Impact of age on cardiovascular drug use in patients with chronic kidney disease

Abstract

Background:
Elderly patients with chronic kidney disease (CKD) are often excluded from clinical trials; this may affect their use of essential drugs for cardiovascular complications. We sought to assess the impact of age on cardiovascular drug use in elderly patients with CKD.

Methods:
We used baseline data from the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort including 3033 adult patients with CKD Stages 3 and 4. We studied the use of recommended drugs for coronary artery disease (CAD), stroke and atrial fibrillation by age, after adjusting for socio-demographic and clinical conditions.

Results:
The patients' mean age was 66.8 years (mean estimated glomerular filtration rate 32.9 mL/min/1.73 m2). The prevalence of CAD was 24.5% [81.3% receiving antiplatelet agents, 75.6% renin-angiotensin system (RAS) blockers, 65.4% β-blockers and 81.3% lipid-lowering therapy], that of stroke 10.0% (88.8% receiving antithrombotic drugs) and that of atrial fibrillation 11.1% (69.5% receiving oral anticoagulants). Compared with patients aged <65 years, older age (≥65 years) was associated with greater use of antithrombotic drugs in stroke [adjusted odds ratio (aOR) (95% confidence interval) = 2.83 (1.04-7.73) for patients aged (75-84 years)] and less use of RAS blockers [aOR = 0.39 (0.16-0.89) for patients aged ≥85 years], β-blockers [aOR = 0.31 (0.19-0.53) for patients aged 75-84 years] and lipid-lowering therapy [aOR = 0.39 (0.15-1.02) for patients aged ≥85 years, P for trend = 0.01] in CAD. Older age was not associated with less use of antiplatelet agents in CAD or oral anticoagulants in atrial fibrillation.

Conclusions:
In patients with CKD, older age per se was not associated with the underuse of antithrombotic drugs but was for other major drugs, with a potential impact on cardiovascular outcomes.

Full text

ORIGINAL ARTICLE
Impact of age on cardiovascular drug use in patients
with chronic kidney disease
Ce´dric Villain
1,2
,Sophie Liabeuf
2,3
,Marie Metzger
2
,Christian Combe
4,5
,
Denis Fouque
6
,Luc Frimat
7,8
,Christian Jacquelinet
2,9
,Maurice Laville
6
,
Serge Brianc¸on
8
,Ronald L. Pisoni
10
,Nicolas Mansencal
2,11
,
Be´ne´dicte Stengel
2
and Ziad A. Massy
1,2
,on behalf of the CKD-REIN
Study Group
1
Service de Ne´ phrologie-Dialyse, CHU Ambroise Pare´, APHP, Boulogne-Billancourt, France,
2
CESP, INSERM
Unite´ 1018, Equipe 5 EpRec, Universite´ Paris-Sud, UVSQ, Universite´ Paris-Saclay, Villejuif, France,
3
Service de
Pharmacologie Clinique, De´partement de Recherche Clinique, CHU d’Amiens, Universite´ de Picardie Jules
Verne, INSERM U-1088, Amiens, France,
4
Service de Ne´phrologie Transplantation Dialyse Aphe´re`ses, CHU de
Bordeaux, Bordeaux, France,
5
INSERM Unite´ 1026, Universite´ de Bordeaux, Bordeaux, France,
6
Universite´de
Lyon, Service de Ne´ phrologie, CarMeN INSERM 1060, Centre Hospitalier Lyon-Sud, Pierre-Be´nite, France,
7
CHRU Nancy-Brabois, Vandœuvre-le` s-Nancy, France,
8
INSERM CIC-EC CIE6 - EA 4360 Apemac, Nancy
Universite´, Vandœuvre-le`s-Nancy, France,
9
Agence de Biome´ decine, La Plaine Saint-Denis, France,
10
Arbor
Research Collaborative for Health, Ann Arbor, MI, USA and
11
Service de Cardiologie, CHU Ambroise Pare´,
APHP, Boulogne-Billancourt, France
Correspondence and offprint requests to: Ziad A. Massy; E-mail: ziad.massy@aphp.fr; Twitter handle: @denisfouque1
ABSTRACT
Background. Elderly patients with chronic kidney disease (CKD) are often excluded from clinical trials; this may affect their
use of essential drugs for cardiovascular complications. We sought to assess the impact of age on cardiovascular drug use
in elderly patients with CKD.
Methods. We used baseline data from the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-
REIN) cohort including 3033 adult patients with CKD Stages 3 and 4. We studied the use of recommended drugs for coronary
artery disease (CAD), stroke and atrial fibrillation by age, after adjusting for socio-demographic and clinical conditions.
Results. The patients’ mean age was 66.8 years (mean estimated glomerular filtration rate 32.9 mL/min/1.73 m
2
). The
prevalence of CAD was 24.5% [81.3% receiving antiplatelet agents, 75.6% renin–angiotensin system (RAS) blockers, 65.4%
b-blockers and 81.3% lipid-lowering therapy], that of stroke 10.0% (88.8% receiving antithrombotic drugs) and that of atrial
fibrillation 11.1% (69.5% receiving oral anticoagulants). Compared with patients aged <65 years, older age (65 years) was
associated with greater use of antithrombotic drugs in stroke [adjusted odds ratio (aOR) (95% confidence interval) ¼2.83
(1.04–7.73) for patients aged (75–84 years)] and less use of RAS blockers [aOR ¼0.39 (0.16–0.89) for patients aged 85 years],
Received: 21.3.2019; Editorial decision: 18.4.2019
V
CThe Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
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199
Clinical Kidney Journal, 2020, vol. 13, no. 2, 199–207
doi: 10.1093/ckj/sfz063
Advance Access Publication Date: 10 June 2019
Original Article

b-blockers [aOR ¼0.31 (0.19–0.53) for patients aged 75–84 years] and lipid-lowering therapy [aOR ¼0.39 (0.15–1.02) for
patients aged 85 years, P for trend ¼0.01] in CAD. Older age was not associated with less use of antiplatelet agents in CAD
or oral anticoagulants in atrial fibrillation.
Conclusions. In patients with CKD, older age per se was not associated with the underuse of antithrombotic drugs but was
for other major drugs, with a potential impact on cardiovascular outcomes.
Keywords: atrial fibrillation, chronic kidney disease, coronary artery disease, elderly, stroke, underuse
INTRODUCTION
Older adults account for a growing proportion of patients with
chronic kidney disease (CKD) [1]. Although the relative risk of
end-stage renal disease remains constant across age groups
with similar glomerular filtration rates (GFRs), the absolute risk
of death is higher than the absolute risk of reaching CKD Stage 5
for elderly patients with CKD [2]. Cardiovascular disease (CVD)
is the leading cause of death in patients with CKD [3]. Although
CVD and CKD share several risk factors (such as diabetes and
hypertension), CKD itself is a major risk factor for CVD [3]. The
incidences of various types of CVD are higher in patients with
CKD than in populations without CKD; these diseases include
both atheromatous CVD [such as coronary artery disease (CAD)
and stroke] and non-atheromatous CVD (such as atrial fibrilla-
tion and heart failure), which often accumulate with age [3,4].
The current guidelines for CVD management are based on
high-level evidence [5–7]. Most of these guidelines state that
non-dialysed patients with CKD should be treated with the
same drug classes as patients without CKD. Even though elderly
patients with CKD experience a high CVD burden, they are often
excluded from clinical trials assessing the efficiency of drugs
used to treat CVD. It has also been reported that patients with
CKD do not receive recommended treatment for various CVDs,
relative to patients with normal kidney function [8–10].
Moreover, age has been associated with the underuse of cardio-
vascular drugs in non-CKD populations [9,11–14]. However, the
impact of age on CVD drug use by patients with CKD has not
been extensively investigated.
By examining data from a large cohort of patients with CKD,
we sought to accurately determine the impact of age and GFR
level on the patients’ use of drugs recommended for several
CVDs. We hypothesized that elderly patients with CKD and CVD
might be less frequently treated than younger patients with
CKD and CVD.
MATERIALS AND METHODS
Population
The present analysis drew on baseline data collected from the
Chronic Kidney Disease-Renal Epidemiology and Information
Network (CKD-REIN) cohort (ClinicalTrials.gov identifier:
NCT03381950), a prospective cohort comprising 3033 CKD
Stages 3–4 patients receiving nephrologist-led care in France.
These patients were recruited from July 2013 to April 2016 by 40
nephrology clinics that were representative in terms of their
geographical location in France and their legal status (i.e. public
or private ownership) [15].
Study eligibility required two measures of estimated GFR
(eGFR) between 15 and 60 mL/min/1.73 m
2
at least 1 month
apart, with no prior chronic dialysis or kidney transplantation.
Patients aged <18 years or unable to give informed consent
were excluded, as were those who planned to move or who
refused to participate. The CKD-REIN patients will be followed
up once a year for at least 5 years. This study is a cross-sectional
analysis of the entire cohort population at inclusion. The study
protocol was approved by the Institut National de la Sante´Etde
la Recherche Me´dicale (INSERM) institutional review board (ref-
erence: IRB00003888), and all patients gave their informed con-
sent to participation.
Information
The CKD-REIN database includes information on medical varia-
bles (clinical variables, a set of routine laboratory values, the
CKD’s history, comorbidities and medications taken) and socio-
demographic variables. The information was collected from pa-
tient interviews and from medical records by trained clinical re-
search associates. For the data on medications, patients were
asked to bring their prescriptions for the previous 3 months to
each follow-up visit. Clinical research associates recorded the
prescription drugs.
Age was divided into four categories: <65, 65–74, 75–84 and
85 years. The eGFR values [calculated according to the Chronic
Kidney Disease - Epidemiology Collaboration (CKD-EPI) creati-
nine equation] were divided into two categories: 30 and
<30 mL/min/1.73 m
2
. The CKD-EPI creatinine value was cor-
rected for ethnicity in patients originating from the French
West Indies or sub-Saharan Africa. Albuminuria (or proteinuria)
was collected either from a 24-h urine sample or a single urine
sample and then expressed as a Kidney Disease: Improving
Global Outcomes (KDIGO) grade (A1, normal; A2, moderately in-
creased; A3, severely increased) [16]. Participants were classed
as having diabetes if (i) diabetes was reported in their medical
records, (ii) they were being treated with a glucose-lowering
medication or (iii) the blood HbA1c level was 7%.
Dyslipidaemia was defined as a history of dyslipidaemia or on-
going treatment with lipid-lowering medication. Data were
available for five activities of daily living (ADL) from the Katz
Index (bathing, dressing, going to the toilet, transference and
feeding) and four instrumental ADL (IADL) from the IADL scale
(ability to use the telephone, handle finances, take medication
and travel). Personal autonomy was defined in two ways: lack of
impairment in the five ADLs or lack of impairment in the four
IADLs. The educational level was defined as the number of
years in full-time education, in two categories: <12 versus 12
years. The CHA2DS2-VASc score was calculated according to
the current guidelines [6].
CVDs studied and the corresponding recommended
drugs
We studied the use of recommended drug classes whose several
medications do not have contraindications for age and GFR:
antiplatelet agents, renin–angiotensin system (RAS) blockers,
b-blockers, and statins or ezetimibe in patients with CAD; oral
anticoagulants in patients with atrial fibrillation and a
200 | C. Villain et al.

CHA2DS2-VASc score 2 in men and 3 in women; antithrom-
botic drugs in patients with a history of stroke or transient
ischaemic attack [5–7]. Appropriate drugs for CAD included
antithrombotic drugs, RAS blockers, b-blockers, and statins or
ezetimibe. The RAS blockers included angiotensin-converting
enzyme inhibitors and angiotensin receptor blockers. Oral anti-
coagulants included vitamin K antagonists and direct oral anti-
coagulants. Antithrombotic drugs included antiplatelet agents
and oral anticoagulants.
Statistical analysis
We first described the use of the drugs recommended for each
CVD by age class. Next, we evaluated the number of appropriate
drugs for CAD per patient, by age and by eGFR. The number of
appropriate drugs in CAD was computed by ordinal logistic re-
gression, and included an age eGFR interaction term. Finally,
we analysed the use of recommended drugs in a logistic regres-
sion for each drug separately in the three disease subgroups.
For each drug, the multivariate analysis included age and eGFR.
The other variables included in the multivariate models were
those with a P <0.1 in a univariate analysis. The following varia-
bles were tested for each drug: sex, albuminuria, diabetes, mari-
tal status, ADL, IADL, educational level, total number of drugs
and a cardiology consultation in the previous year. The other
tested variables were potential confounding factors for each
drug: oral anticoagulant use, liver cirrhosis and a history of gas-
trointestinal bleeding for the analysis of antiplatelet agents;
systolic blood pressure, a history of acute kidney injury (AKI)
and heart failure for the analysis of RAS blockers; asthma or
chronic obstructive pulmonary disease (COPD), systolic blood
pressure, atrial fibrillation and heart failure for the analysis of
b-blockers; body mass index and serum albumin for the analy-
sis of statins or ezetimibe; liver cirrhosis, a history of gastroin-
testinal bleeding and a history of stroke or transient ischaemic
attack for the analysis of oral anticoagulants in atrial fibrilla-
tion; liver cirrhosis, a history of gastrointestinal bleeding and a
history of atrial fibrillation for the analysis of antithrombotic
drugs in stroke or transient ischaemic attack. Since a small
number of patients had experienced brain haemorrhages, this
variable was not included in the analysis of antithrombotic
drugs. The interaction between age and eGFR was tested for
each drug.
Missing data were taken into account by performing multi-
ple imputations. For each missing value, 20 imputations were
computed, leading to 20 different databases. The results of the
20 databases were pooled according to Rubin’s rules [17].
All statistical analyses were performed with R software (R
Foundation, Vienna, Austria, version 3.3.0; library mice). The
threshold for statistical significance was set to P <0.05.
RESULTS
All the 3033 patients in the CKD-REIN cohort were included in
the present analysis. The characteristics of the study population
are summarized in Table 1. The mean age was 66.8 years, 65% of
the patients were male and 41.3% had diabetes. A total of 25% of
the patients had a history of CAD, 11.1% had a history of atrial
fibrillation with a CHA2DS2-VASc score 2 (men) or 3 (women)
(the prevalence regardless of the CHA2DS2-VASc score was
11.5%) and 10.0% had a history of stroke or transient ischaemic
attack. Among the patients with CAD, 81.3% were being treated
with antiplatelet agents, 75.6% with RAS blockers, 65.4% with
b-blockers and 82.7% with statins or ezetimibe. Oral
anticoagulants were used by 69.5% of the patients with atrial fi-
brillation and a CHA2DS2-VASc score 2 (men) or 3 (women);
of these, 3.7% were being treated with a direct oral anticoagu-
lant. Antithrombotic drugs were used by 88.8% of the patients
with a history of stroke or transient ischaemic attack. The per-
centages of patients using drugs recommended in CVD are
shown by age class in Figure 1. Results by sex are shown in
Supplementary data. Older patients tended to use CAD drugs
less than younger patients (univariate P for trend ¼0.05 for anti-
platelet agents, 0.01 for RAS blockers, <0.001 for b-blockers and
0.001 for statins or ezetimibe). The numbers of appropriate
drugs for CAD per patient are shown in Figure 2. Older age (but
not lower eGFR) was significantly associated with a lower total
number of appropriate drugs for CAD. The interaction term be-
tween age and eGFR was not significant (P ¼0.47). In contrast,
there was no age trend for the use of oral anticoagulants in
patients with atrial fibrillation (P for trend ¼0.11). There was a
trend towards the more frequent use of antithrombotic drugs in
older patients with stroke or transient ischaemic attack (P for
trend ¼0.04). The numbers of appropriate drugs for CAD per pa-
tient by sex are shown in Supplementary data.
Antithrombotic drug use
In a multivariate analysis, age was not associated with the use
of antiplatelet agents in CAD after adjustment for oral anticoag-
ulant use (Table 2). A higher number of prescribed drugs were
associated with a greater probability of treatment with antipla-
telet agents in CAD. The latter association was found to be sta-
tistically significant for all drugs analysed in this study (Tables 2
and 3). Similarly, age was not associated with the use of oral
anticoagulants in patients with atrial fibrillation but was associ-
ated with elevated use of antithrombotic agents in patients
with CKD and a history of stroke or transient ischaemic attack
(P-value for trend ¼0.05). A low eGFR was not significantly asso-
ciated with the use of antithrombotic drugs studied here. A sig-
nificant, positive interaction between age and eGFR was found
only for the use of antithrombotic agents in patients with a his-
tory of stroke or transient ischaemic attack.
Use of other specific drugs for CAD
In the multivariate analysis, patients with CKD and CAD aged
>85 years were significantly less likely to be treated with RAS
blockers than patients aged <65 years (Table 3). Patients aged
between 65 and 85 years were less likely to be treated with
b-blockers than patients aged <65 years. The P-values for trend
according to age were statistically significant for b-blockers and
for statins or ezetimibe, indicating lower rates of use of these
drugs in older patients with CKD and CAD.
Surprisingly, RAS blockers were significantly less used in
patients with heart failure and an eGFR of <30 mL/min/1.73 m
2
.
A history of AKI was also associated with underuse of this drug
class. b-blockers were less used in patients with asthma or
COPD but more used in patients with heart failure. Statins or
ezetimibe were used more frequently used in men (Table 3).
The interactions between age and eGFR were not significant for
these three drug classes.
DISCUSSION
We found that the recommended drugs for CVD were being
used in a large majority of patients with CKD receiving nephrol-
ogy care. In the CKD-REIN cohort, age per se was not associated
Cardiovascular drug use by age in CKD patients |201

with the use of antiplatelet agents in CAD or the use of oral anti-
coagulants in atrial fibrillation. Interestingly, we observed the
greater use of antithrombotic drugs in older patients with a his-
tory of stroke or transient ischaemic attack. In contrast, RAS
blockers, b-blockers and lipid-lowering therapies were used less
in older patients with CAD than in younger ones, despite a
higher overall number of prescribed drugs in the elderly
patients. Furthermore, a low eGFR (<30 mL/min/1.73 m
2
) was
not associated with underuse of any studied drug classes, with
the exception of RAS blockers in CAD.
In this study, the percentages of patients using a particular
drug were in line with previous reports on patients with chronic
CAD; these literature values range from 75% to 88% for antipla-
telet agents, 52% to 86% for RAS blockers, 57% to 75% for
Table 1. Characteristics of the study population by age category
Variable Age (years) CKD-REIN
population
Imputed
values (%)<65 65–74 75–84 85
Sample size (% of the study population) 1059 (34.9) 1057 (34.8) 800 (26.4) 117 (3.9) 3033 (100.0)
Socio-demographic parameters and functional status
Age (years)
a
52.8 610.0 69.3 62.8 79.0 62.7 87.2 62.1 66.8 612.9 0.0
Male sex
b
59.2 69.3 68.6 65.0 65.4 0.0
At least one impairment in ADL
b
6.8 9.3 11.1 9.9 8.9 11.7
At least one impairment in IADL
b
18.1 25.2 35.6 47.4 26.3 11.7
Marital status
b
Married or living together 61.3 70.6 66.6 52.8 65.6 12.7
Single 21.2 6.7 4.7 2.3 11.1
Widow(er) or divorced 17.5 22.7 28.7 45.0 23.3
Did not complete high school
b
55.5 65.0 70.5 75.2 63.5 1.1
Comorbidities
Diabetes
b
29.8 49.0 47.9 30.2 41.3 0.7
Hypertension
b
85.0 92.9 94.2 99.1 90.7 0.3
Systolic blood pressure (mmHg)
a
137.0 619.0 144.1 620.5 146.3 620.3 149.1 622.4 142.4 620.4 2.4
Heart failure
b
6.6 12.4 14.5 23.1 13.1 0.3
CAD
b
12.7 28.0 34.9 29.1 24.5 2.1
Atrial fibrillation
b
4.0 11.9 18.2 29.1 11.5 0.3
Stroke or transient ischaemic attack
b
5.8 10.4 14.5 13.2 10.0 2.5
Asthma/COPD
b
10.5 15.0 14.8 10.3 13.2 2.2
Liver cirrhosis
b
2.3 1.9 1.0 0.9 1.8 5.7
History of gastrointestinal bleeding
b
3.0 3.4 6.2 4.5 4.0 5.8
Cardiology consultation during the previous year
b
52.1 73.5 81.0 78.2 68.2 17.3
Nutritional and nephrological parameters
Dyslipidaemia
b
63.1 81.3 79.4 73.2 74.1 2.5
LDL cholesterol (mmol/L)
a
2.9 61.1 2.6 61.0 2.5 61.0 2.9 61.0 2.7 61.1 16.0
HDL cholesterol (mmol/L)
a
1.4 60.5 1.3 60.5 1.3 60.4 1.4 60.4 1.3 60.5 14.0
Body mass index (kg/m
2
)
a
27.9 66.2 29.8 66.0 28.6 65.1 27.3 64.1 28.7 65.9 2.1
Serum albumin (g/L)
a
40.3 64.8 40.1 64.0 39.9 63.9 39.9 64.2 40.1 64.3 18.9
eGFR (mL/min/1 .73 m
2
)
a
34.5 613.1 33.4 612.0 30.9 610.9 27.7 69.9 32.9 612.2 0.0
CKD stage
3 58.4 57.4 49.8 40.2 55.1 0.0
4 41.6 42.6 50.2 59.8 44.9
Albuminuria
b
A1 22.1 29.2 33.3 28.6 27.8 11.2
A2 28.2 31.7 34.9 38.3 31.6
A3 49.7 39.1 31.8 33.1 40.6
History of AKI
b
23.8 23.4 23.8 21.4 23.6 8.0
Drugs
Antiplatelet agents
b
23.9 47.5 53.3 47.9 40.8 0.0
Oral anticoagulants
b
7.1 14.8 21.8 29.1 14.5 0.0
Antithrombotic drugs 29.7 58.5 69.2 76.1 52.0
RAS blockers
b
76.8 77.3 71.6 54.7 74.7 0.0
b-blockers
b
35.8 44.6 44.9 42.7 41.4 0.0
Statins or ezetimibe
b
49.2 68.1 63.3 53.8 59.7 0.0
Total number of drugs
a
6.8 64.0 8.6 64.0 8.8 63.5 8.8 63.7 8.0 63.9 0.0
a
Expressed as the mean 6standard deviation.
b
Expressed as the proportion of the age category.
ADL, activities of daily living; IADL, instrumental activities of daily living; eGFR, estimated glomerular filtration rate, according to the CKD-EPI equation; albuminuria or
proteinuria was expressed as the KDIGO grade (A1: normal; A2: moderately increased; A3: severely increased); COPD, chronic obstructive pulmonary disease; antith-
rombotic drugs included antiplatelet agents and oral anticoagulants; RAS, reninangiotensin system; LDL, low-density lipoprotein; HDL, high-density lipoprotein; AKI,
acute kidney injury; CKD, chronic kidney disease.
202 | C. Villain et al.

b-blockers and 38% to 96% for lipid-lowering therapies [18–23].
Recent studies have reported that between 56% and 75% of pa-
tient with atrial fibrillation use oral anticoagulants, which is in
line with the findings of our study [13,14]. In the literature, the
percentage of patients taking an antithrombotic drug on dis-
charge after hospitalization for stroke is higher than that
recorded in this study, although data on the chronic use of
antithrombotic drugs in patients with a history of stroke are
scarce [12,24].
CAD is frequent in patients with CKD [3]. The CAD drugs
studied here have been shown to be effective in non-dialysed
patients with CKD (although the evidence for b-blockers is
FIGURE 1: Percentage of CVD drug use by age class in patients with CKD. RAS: reninangiotensin system; the antithrombotic drugs included antiplatelet agents and oral
anticoagulants.
Four appropriate drugs
Three appropriate drugs
Two appropriate drugs
Zero or one appropriate drug
Percentage of patient s
0 20 40 60 80 100
eGFR (ml/min/1.73m²) ≥ 30 <30 ≥ 30 <30 ≥ 30 <30 ≥ 30 <30
58 ≥
]
4
8-
5
7[
]4
7-
56[5
6
<
)s
r
a
ey
( e
g
A
FIGURE 2: Percentages of patients according to the number of recommended drugs used to treat CAD: comparison by age class and estimated glomerular filtration rate
(eGFR) class. The appropriate drugs for CAD included antithrombotic drugs (antiplatelet agents or oral anticoagulants), renin–angiotensin blockers, b-blockers, and sta-
tins or ezetimibe.
Cardiovascular drug use by age in CKD patients |203

unclear) [25] and are therefore recommended in the current
guidelines [5,7]. However, previous studies have observed lower
use of the recommended CAD drugs in patients with lower
eGFRs [8,9]. In fact, higher CKD stages have been associated
with the less frequent initiation of these drugs and worse long-
term adherence [8,9,19]. We did not observe this relationship
in this study, although the range of eGFRs was narrower than in
most of the literature publications. However, we did observe
underuse of RAS blockers in patients with lower eGFRs and in
patients with heart failure. The underuse of antiplatelet agents
in patients treated with oral anticoagulants for another indica-
tion was observed elsewhere [22].
Older age has already been found to be associated with
underuse of recommended drugs in non-CKD patients with
CAD [9,11]. There are also data on these recommended drugs in
elderly patients with CAD [9,21,26,27]. The current guidelines
for CAD strongly recommend secondary prevention with these
drugs in elderly patients [5,7]. Our study distinguishes the dif-
ferent drug classes and found different use patterns according
to age. We did not find any association between age and use of
antiplatelet agents, but RAS blockers, b-blockers and lipid-
lowering agents were all underused in the oldest patients stud-
ied here. As is the case for low GFR, the literature data show
that older age is associated with less frequent initiation of these
drugs after a coronary event and with worse long-term adher-
ence [9,11,19].
Atrial fibrillation and CKD are strongly associated [3].
Whereas patients with CKD have a higher risk of thromboembo-
lism than non-CKD patients, the risk of anticoagulant-related
bleeding is also higher. This has prompted debate on the bene-
fit–risk ratio of these drugs in patients with CKD, although most
of the data come from observational studies [10,28,29].
Although the association between low GFR and underuse of oral
anticoagulants in atrial fibrillation has not been thoroughly
assessed, our present data did not highlight such a relationship.
Age has previously been found to be associated with the under-
use of oral anticoagulants, despite the fact that the latter drugs
are clearly effective in the elderly [13,14,30]. An earlier study
found an association between loss of autonomy and underuse
of oral anticoagulants [13]. In contrast to these literature stud-
ies, we did not observe underuse of oral anticoagulants in el-
derly patients with CKD. This disparity might be due to
differences in medical practice between CKD and non-CKD
patients, or between France and other countries.
We found that antithrombotic drugs were more frequently
used in older patients with a history of stroke or transient ischae-
mic attack. Previous studies have found conflicting results for
the association between age and the use of oral anticoagulants
on discharge after hospitalization for a stroke due to atrial fibril-
lation [12,24]. However, in a study of the use of antithrombotic
drugs in patients with recurrent stroke, older age was not associ-
ated with drug underuse [23]. Moreover, a study of drug discon-
tinuation 1 year after a stroke found that age was associated with
greater use of drugs for secondary prevention of stroke [31].
Another study found that older age was associated with better
long-term adherence to antiplatelet agents and worse adherence
to oral anticoagulants after stroke [32].
Our analysis had several strengths. First, we used data from
a large cohort of patients with CKD: a high proportion of the el-
derly patients had a history of CVD. Secondly, the database in-
cluded a large number of variables, which made it possible to
take account of potential confounding factors (e.g. personal au-
tonomy and educational). However, our study also had some
limitations. First, the cross-sectional design prevented us from
establishing whether the studied drugs were never taken at all
or were discontinued due to side effects, since elderly patients
are particularly exposed to iatrogenic risks. Secondly, the ethi-
cal requirement for informed consent might mean that patients
with dementia at baseline were not included; this might have
led to selection bias. Lastly, our patients were recruited by
Table 2. Percentages and adjusted odds ratios (95%CI) for antithrombotic drug use in patients with CKD and CAD, atrial fibrillation or a history
of stroke or transient ischaemic attack
Antiplatelet agent use
in patients with CAD
Oral anticoagulant use in patients with
atrial fibrillation with CHA2DS2-VASc
2 score (men) or 3 (women)
Antithrombotic drug use
in patients with stroke or
transient ischaemic attack
Variable n/N ¼604/744 (81.3%) n/N ¼233/336 (69.5%) n/N ¼269/297 (88.8%)
% use aOR (95% CI) % use aOR (95% CI) % use aOR (95% CI)
Age (years)
<65 (ref.) 83.7 1 67.9 1 81.4 1
65–74 83.3 1.46 (0.77–2.76) 77.4 1.73 (0.69–4.32) 88.5 1.92 (0.76–4.86)
75–84 79.7 1.45 (0.76–2.76) 64.0 0.94 (0.39–2.26) 92.8* 2.83 (1.04–7.73)**
85 67.4* 0.76 (0.26–2.19) 64.7 1.05 (0.35–3.10) 90.9 3.09 (0.38–25.12)
P-value for trend 0.81 0.22 0.05
eGFR 30 mL/min/1.73 m
2
(ref.) 82.5 1 72.0 1 89.8 1
eGFR <30 mL/min/1.73 m
2
80.0 0.73 (0.47–1.14) 65.8 0.72 (0.44–1.18) 87.9 0.52 (0.23–1.16)
No oral anticoagulant (ref.) 90.5 1
Oral anticoagulant use 48.6* 0.06 (0.04–0.10)**
Total number of drugs (per 1
drug increment)
1.23 (1.14–1.32)** 1.09 (1.02–1.17)** 1.30 (1.13–1.50)**
*P <0.05 versus the reference (ref.) in a univariate analysis.
**P<0.05 versus the reference (ref.) in multivariate analysis.
The odds ratios were calculated using multivariable logistic regression; the antithrombotic drugs include antiplatelet agents and oral anticoagulants; eGFR, estimated
glomerular filtration rate, according to the CKD-EPI equation; the variables included were age, eGFR and variables with a P <0.1 in the univariate analysis.
aOR, adjusted odds ratio.
204 | C. Villain et al.

nephrology departments and so might not reflect exactly pre-
scription patterns in patients with CKD as a whole.
In a French cohort of patients with CKD receiving nephrol-
ogy care, older age was not associated with the underuse of
antithrombotic drugs for CAD, atrial fibrillation and stroke.
However, in contrast to the current guidelines, elderly patients
with CKD and CAD were less likely to be treated with RAS block-
ers, b-blockers and lipid-lowering agents than younger patients
were. Robust evidence on the effectiveness of CVD drugs is
available for elderly patients and for patients with CKD but not
for elderly patients with CKD. The latter population has a high
cardiovascular mortality rate; further randomized controlled tri-
als and longitudinal studies are therefore needed to assess the
benefits and risks of CVD drugs and the reasons for their
underuse.
SUPPLEMENTARY DATA
Supplementary data are available at ckj online.
ACKNOWLEDGEMENTS
The authors would like to thank the CKD-REIN study coordi-
nation staff for their efforts in setting up the CKD-REIN co-
hort: M.M., Elodie Speyer, Ce´ line Lange, Sophie Renault,
Reine Ketchemin and all the clinical research associates.
The CKD-REIN Study Group. Steering committee and coordi-
nators include: Carole Ayav, Vanessa Besson-Dubourg, S.B.,
Dorothe´ e Cannet, C.C., D.F., L.F., Yves-Edouard Herpe, C.J.,
M.L., Z.A.M., Christophe Pascal, Bruce M. Robinson, B.S.,
Ce´ line Lange, Karine Legrand, S.L., M.M. and Elodie Speyer.
Table 3. Percentages and adjusted odds ratios (95%CI) for drug use in patients with CKD and CAD
RAS blocker use b-blocker use Statin or ezetimibe use
Variable n/N ¼562/744 (75.6%) n/N ¼486/744 (65.4%) n/N ¼615/744 (82.7%)
% use aOR (95% CI) % use aOR (95% CI) % use aOR (95% CI)
Age (years)
<65 (ref.) 78.3 1 79.2 1 86.2 1
65–74 79.1 1.07 (0.63–1.80) 66.5* 0.47 (0.28–0.78)*** 86.7 0.96 (0.51–1.82)
75–84 73.7 0.92 (0.54–1.56) 57.0* 0.31 (0.19–0.53)*** 78.9** 0.59 (0.32–1.10)
85 50.0* 0.38 (0.16–0.89)*** 70.4 0.62 (0.25–1.54) 64.5* 0.39 (0.15–1.02)
P-value for trend 0.11 <0.001 0.01
Female sex (ref.) 69.4 1 75.7 1
Male sex 77.2* 1.41 (0.91–2.19) 84.5* 2.25 (1.36–3.72)***
No diabetes (ref.) 71.6 1
Diabetes 78.3* 1.30 (0.88–1.92)
No heart failure (ref.) 79.4 1 63.2 1
Heart failure 65.0* 0.48 (0.32–0.70)*** 74.6* 1.47 (1.01–2.14)***
No history of AKI 79.9 1
History of AKI 64.2* 0.44 (0.30–0.66)***
No asthma or COPD (ref.) 67.8 1
Asthma/COPD 53.1* 0.44 (0.29–0.68)***
Body mass index (per 1 kg/m
2
increment) 1.02 (0.98–1.07)
eGFR 30 mL/min/1.73 m
2
(ref.) 80.7 1 64.9 1 82.9 1
eGFR <30 mL/min/1.73 m
2
70.5* 0.60 (0.42–0.88)*** 66.6 1.08 (0.80–1.46) 82.4 0.91 (0.60–1.39)
Total number of drugs (per 1 drug increase) 1.13 (1.06–1.19)*** 1.09 (1.04–1.14)*** 1.23 (1.15–1.32)***
Autonomy for ADL (ref.) 76.8 1
At least one impairment 66.7* 0.57 (0.32–1.02)
Autonomy for IADL (ref.) 79.3 1
At least one impairment 69.2* 0.68 (0.45–1.04)
Married or concubine (ref.) 67.6 1 85.4 1
Single 64.9 0.62 (0.31–1.22) 85.6 0.87 (0.34–2.19)
Widow(er) or divorced 59.9** 0.66 (0.44–0.98)*** 74.2* 0.58 (0.36–0.93)***
Completed high school (ref.) 80.1 1
Did not complete high school 73.6** 0.75 (0.49–1.14)
*P <0.05 versus the reference (ref.) in a univariate analysis.
**P <0.10 the ref. in a univariate analysis.
***P <0.05 versus the reference (ref.) in multivariate analysis.
The odds ratios were calculated using multivariable logistic regression; eGFR, estimated glomerular filtration rate, according to the CKD-EPI equation; albuminuria or
proteinuria was expressed as the KDIGO grade (A1: normal; A2: moderately increased; A3: severely increased); AKI, acute kidney injury; COPD, chronic obstructive pul-
monary disease; RAS, reninangiotensin system; ADL, activities of daily living; IADL, instrumental activities of daily living; the variables included were age, eGFR and
variables with P <0.1 in the univariate analysis.
aOR, adjusted odds ratio.
Cardiovascular drug use by age in CKD patients |205

CKD-REIN investigators/collaborators include: Thierry
Hannedouche, Bruno Moulin, Se´ bastien Mailliez, Gae´ tan
Lebrun, Eric Magnant, Gabriel Choukroun, Benjamin
Deroure, Adeline Lacraz, Guy Lambrey, Jean Philippe
Bourdenx, Marie Essig, Thierry Lobbedez, Raymond Azar,
Hace` ne Sekhri, Mustafa Smati, Mohamed Jamali, Alexandre
Klein, Michel Delahousse, C.C., Se´ verine Martin, Isabelle
Landru, Eric Thervet, Z.A.M., Philippe Lang, Xavier
Belenfant, Pablo Urena, Carlos Vela, L.F., Dominique
Chauveau, Viktor Panescu, Christian Noel, Franc¸ois
Glowacki, Maxime Hoffmann, Maryvonne Hourmant,
Dominique Besnier, Angelo Testa, Franc¸ois Kuentz, Philippe
Zaoui, Charles Chazot, Laurent Juillard, Ste´ phane Burtey,
Adrien Keller, Nassim Kamar, D.F. and M.L.
FUNDING
CKD-REIN is supported by the Agence Nationale de la
Recherche through the 2010 Cohortes-Investissements d’Avenir
programme and the 2010 national Programme Hospitalier de
Recherche Clinique programme. CKD-REIN is also supported
by a public–private partnership with Amgen, Fresenius
Medical Care and GlaxoSmithKline (GSK) since 2012, Lilly
France since 2013, Otsuka Pharmaceutical since 2015, Baxter
and Merck Sharp & Dohme-Chibret (MSD France) from 2012
to 2017, Sanofi-Genzyme from 2012 to 2015 and Vifor
Fresenius since 2018. Inserm Transfert set up the collabora-
tion in 2011 and has managed it since then.
AUTHORS’ CONTRIBUTIONS
C.V., S.L., M.M., N.M., B.S. and Z.A.M. contributed to the
study concept and design. S.L., M.M., C.C., D.F., L.F., C.J., M.L.,
S.B., R.L.P., B.S. and Z.A.M. performed the acquisition of
data. C.V., S.L., M.M., B.S. and Z.A.M. performed the analysis
and interpretation of data. C.V., B.S. and Z.A.M. contributed
to drafting the article. S.L., M.M., C.C., D.F., L.F., C.J., M.L.,
S.B., R.L.P. and N.M. contributed to the critical revision of the
manuscript for important intellectual content. All authors
approved the final version of the manuscript.
CONFLICT OF INTEREST STATEMENT
C.V., S.L., M.M., C.C., D.F., L.F., C.J., M.L., S.B., R.L.P. and N.M. have
nodisclosuresrelativetothisstudy.B.S.declaresbeingmember
of a scientific advisory board on a project funded by MSD. Z.A.M.
has received grants for CKD-REIN and other research projects
from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline,
MerckSharpandDohme-Chibret,Sanofi-Genzyme,Lilly,Otsuka
and the French government, as well as fees and grants to chari-
ties from Amgen, Bayer and Sanofi-Genzyme.
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