk sedimentair zijn.
Een sedentaire levensstijl is gerelateerd aan een verhoogd risico op toename van atherosclero-
se en CV-metabole ziekten, zoals CHF en het metabool syndroom (7).Onderzocht werd of li-
chamelijke training een gunstige invloed had op symptomen van CHF, NT-proBNP, het meta-
bool syndroom en CV-metabole indices bij residentiële ouderen. Een pilot, enkelvoudig-
207
geblindeerde, gerandomiseerde en gecontroleerde haalbaarheidstudie werd uitgevoerd in vier
verzorgingstehuizen. In samenwerking met andere onderzoekers (9) werd bestudeerd of een
gestandaardiseerd trainingsprogramma invloed heeft op symptomen van CHF, NT-proBNP en
het metabool syndroom. De andere onderzoekers (8) onderzochten of hetzelfde gestandaardi-
seerde oefenprogramma de, door hen gekozen, meer functionele eindpunten beïnvloedt in ver-
gelijkbare groepen. De trainingsinterventie omvatte een begeleide training van matig-tot-hoge
intensiteit van één uur, twee keer per week gedurende 16 opeenvolgende weken. De training
bestond uit progressieve weerstandstraining van bovenste en onderste extremiteiten en van de
romp, uit statische en dynamische evenwichtstraining en uit functionele training. De interventie
van de controle groep bestond uit een begeleid, niet-fysiek, sociaal programma van dezelfde
frequentie, duur, lengte en locatie. De studie eindpunten bestonden uit symptomen van CHF
(vermoeidheid, kortademigheid), en NT-proBNP, uit lichaamsmetingen en uit laboratoriumresul-
taten, die als combinatie bekend zijn als parameters van het "metabool syndroom". Het syn-
droom is gedefinieerd als aanwezigheid van drie uit vijf lichaamsmetingen en laboratoriumresul-
taten. Deze metingen omvatten de taille, de bloeddruk, de nuchtere glucose, de triglyceriden en
het high-density lipoproteïne (HDL)-cholesterol. Glucose wordt vervangen door geglyceerd he-
moglobine (HbA1c), aangezien een nuchtere bloedafname logistiek niet haalbaar bleek te zijn.
Als resultaat, kwamen van de 434 residentiële ouderen, 163 in aanmerking voor deelname.
Helaas, waren slechts 52 (12%) bereid om deel te nemen aan de studie. Van deze 52, vielen
er zes af tijdens de studie vanwege redenen die niet waren gerelateerd aan de training. De res-
terende 46 deelnemers waren 85±6 jaar, 65% was vrouw en allen werden gerandomiseerd
voor trainingsgroep (n=24) of controle groep (n=22). De “intention-to-treat analyse” toonde
geen significante verandering van welke variabele dan ook bij de trainingsgroep vergeleken met
de controles. De groep die geanalyseerd werd “as-treated” voltooide de helft of meer van de 32
trainingssessies. De vrouwen van de laatstgenoemde groep bleken een afname van taille om-
vang te hebben [-8 (spreiding -15--2) cm]. De controles toonden een significante verlaging
van triglyceriden [-8 (-17-0) mg/dL] en een stijging van NT-proBNP [67 (7-126) pg/mL].
208
Het aantal bijgewoonde sessies was omgekeerd gerelateerd aan de niet-nuchtere triglyceriden
bij de trainingsgroep (p = 0,024). Wij concludeerden dat fysieke training onder begeleiding,
uitgevoerd door residentiële ouderen gedurende een korte periode, geen effect had op sympto-
men en een biomarker van CHF, noch op CV-metabole indexen. Een mogelijke verklaring voor
de neutrale resultaten is de hoge leeftijd van de residentiële ouderen (gemiddeld 85 jaar), die
gepaard gaat met een verlies van spieruithoudingsvermogen en door een trainingsaanbod dat
onvoldoende is afgestemd op het individu.
209
Kort samengevat zijn de resultaten van deze thesis: de prevalenties van CHF bij residentiële ouderen zijn 23% in Groningen hetgeen strookt
met de literatuur (9), en >30% op Aruba (hoofdstukken 2.1 en 2.2).
bij Nederlandse residentiële ouderen komt CHF vaak voor. Het gebruik van natriureti-
sche peptiden, als aanvullende test voor CHF, moet verder bestudeerd worden. Bij resi-
dentiële ouderen in Groningen, kunnen onjuiste diagnoses van CHF worden terugge-
bracht door diagnostisch natriuretische peptiden toe te passen (hoofdstuk 2.1 en 2.2).
bepaling van NT-proBNP concentraties in de urine van patiënten met CHF heeft geen
voordelen vergeleken met plasma-NT-proBNP concentraties. Deze bevinding komt voort
uit de grote intra-individuele variabiliteit van urine-NT-proBNP die vergelijkbaar is met
die in plasma-NT-proBNP (hoofdstuk 2.3).
bij residentiële ouderen, zijn bepalingen van natriuretische peptiden van prognostische
betekenis (HR van NT-proBNP 1,02 en BNP 1,16 (HR van BNP is 2.2 (10)), waarbij
het resultaat van BNP overeenkomt met dat in de literatuur (10) (hoofdstuk 3).
CHF bij residentiële ouderen is gerelateerd aan de behoefte aan meer ADL-hulp verge-
leken met ouderen zonder CHF (hoofdstuk 4).
een korte periode van training uitgevoerd door residentiële ouderen heeft geen effect op
CHF noch op CV indices (zoals b.v. het metabool syndroom). Er zijn geen studies voor-
handen om dit te kunnen vergelijken (hoofdstuk 5).
210
211
Hoofdstuk 7.2
DISCUSSIE
212
We toetsten onze hypothese (Introductie) die stelt dat de diagnostiek van niet-acuut HF, zoals
die aanbevolen wordt in de algemene HF richtlijnen (2-4), niet toegepast kan worden op resi-
dentiële ouderen. Daartoe, gebruikten we de afkapwaarden van de natriuretische peptiden
(NP’s) zoals aanbevolen door de HF richtlijnen (2-4) in het cohort Groninger residentiële oude-
ren (hoofdstuk 2.1). Het is van belang te vermelden dat zowel de ESC als de Multidisciplinaire
HF richtlijn (2;3) dezelfde afkapwaarden adviseren (NT-proBNP 125 and BNP 35 pg/mL) en
dat de laatste waarden lager zijn vergeleken met die van de NICE HF richtlijn (namelijk NT-
proBNP 400 and BNP 100 pg/mL) (4). Gebruikmakend van deze afkapwaardes uit de richtlij-
nen, berekenden we de voorspellende waarden voor de diagnose CHF, in residentiële ouderen van één Gronings verpleeghuis (Tabel 1). Tevens bepaalden we de voorspellende waardes ook
bij hogere afkapwaarden zoals bij NT-pro BNP 900 pg/mL en BNP 100 pg/mL. Jaren na onze
studie publiceerde Mason et al. (11) een artikel over voorspellende waarden van NP’s voor CHF
bij Engelse residentiële ouderen. De afkapwaarden van de studie van Mason et al. verschilden
weinig van die uit onze studie. De laatstgenoemde studie groep valideerde haar resultaten met de NT-proBNP en BNP afkapwaarden volgens de NICE guideline (4)(Tabel 1).
213
Tabel 1. Voorspellende waarden van NT-proBNP en BNP voor de diagnose hartfalen
in twee populaties residentiële ouderen: de Groninger (NL) (hoofdstuk 2.1) en de Britse
populatie (11).
afkapwaarde
pg/mL sensitiviteit specificiteit PPV NPV
Groninger RE (NL)
NT-proBNP1 125 1.00 0.28 0.29 1.00
NT-proBNP 450 0.71 0.67 0.42 0.91
NT-proBNP 900 0.67 0.85 0.56 0.89
BNP1 35 0.88 0.39 0.30 0.91
BNP 50 0.88 0.63 0.31 0.89
BNP2 100 0.71 0.70 0.41 0.88
British RE (11)
NT-proBNP2 400 0.56 0.69 0.35 0.84
NT-proBNP 760 0.62 0.75 0.42 0.87
BNP 115 0.67 0.68 0.38 0.88
Residentiële ouderen (residential elderly), RE; Nederland, NL; PPV, positief voorspellende
waarde; NPV, negatief voorspellende waarde; NT-proBNP, N-terminal amino pro B-type natri-
uretic peptide; B-type natriuretic peptide.
1 ESC HF richtlijn (2) en multidisciplinaire HF richtlijn (3)
2 NICE HF richtlijn (4).
De groep van Mason (11) en wij onderzochten niet uitsluitend NP’s maar ook combinaties van
medische voorgeschiedenis, klachten en symptomen, ECG, en NP’s met het doel om CHF aan
te tonen. Wij beiden vonden dat geen van de mogelijke combinaties van parameters, de voor-
214
spellende waarden verbeterde vergeleken met die berekend met behulp van NP’s alleen. De
resultaten van Mason’s studiegroep, vooral wat betreft de PPV, komen goed overeen met onze
bevindingen.
Beide onderzoeksgroepen rapporteren ook dat toepassing van de HF richtlijnen (2-4) op Ne-
derlandse en Engelse residentiële ouderen, daarin resulteert dat meer dan de helft van de CHF
diagnoses gemist worden (te veel fout negatieven). Ook verlaging van de afkapwaarden (2;3)
ten opzichte van de NICE richtlijn (4) levert geen enkele verbetering op. Samen met de Mason
groep, komen we tot de conclusie dat de gevonden voorspellende waarden ongeschikt zijn om
CHF aan te tonen maar alleen geschikt zijn om CHF uit te sluiten.
Daarom besloten we om in dit proefschrift het algoritme van de Multidisciplinaire HF richtlijn (3)
aan te passen voor residentiële ouderen. Deze aanpassingen houden in dat NP’s alleen ge-
bruikt worden om CHF uit te sluiten, dat echocardiografie noodzakelijk is om CHF aan te tonen,
dat de afkapwaarden uit de NICE richtlijn (4) gebruikt worden, en dat echocardiografie ook door
laboratoria voor de eerstelijnsgezondheidszorg uitgevoerd worden (www.Certe.nl).
Toch toonde Oudejans et al. (12) aan bij geriatrische poliklinische patiënten van wie >40%
CHF had, dat de bepaling van NP’s in combinatie met andere diagnostische tests wel degelijk
accuraat is om zowel CHF aan te tonen als om CHF uit te sluiten. Waarschijnlijk was de PPV
voor CHF bij ons onderzoekscohort lager omdat de vooraf kans op CHF lager was door de la-
gere CHF prevalentie 23%, vergeleken met de vooraf kans bij de poliklinische patiënten (CHF
prevalentie >40%). In tegenstelling tot de resultaten van de Oudejans groep (12) maar in
overeenstemming met de resultaten van Mason et al. en onze studie groep [Chapter 1.2 en
(11)], hebben we onze aanbevelingen voor residentiële ouderen bijgesteld. Onze hypothese is
deels verworpen omdat de algemene HF richtlijnen ongeschikt zijn om CHF aan te tonen bij
residentiële ouderen. Daarnaast werd onze hypothese deels aanvaard omdat CHF wel uitge-
sloten kan worden met behulp van NP’s volgens de HF richtlijnen.
215
Uitgaande van onze pas verworven inzichten wordt geadviseerd om een echocardiogram te la-
ten maken om CHF aan te tonen. Theoretisch worden NP’s aanbevolen om CHF uit te sluiten
alhoewel we ons realiseren dat uitsluiten van CHF niet volstaat in de dagelijkse praktijk. Deze
adviezen hebben we opgenomen in een diagnostisch algoritme voor CHF (d.w.z. niet-acuut HF) voor residentiële ouderen (Figuur 1).
216
217
Hoofdstuk 7.3
AANBEVELINGEN EN TOEKOMST PERSPECTIEVEN
218
In de discussie stelden we vast dat algemene HF richtlijnen ongeschikt zijn om CHF te diagnos-
tiseren bij residentiële ouderen. Ook is bij de individuele residentiële oudere, een echocardio-
gram essentieel om de diagnose CHF te stellen. Daartoe hebben we het Nederlandse diagnos-tische algoritme voor alle CHF patiënten (3), aangepast aan die specifieke groep (Figuur 1). In
de toekomst is het van essentieel belang om dit aangepaste diagnostische CHF algoritme te
toetsen op accuratesse en kosten. Daarom raden we aan om het aangepaste diagnostische
CHF algoritme te valideren in nieuwe populaties residentiële ouderen.
In de introductie, het hoofdstuk over HF diagnostiek benadrukten we de beperkte mogelijkheden
om een echocardiogram aan te vragen. Met de recente beschikbaarheid van echocardiografie
voor eerstelijns patiënten in Nederland, lijkt die barrière, om CHF accuraat te diagnostiseren
geslecht te zijn. Aansluitend pleiten we ervoor om een echocardiogram thuis of in de instelling
te kunnen maken voor die residentiële oudere die immobiel zijn.
We geven redacteuren van de Multidisciplinaire HF richtlijn (3) in overweging om de richtlijn
aan te passen aan residentiële ouderen. De aanpassingen betreffen alleen niet-acuut HF. De
wijzigingen bestaan daar uit dat CHF alleen kan worden aangetoond met een echocardiogram,
dat CHF uitgesloten kan worden met NP’s en dat ook verwezen kan worden naar eerstelijns
laboratoria voor echocardiografie (www.Certe.nl).
In Hoofdstuk 3 presenteerden we de prognostische betekenis van NP’s voor één-jaars overle-
ving van residentiële ouderen met bewezen CHF. Op grond daarvan wordt geadviseerd om een
NP bepaling toe te voegen aan de palliatieve zorgplanning voor (residentiële) ouderen met een
beperkte levensverwachting. We laten in Hoofdstuk 4 de relatie zien tussen CHF en de behoefte aan meer ADL-hulp verge-
leken met residentiële ouderen zonder CHF. Vanwege deze relatie raden we zorgteams aan om
oog te hebben voor toegenomen behoeften aan ADL-hulp van residentiële ouderen met CHF.
219
Hoofdstuk 5 leert ons dat bij residentiële ouderen die trainden gedurende vier maanden, geen
verandering gezien werd van CHF noch van CV-metabole indices. Het uitblijven van verbetering
werd verklaard door de hoge leeftijd en het bijkomend verlies van spieruithoudingsvermogen.
Bovendien was de frequentie van trainen te laag en de duur te kort hetgeen ook bijdroeg aan
het uitblijven van effect. Op basis hiervan wordt aanbevolen om, in de toekomst, residentiële
ouderen te bestuderen tijdens en na een individueel trainingsprogramma van drie maal per
week gedurende een langere tijd. Een voorbeeld van een individueel programma vormt de mo-
gelijkheid voor de oudere om zelf zijn trainingsvorm te kiezen. Dergelijke programma’s lijken
effectiever te zijn dan vaststaande programma’s. Bovendien wordt sterk aangeraden om regel-
matig aandacht te besteden aan de motivatie van residentiële ouderen om te trainen omdat we
te maken hadden met een klein aantal deelnemers in onze studie (Hoofdstuk 5).
Uitgaande van onze resultaten die deels verwerkt zijn in het diagnostisch CHF algoritme speci-
fiek voor residentiële ouderen (chapter 6.2), doen we de volgende aanbevelingen:
Aan redacteuren van medische bijscholing (bv CME-scholing.nl), geven we de suggestie om
onze nieuwe inzichten op het gebied van CHF te verwerken in bijscholingen voor specialisten
ouderengeneeskunde (SO). Het gaat om de gevonden CHF prevalentie van tenminste 23% bij
residentiële ouderen. Bovendien dat CHF bij voorkeur gediagnostiseerd wordt volgens het dia-gnostische CHF algoritme dat we aangepast hebben aan residentiële ouderen (Figuur 1). Ver-
der dat palliatieve zorg voor de residentiële oudere beter gepland kan worden door gebruik te
maken van een natriuretische peptide bepaling. Ook van belang is dat noch CHF symptomen
en een CHF marker, noch CV-metabole indices bij residentiële ouderen verbeteren na een vier
maanden durende training. Daarentegen is het niet onmogelijk dat fysieke training voordelen
oplevert wanneer de training langere periode plaatsvindt en op individuele leest geschoeid is.
Hieronder wordt verstaan dat de oudere zelf kiest of hij gaat lopen, fietsen, zwemmen of de
fitnessclub bezoekt.
220
ouderengeneeskunde 1e lijn
HF polikliniek
Figuur 1. Diagnostisch algoritme voor niet-acuut hart falen bij residentiële ouderen. NT-proBNP, B-type natriuretic peptide; NT-proBNP, amino-terminaal-pro BNP; SO, specialist ouderengeneeskunde; HFrEF, hartfalen met afgenomen ejectie fractie; HFpEF, hartfalen met behouden ejectie fractie.
Residentiële ouderen met klachten en symptomen verdacht voor niet-acuut hartfa-len (HF) in een zorginstelling of eerstelijnsgezondheidszorg
Lichamelijk onderzoek, ecg, lab. Overweeg comorbiditeit, toename HF en verwijzing cardioloog
NT-proBNP<400 pg/mL of BNP<100 pg/mL, afwijkend ECG
HF is onwaarschijnlijk, overweeg andere oorzaken van klachten
Patient bij wie HF niet is vastge-steld
Lichamelijk onderzoek, ecg, NT-proBNP of BNP (Hb, eGFR, TSH, K+, glucose)
Patient met de diagnose HF
echocardiografie
HFrEF / HFpEF is waarschijnlijk
Onderzoek naar (behandelbare) oorzaak HF
Analyse van oorzaak/ geen behan-delbare oorzaak van HF
Overleg met SO/HA over gewenste behandeling. Behandeling
Verwijzing terug naar SO/HA met behandeladvies
Behandeling van HF door SO of huisarts (HA)
ja
Neeno Neg.
Pos.
221
DANKWOORD
Jaren geleden stond ik bij een verpleeghuisbewoner verdacht van hartfalen. Bij het raadplegen
van de toen vigerende richtlijnen voor hartfalen, dacht ik direct dat de diagnostiek van hartfalen
beter moest kunnen. Nu schrijf ik het dankwoord van mijn proefschrift waarin ik aantoon dat de
kwaliteit van leven van verpleeghuisbewoners met hartfalen inderdaad verbetert als je de dia-
gnose correct stelt. Veel is daaraan vooraf gegaan. Het is fantastisch dat dit gelukt is. De vele
mensen die hieraan hebben bijgedragen wil ik graag bedanken.
Mijn eerste dank gaat uit naar de verpleeg- en verzorgingshuisbewoners, hun mantelzorgers en
de patiënten. Zonder hen waren de onderzoeken niet mogelijk geweest.
Prof. dr. F.A.J. Muskiet, beste Frits, van het begin af aan was je enthousiast om (NT-pro)BNP
te gaan bepalen bij verpleeghuisbewoners in het kader van hartfalen diagnostiek. Na elke on-
derzoeksbespreking, gaf je “college” niet alleen over hartfalen, (patho)fysiologie, veroudering
en insuline resistentie, maar ook over laag-gradige ontsteking o.a. in de hersenen, vitamine D
en life-style. Ik heb gretig naar je geluisterd. Van jou heb ik geleerd op het scherpst van de
snede te discussiëren.
Prof. J.L. Hillege, beste Hans, je vroeg altijd eerst wat ik wilde bereiken met het onderzoek.
Daarna kwam je een met een praktisch voorstel voor berekeningen. Je hebt bijgedragen aan de
groei van mijn statistisch inzicht.
Dr. M.J.L. de Jongste, beste Mike, je hebt me altijd positief gesteund bij het verwezenlijken van
dit proefschrift. Bij het maken van onderzoeksdesigns, zei je dat je je tijd ver vooruit was. Dat
bleek ok zo te zijn. Ons onderzoeksdesign werd later op grote schaal toegepast. Ook heb je mij
goed begeleid bij het raadplegen van anderen op het juiste moment. Ik heb heel veel van je
geleerd. Elk overleg gaf mij hernieuwde energie en richting. Daarvoor wil ik je hartelijk bedan-
ken. Dr. I.C.C. van der Horst, beste Iwan, dank voor je opbouwende commentaar. Prof. dr. R.A.
de Boer, beste Rudolf dank voor de prettige samenwerking.
222
De leden van de beoordelingscommissie wil ik hartelijk bedanken voor de tijd die ze hebben
genomen om mijn proefschrift te beoordelen: prof. de. W.P. Achterberg (beste Wilco) en prof.
dr. A.W. Hoes. Prof. dr. A.A. Voors, beste Adriaan, fijn dat je de tijd hebt genomen om mijn
proefschrift te beoordelen en dat je de tijd gaat nemen om te opponeren.
In het verpleeghuis “het Zonnehuis-Noord”, Zuidhorn is mijn onderzoek begonnen. Samen met
jullie, Mike en Frits, hebben we ons voorstel voor hartfalen diagnostiek met behulp van (NT)-
proBNP geïntroduceerd en konden we van start. Drs. J. Koster, beste Johan dank voor jouw
inspanning om goede (98%) echografische afbeeldingen te maken. Dank aan de laboratorium
medewerkers van het Zonnehuis, jullie waren altijd bereid om bloed af te nemen en ecgs te
maken, en dank aan de administratieve medewerkers voor jullie hulp bij het regelen van afspra-
ken. Heel prettig om met je samen te werken, Judith, in de (voormalige) Westerburcht. Ik be-
waar goede herinneringen aan de tweejaarlijkse onderzoeksbesprekingen met de Zonnehuis-
groep in Soesterberg. Dank Zonnehuisgroep voor de financiële steun.
Dankzij de flexibiliteit van jullie, dr. E. Weening en dr. M.H.G. de Greef, konden we aanhaken
aan het bewegingsonderzoek in vier verzorgingshuizen in Groningen. Ik heb de samenwerking
met jou Betsie, en de gesprekken met jou, Mathieu als heel inspirerend ervaren. Het manage-
ment team van De Hoven, hebben het ons financieel mogelijk gemaakt om ecgs en NT-proBNP
bepalingen te laten doen. Mijn dank gaat uit naar de interesse voor ons onderzoek die de We-
tenschappelijke Raad van De Hoven, Prof. dr. D.L. Knook en Meindert Bolt hebben getoond.
Dank voor de leuke samenwerking met jullie, de bewegingsmedewerkers uit Appingedam.
Van het Universitair Medisch Centrum Groningen (UMCG), wil ik bedanken Eduard Heine, voor
het bewaren van onze bloedmonsters op het laboratorium. Egbert Knol, je hebt statistische be-
werkingen van de scorelijsten goed uitgelegd, bedankt. Alma Guikema, dank je voor je hulp bij
het printen en verzenden van de boekjes. Eline, ik heb het als verrijking ervaren om samen met
je te schrijven aan het onderzoek dat je op Aruba hebt uitgevoerd. Wat hebben we gestaag ge-
223
werkt aan ons stuk, Anneliene. Ik heb respect voor je nauwkeurigheid van data verwerking.
Dank je voor onze prettige samenwerking op afstand.
Beste Corina, Jos, Meindert, Evert, Luch, Hilde, Nazir, Judith en Victoria, wat zijn onze toets-
groep bijeenkomsten van belang geweest. Daarin konden we veilig moeilijkheden en mogelijk-
heden bespreken in de ouderengeneeskunde. Hartelijk dank daarvoor.
Christien, we hebben niet alleen gezocht naar goeie Engelse termen. Ik ervaar het als heel
prettig om levensvragen met je te bespreken en daarna samen te lachen. Zo’n vriendschap
geeft kracht. Ik ben zo blij dat je een van mijn paranimfen bent. Daphne, dank voor je Engelse
woorden! Ria, dank voor de vele gesprekken over hoe onze doelen te bereiken. Feilloos wist je
direct knelpunten te noemen en deze te relativeren met een lach. Laten we daarmee doorgaan.
Lex, dank voor je bijdrage aan het Nederlands. Ik mag je niet bedanken Engbert, maar noem
hier wel je bijdrage aan tekst en opmaak.
Als laatste maar zo belangrijk, kom ik toe aan mijn familie. Lieve Els en Hanneke, jullie zijn als
zussen een inspiratie bron voor mij hoe te gaan voor wat je wilt. Altijd heb ik steun gevoeld bij
je in dit traject. Ik ben er trots op Els, dat je mijn paranimf bent.
Lieve Philip, Erik, Wendelien en Sunna, er is in de wereld geen groter geluk dan jullie. Dankzij
jullie, doe ik mee met de, voor mij “volgende generatie”. De warmte en humor die ik voel als
we bij elkaar zijn, maken me tot een gelukkig mens. Patijn, Rick, Froukje en Danielle, dank je
wel dat jullie ons zijn komen versterken. En Quinten, dankzij jou heb ik een nieuwe rol.
Tenslotte, Willem, jou wil ik bedanken voor alle jaren continue steun. Steeds heb je meege-
dacht over mijn toekomst, welke stappen ik zou zetten. Je hebt vele uren alleen doorgebracht
als ik achter de pc zat. Met al mijn liefde draag ik dit proefschrift aan je op. Je bent de belang-
rijkste in mijn leven die dit allemaal mogelijk heeft gemaakt. Je bent mijn basis van waaruit ik
kan groeien. Ik kijk ernaar uit dat we weer meer tijd hebben voor elkaar.
224
CURRICULUM VITAE
Maaike Barents obtained her medical degree in 1977 at the Rijks Universiteit Groningen
(RUG). She started to investigate the diagnosis of cow’s milk allergy among infants while work-
ing for the Dutch Youth Health Organization in cooperation with the UMCG, Children’s Depart-
ment (prof. dr. H.S.A. Heymans).
In 1994, she acquired her specialty degree as physician-sexuologist at the Dutch Society of
Sexuologists, NVVS.
After her residency in the Academic Rehabilitation Centre in Haren (prof. Dr. J.H. Arendzen and
drs. L.D.W. Vos) she decided to specialize in elderly care medicine at the Free University of
Amsterdam in collaboration with nursing home het Zonnehuis in Zuidhorn. In the same time, she
took the initial steps for the work as described in this thesis in collaboration with the UMCG
(Thorax centre, Department of cardiology (dr. M.J.L. de Jongste) and Department of Clinical
Chemistry (prof. F.A.J. Muskiet)). When settled as elderly care physician in Groningen and in
addition to patient care, she completed her Ph D work at the last described Department. She is
married to Willem Bohmers and they have two sons (Philip, 1978 and Erik, 1980) and two
daughters (Wendelien, 1982 and Sunna, 1984).