Suboptimal achievement of low-density

Archives of Cardiovascular Disease (2017) 110, 167—178
Available online at
ScienceDirect
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CLINICAL RESEARCH
Suboptimal achievement of low-density
lipoprotein cholesterol targets in French
patients with coronary heart disease.
Contemporary data from the DYSIS II
ACS/CHD study
Difﬁculté d’atteinte des cibles de LDL cholestérol chez les patients
coronariens français : données récentes de l’étude DYSIS II ACS/CHD
Jean Ferrières a,b,∗, Maja Velkovski Rouyer c,
Dominik Lautsch d, Veronica Ashton e,
Baishali M. Ambegaonkar e, Philippe Brudi e,
Anselm K. Gitt f , for the Dyslipidemia International
Study (DYSIS) II France Study Group1
a
Department of Cardiology B, Toulouse Rangueil University Hospital (CHU), TSA 50032, 31059
Toulouse cedex, France
b
UMR 1027, Department of Epidemiology and Public Health, Inserm, université de Toulouse,
Toulouse, France
c
MSD France, Paris, France
d
MSD, Vienna, Austria
e
Merck and Co Inc, Kenilworth, NJ, USA
f
Herzzentrum Ludwigshafen, Medizinische Klinik B, Kardiologie, Ludwigshafen, Germany
Received 6 July 2016; received in revised form 24 November 2016; accepted 29 November 2016
Available online 13 February 2017
Abbreviations: ACS, acute coronary syndrome; CHD, coronary heart disease; DYSIS, Dyslipidemia International Study; EAS, European
Atherosclerosis Society; ESC, European Society of Cardiology; EUROASPIRE, European Action on Secondary and Primary Prevention by Intervention to Reduce Events; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; L-TAP, Lipid
Treatment Assessment Project; SD, standard deviation.
∗ Corresponding author. Department of Cardiology B, Toulouse Rangueil University Hospital (CHU), Toulouse, France.
E-mail address: [email protected] (J. Ferrières).
1 A complete list of the DYSIS II French investigators is included in Appendix A.
http://dx.doi.org/10.1016/j.acvd.2016.11.004
1875-2136/© 2017 Elsevier Masson SAS. All rights reserved.
168
KEYWORDS
Hyperlipidaemia;
Statins;
LDL-cholesterol;
Coronary heart
disease;
Target
MOTS CLÉS
Hyperlipidémie ;
Statines ;
LDL-cholestérol ;
Maladie coronaire ;
Objectif
J. Ferrières et al.
Summary
Background. — European guidelines recommend a low-density lipoprotein cholesterol (LDL-C)
target of < 1.8 mmol/L (70 mg/dL), and/or a ≥ 50% reduction when the target level cannot be
reached, for patients at very high cardiovascular risk, and high-potency lipid-lowering therapy
(LLT) in patients with an acute coronary syndrome (ACS).
Aim. — To document the prevalence of lipid abnormalities and the achievement of lipid targets
among patients surviving an ACS and in patients with stable coronary heart disease (CHD), using
data from the DYSIS II study.
Methods. — DYSIS II was an observational cross-sectional study conducted in 21 countries
(2012—2014). We report data from the French cohort, comprising patients hospitalized with
an ACS and patients diagnosed with stable CHD. Data on patient characteristics, risk factors,
treatments and lipid proﬁle were collected. LDL-C target achievement was assessed based on
the European guidelines endorsed by the French Society of Cardiology.
Results. — Of the 468 ACS patients, 277 (59.2%) were receiving LLT at admission to hospital;
22.6% were hospitalized for a recurrent event. Statins were used in 96.6% (450/466) of patients
at discharge and in 95.1% (310/326) at 120-day follow-up, at which time 50.6% (80/158) of
patients with available data achieved the LDL-C goal. Most of the 436 patients with stable CHD
(97.2%) were on LLT (56.8% on high-intensity therapy); 29.2% of patients on LLT met the LDL-C
treatment target < 1.8 mmol/L (70 mg/dL).
Conclusion. — These observational data show the progress made in the treatment of ACS from
the acute phase up to 3 months, and highlight key areas for improvement in the prevention
of recurrent events in patients with CHD in France. The use of higher intensity or combination
LLT as recommended in secondary prevention are needed to increase the achievement of LDL-C
treatment targets and reduce the risk of morbidity and mortality due to CHD.
© 2017 Elsevier Masson SAS. All rights reserved.
Résumé
Contexte. — Les recommandations européennes préconisent un objectif pour le cholestérol
des lipoprotéines de basse densité (LDL-C) inférieur à 1,8 mmol/L (70 mg/dL), et/ou ≥ 50 %
de réduction de LDL-C lorsque l’objectif ne peut pas être atteint, pour les patients à très
haut risque cardiovasculaire, avec des traitements hypolipidémiants de forte intensité pour les
patients avec un syndrome coronarien aigu (SCA)
Objectif. — Documenter la prévalence des anomalies lipidiques et l’atteinte des objectifs
lipidiques parmi les patients après un SCA ainsi que parmi les patients avec une maladie
coronaire (MC) stable en utilisant les données de l’étude DYSIS II.
Méthodes. — DYSIS II était une étude observationnelle transversale menée dans les 21 pays
(2012—2014). Nous rapportons les données de la cohorte française, comprenant les patients
hospitalisés avec un SCA et les patients avec une MC stable. Les données sur les caractéristiques
des patients, les facteurs de risque, le traitement et le proﬁl lipidique ont été collectées.
L’atteinte des objectifs lipidiques a été déterminée selon les recommandations européennes
validées par la Société française de cardiologie.
Résultats. — Parmi les 468 patients avec un SCA, 277 (59,2 %) recevaient de traitement
hypolipidémiant à l’admission à hôpital ; 22,6 % ont été hospitalisés à la suite d’un événement coronarien récurrent. Les statines étaient utilisées chez 96,6 % (450/466) des patients
à la sortie de l’hospitalisation et chez 95,1 % (310/326) lors du suivi à 120 jours ; lors de ce
suivi, 50,6 % (80/158) des patients pour lesquels les données étaient disponibles avaient atteint
les objectifs de LDL-C. La majorité des 436 patients avec MC stable (97,2 %) recevaient un
traitement hypolipidémiant (56,8 % des traitements de forte intensité) ; 29,2 % de patients
sous traitement avaient atteint l’objectif de LDL-C inférieur à 1,8 mmol/L (70 mg/dL).
Conclusion. — Ces données observationnelles montrent les progrès obtenus dans la prise en
charge en aigu et lors du suivi à 3 mois après l’événement et soulignent les possibilités
d’amélioration de la prise en charge et de la prévention des événements récurrents chez les
patients avec une maladie coronaire en France. L’intensiﬁcation des traitements en prévention
secondaire par une augmentation des doses ou des associations médicamenteuses est nécessaire aﬁn d’améliorer l’atteinte des objectifs lipidiques et réduire le risque de morbi-mortalité
coronaire.
© 2017 Elsevier Masson SAS. Tous droits réservés.
Suboptimal LDL-C levels in French CHD patients
Background
Hypercholesterolemia is a major contributor to the development of atherosclerosis and coronary heart disease (CHD),
with all-cause mortality rising in association with increasing concentrations of low-density lipoprotein cholesterol
(LDL-C) [1,2]. A large prospective meta-analysis involving over 90,000 individuals, almost half of whom had
pre-existing CHD, showed that every 1 mmol/L reduction in LDL-C achieved with statin therapy resulted in
a 21% reduction in major vascular events [3]. Guidelines from the European Society of Cardiology/European
Atherosclerosis Society (ESC/EAS) recommend an LDL-C target of < 1.8 mmol/L (70 mg/dL), and/or a ≥ 50% reduction
from baseline when this target cannot be reached, for
patients at very high cardiovascular risk, and the administration of high-potency statin therapy as the ﬁrst choice in
patients presenting with an acute coronary syndrome (ACS)
[4]. Not all patients achieve these lipid goals, and require
the addition of a non-statin lipid-lowering therapy (LLT) such
as ezetimibe, while others are intolerant of statin therapy
[4]. Ezetimibe, when combined with a statin, results in an
additional 20—25% reduction in LDL-C compared with statin
monotherapy [5,6]. The recently published IMPROVE-IT trial
also demonstrated that ezetimibe, on top of statin therapy,
improved cardiovascular outcomes [7].
In a previous examination of the ﬁrst 12 countries (11
European countries and Canada) included in the DYSIS study
[8], conducted between April 2008 and February 2009,
half of the 22,063 statin-treated patients age ≥ 45 years did
not achieve their therapeutic LDL-C goal, highlighting a
gap between evidence-based recommendations and clinical
practice. Among the patients enrolled in France, only 39.6%
achieved the target lipid values [9]. We sought to document
the prevalence of lipid abnormalities and the achievement
of lipid targets among patients who have had an ACS and
in patients with stable CHD in France, using data from the
global Dyslipidemia International Study (DYSIS) II ACS/CHD
study.
Methods
Study design and population
DYSIS II was a cross-sectional observational study conducted
in 21 countries in Asia-Paciﬁc, Europe and Middle East/Africa
between 2012 and 2014. Two distinct patient populations
were enrolled: those hospitalized with an ACS (DYSIS II ACS)
and those diagnosed with stable CHD (DYSIS II CHD). The
study design is shown in Fig. 1.
Patients who were eligible for enrolment in DYSIS II ACS
were:
• ≥ 18 years of age;
• had been hospitalized for an ACS (ST-segment elevation
myocardial infarction, left bundle branch block, nonST-segment elevation myocardial infarction or unstable
angina) at the time of enrolment;
• had a full lipid proﬁle performed on blood drawn within
24 hours of admission;
• had either been on LLT for ≥ 3 months or were not taking
any LLT.
169
Patients were given a booklet at enrolment and
instructed to take it with them when they next visited their
physician following discharge from the index event. The
booklet was retained by the patient and was completed by
their physician during subsequent consultations, capturing
the patient’s lipid proﬁle and other basic characteristics.
The purpose of the booklet was to gather accurate information that could be reported by the patient during the
follow-up telephone interview, which was carried out with
patients (or their next of kin) 120 ± 15 days after the index
event.
DYSIS II CHD enrolled patients ≥ 18 years of age with
stable CHD during a single visit to their physician on an
outpatient basis. Physicians were representative of the general population of clinicians managing patients for secondary
prevention in France, and included general practitioners or
family physicians, internists and cardiologists. Stable CHD
was deﬁned as one or more of the following:
• > 50% stenosis on coronary angiography or computed
tomography;
• previous percutaneous coronary intervention; previous
coronary artery bypass graft;
• history of ACS > 3 months previously.
Patients were required to have had a fasting lipid proﬁle
done within the previous 12 months, either while on LLT
for ≥ 3 months or not on any LLT. Patients with a history
of ACS within the previous 3 months were not eligible for
enrolment in DYSIS CHD.
To avoid selection bias, centres participating in DYSIS II
were strongly encouraged to enrol all consecutive patients
who fulﬁlled the inclusion criteria. Patients enrolled in clinical trials involving medication were not eligible.
Data on patient characteristics, risk factors, treatments
(LLT and selected concomitant pharmacological therapies)
and laboratory values were collected using an electronic
case report form. LDL-C target achievement was assessed
based on the 2011 ESC/EAS guidelines for patients at very
high cardiovascular risk (LDL-C < 1.8 mmol/L [70 mg/dL]) [4].
DYSIS II was strictly observational in nature and the protocol did not recommend or discourage any treatments,
procedures, diagnostics or examinations that were not part
of those delivered in routine medical care. As such, the study
served to comprehensively document current secondary prevention practices in patients with CHD or ACS, regardless of
current treatment.
This study was conducted in accordance with good epidemiological and clinical practice, and all applicable laws,
rules and regulations, and was approved by the authorities
in all participating countries. All subjects provided written
informed consent to participate.
Objectives
The primary objective in the French cohort of this observational study was to document real-life lipid concentrations
relative to the targets in the 2011 ESC/EAS guidelines
for the management of dyslipidaemias [4] in patients
hospitalized with an ACS and in those with stable CHD, who
had either been on LLT for ≥ 3 months or were not taking
any LLT. Key secondary objectives were to describe the
170
J. Ferrières et al.
Figure 1. Study design of DYSIS II ACS/CHD. DYSIS II ACS day 0: time of enrolment, deﬁned as day of hospital discharge. DYSIS II ACS day
120 ± 15: time of follow-up telephone interview, 120 ± 15 days after day 0. DYSIS II CHD day 0: time of enrolment, deﬁned as the day of the
physician visit. ACS: acute coronary syndrome; CABG: coronary artery bypass graft; CHD: coronary heart disease; CT: computed tomography;
DYSIS II: Dyslipidemia International Study II; LLT: lipid-lowering therapy; NSTEMI: non-ST-segment elevation myocardial infarction; PCI:
percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction; T0 : day 0; T120 : day 120.
patient characteristics and risk proﬁles, to document drug
usage patterns and to determine lipid goal achievements.
Study management
A site management team (Institut für Herzinfarktforschung
Ludwigshafen, Ludwigshafen, Germany) was responsible for
training the site personnel on all aspects of the study and
was a resource for data-collection questions and query resolution. This team closely monitored patient enrolment and
data submission at each site and performed calls, as necessary, to stimulate enrolment or data submission.
Standardized data management procedures were undertaken to ensure the integrity and analytical utility of the
study data, including handling rules for missing or incomplete data, range checks and data transformations. Data
quality checks were carried out at the time of data entry
and before creation of the analysis dataset. Data were
anonymized to protect patient conﬁdentiality. Source documentation and data accuracy were veriﬁed in 25% of
cases.
Statistical analysis
Categorical variables are described using count (percentage)
and continuous quantitative variables as mean ± standard
deviation (SD) or median (interquartile range [IQR]). Treatment patterns, healthcare usage patterns, and all other
documented variables were compared among prespeciﬁed
subgroups using the chi-square test or Mann-WhitneyWilcoxon test, as appropriate. In all analyses, a value of
P ≤ 0.05 was considered statistically signiﬁcant. All analyses
were performed using SAS software version 9.3 (Cary, NC,
USA).
Results
DYSIS II ACS
DYSIS II ACS was conducted in 24 coronary care units in
France. Of the 468 patients enrolled, half (50.6%) had
ST-segment elevation myocardial infarction or left bundle
Characteristics of patients with an ACS or with stable CHD.
Variable
ACS
All ACS
(n = 468)
Age (years)
Men
Systolic BP (mmHg)
Diastolic BP (mmHg)
Medical history
Myocardial infarction
CKD
Diabetes mellitus type 2a
Hypercholesterolaemiab
PAD
Stroke (ischaemic or
haemorrhagic)
Type of ACS
ST elevation/LBBB MI
Non-ST elevation MI
Unstable angina
Risk factors for CHD
Current smoker
Family history of premature
CVDc
Sedentary lifestyled
Metabolic syndrome
(NCEP-ATP III)
Hypertensione
Central obesityf
BMI > 30 kg/m2
Stable CHD
Incident ACS (n = 362)
Recurrent ACS (n = 106)
No LLT (n = 181)
LLT (n = 181)
No LLT (n = 10)
LLT (n = 96)
65 ± 12
375 (80.1)
138 ± 24
80 ± 16
60 ± 12
154 (85.1)
140 ± 26
82 ± 16
68 ± 11
134 (74.0)
139 ± 24
80 ± 16
69 ± 11
5 (50.0)
133 ± 19
73 ± 14
106 (22.6)
18 (3.8)
102 (21.8)
312/463 (67.4)
43/466 (9.2)
28/463 (6.0)
0
5 (2.8)
23 (12.7)
62 (34.3)
7 (3.9)
5/179 (2.8)
0
6 (3.3)
46 (25.4)
162/177 (91.5)
20/179 (11.2)
15/179 (8.4)
237 (50.6)
191 (40.8)
40 (8.5)
118 (65.2)
59 (32.6)
4 (2.2)
131 (28.0)
146/418 (34.9)
All CHD
(n = 436)
No LLT
(n = 12)
LLT
(n = 424)
65 ± 13
82 (85.4)
135 ± 23
75 ± 13
69 ± 12
349 (80.0)
132 ± 13
76 ± 9
74 ± 12
11 (91.7)
134 ± 13
82 ± 7
69 ± 12
338 (79.7)
132 ± 13
76 ± 9
10 (100)
2 (20.0)
3 (30.0)
6 (60.0)
2 (20.0)
0
96 (100)
5 (5.2)
30 (31.3)
82/95 (86.3)
14 (14.6)
8 (8.3)
236/435 (54.3)
22 (5.0)
117/434 (27.0)
323/426 (75.8)
64/431 (14.8)
16/425 (3.8)
7 (58.3)
0
2 (16.7)
6 (50.0)
0
0
229/423 (54.1)
22 (5.2)
115/422 (27.3)
317/414 (76.6)
64/420 (15.2)
16/413 (3.9)
77 (42.5)
81 (44.8)
23 (12.7)
3 (30.0)
6 (60.0)
1 (10.0)
39 (40.6)
45 (46.9)
12 (12.5)
—
—
—
—
—
—
—
—
—
73 (40.3)
52/171 (30.4)
36 (19.9)
59/156 (37.8)
4 (40.0)
3/8 (37.5)
18 (18.8)
32/83 (38.6)
33 (7.6)
129/338 (38.2)
1 (8.3)
3/10 (30.0)
32 (7.5)
126/328 (38.4)
139/322 (43.2)
56/122 (45.9)
58/134 (43.3)
27/63 (42.9)
52/115 (45.2)
18/40 (45.0)
4/7 (57.1)
0
25/66 (37.9)
11/17 (64.7)
178/428 (41.6)
55/217 (25.3)
3 (25.0)
2/7 (28.6)
175/416 (42.1)
53/210 (25.2)
395 (84.4)
113/135 (83.7)
115 (24.6)
127 (70.2)
54/69 (78.3)
38 (21.0)
169 (93.4)
38/42 (90.5)
46 (25.4)
8 (80.0)
2/2 (100)
2 (20.0)
91 (94.8)
19/22 (86.4)
29 (30.2)
428 (98.2)
207/290 (71.4)
88 (20.2)
10 (83.3)
5 (41.7)
2 (16.7)
418 (98.6)
202/278 (72.7)
86 (20.3)
Suboptimal LDL-C levels in French CHD patients
Table 1
Data are expressed as mean ± standard deviation, n (%) or n/N (%), where data are missing. ACS: acute coronary syndrome; BMI: body mass index; BP: blood pressure; CHD: coronary heart
disease; CKD: chronic kidney disease; CVD: cardiovascular disease; LBBB: left bundle branch block; LLT: lipid-lowering therapy; MI: myocardial infarction; NCEP-ATP: National Cholesterol
Education Program Adult Treatment Panel; PAD: peripheral artery disease.
a Previously diagnosed or current treatment or fasting plasma glucose ≥ 7 mmol/L (≥ 126 mg/dL).
b Known history of hypercholesterolemia or currently taking lipid-lowering therapy or low-density lipoprotein cholesterol > 4.1 mmol/L (160 mg/dL).
c Parent, brother or sister with myocardial infarction or sudden death before age 55 years (male) or age 65 years (female).
d Deﬁned as < 20—30 minutes of walking on 3—4 days each week.
e BP ≥ 140/90 mmHg, antihypertensive medication, previously diagnosed hypertension.
f Waist circumference ≥ 94 cm in men or ≥ 80 cm in women.
171
172
Table 2
Chronic treatments in patients with ACS or stable CHD.
Variable
ACSa
All patients (n = 468)
Aspirin
P2Y12 inhibitor
ACE inhibitor
or ARB
Beta-blocker
Calcium
channel
blocker
Anticoagulant
Nitrate
Diuretic
Oral
antidiabetic
drug
Stable CHDb
Incident ACS (n = 362)
Recurrent ACS (n = 106)
No LLT (n = 181)
LLT (n = 181)
No LLT (n = 10)
173/467 (37.0)
92 (19.7)
217/466 (46.6)
16 (8.8)
9 (5.0)
43 (23.8)
77 (42.5)
37 (20.4)
103 (56.9)
5 (50.0)
4 (40.0)
4 (40.0)
169/465 (36.3)
98/465 (21.1)
15 (8.3)
16 (8.8)
80 (44.2)
51/180 (28.3)
25/467 (5.4)
21/466 (4.5)
82/465 (17.6)
103 (22.0)
4
2
12
22
10 (5.5)
11 (6.1)
44/180 (24.4)
51 (28.2)
(2.2)
(1.1)
(6.6)
(12.2)
All patients
(n = 436)
No LLT
(n = 12)
75/95 (78.9)
42 (43.8)
67/94 (71.3)
349/435 (80.2)
171 (39.2)
336 (77.1)
8/11 (72.7)
0
4 (33.3)
341 (80.4)
171 (40.3)
332 (78.3)
5 (50.0)
3 (30.0)
69/94 (73.4)
28/94 (29.8)
336 (77.1)
131 (30.0)
8 (66.7)
3 (25.0)
328 (77.4)
128 (30.2)
1
1
4
3
10/95 (10.5)
7/94 (7.4)
22/94 (23.4)
27 (28.1)
42 (9.6)
55 (12.6)
119 (27.3)
120 (27.5)
4
3
1
2
38
52
118
118
(10.0)
(10.0)
(40.0)
(30.0)
LLT
(n = 424)
LLT (n = 96)
(33.3)
(25.0)
(8.3)
(16.7)
(9.0)
(12.3)
(27.8)
(27.8)
Data are expressed as n (%) or n/N (%), where data are missing. ACE: angiotensin-converting enzyme; ACS: acute coronary syndrome; ARB: angiotensin II receptor blocker; CHD: coronary
heart disease; LLT: lipid-lowering therapy.
a On admission.
b At the time of latest lipid test.
J. Ferrières et al.
Suboptimal LDL-C levels in French CHD patients
Table 3
173
Lipid-lowering treatments in patients with an ACS or with stable CHD.
CHD patientsa
ACS patients
No lipid-lowering therapy
Statin
Atorvastatin
Dose potency, mg/day
Rosuvastatin
Dose potency, mg/day
Pravastatin
Dose potency, mg/day
Simvastatin
Dose potency, mg/day
Unknown
Non-statin lipid-lowering treatment
Ezetimibe
Otherb
At admission
(n = 468)
At discharge
(n = 466)
(n = 436)
191 (40.8)
260/468 (55.6)
92 (35.4)
40 (10, 40)
85 (32.7)
10 (5, 20)
34 (13.1)
20 (20, 40)
41 (15.8)
20 (20, 20)
3 (1.2)
40/468 (8.5)
22 (55.0)
18 (45.0)
14 (3.0)
450/466 (96.6)
273 (60.7)
80 (40, 80)
133 (29.6)
20 (10, 20)
21 (4.7)
40 (20, 40)
23 (5.1)
20 (20, 40)
−
26/466 (5.6)
16 (61.5)
10 (38.5)
12 (2.8)
404/436 (92.7)
182 (45.0)
40 (20, 60)
103 (25.5)
10 (5, 10)
46 (11.4)
25 (20, 40)
65 (16.1)
20 (20, 40)
7 (1.7)
75/436 (17.2)
58 (77.3)
19 (25.3)
Data are expressed as n (%), median (interquartile range), or minimum, maximum. ACS: acute coronary syndromes; CHD: coronary heart
disease.
a At time of latest lipid test.
b Omega 3 or ﬁbrate.
branch block, 40.8% had non-ST-segment elevation myocardial infarction, and 8.5% had unstable angina (Table 1). The
mean age of the ACS population was 65 ± 12 years and 80.1%
were men. More than one-ﬁfth (22.6%) had been hospitalized for a recurrent ischaemic event; these patients had a
more severe medical history, including a higher prevalence
of chronic kidney disease, type 2 diabetes mellitus, and
peripheral artery disease, than patients with a ﬁrst (incident) ACS, and 90.6% were on LLT compared with 50.0% of
those with an incident ACS. Patients with an incident ACS
who were receiving LLT were older than those not on LLT
and had a more severe medical history (Table 1).
Chronic non-LLT treatments being taken at hospital
admission are detailed in Table 2. The rate of aspirin use was
37.0% overall (19.7% of patients received a P2Y12 inhibitor),
driven by higher rates among patients with recurrent ACS
and, to a lesser extent, in patients with an incident ACS
on LLT. The use of beta-blockers, angiotensin-converting
enzyme inhibitors, and angiotensin II receptor blockers was
higher in the population with a history of ACS and in patients
with incident ACS on LLT.
Of the 468 patients, 260 (55.6%) were taking a statin,
40 (8.5%) were taking a non-statin LLT, and 191 (40.8%)
were receiving no LLT at admission to hospital (Table 3).
The most frequently taken statins were atorvastatin (35.4%
of 260 patients on a statin) and rosuvastatin (32.7%). Ezetimibe (55.0% of 40 patients on non-statin LLT) was the
most frequently taken non-statin LLT. The most common
treatment at admission was statin monotherapy (50.6%);
4.3% were on combination LLT with a statin plus ezetimibe
(Fig. 2A). Rates of use of statin monotherapy had increased
to 91.4% at discharge. Use of statin plus ezetimibe did
not change between admission (4.3%) and discharge (3.0%)
(Fig. 2A).
Figure 2. A. LLT on hospital admission, at discharge and at 120day follow-up in all ACS patients (a data on non-statin LLT available
in 466/468 patients at discharge). B. Intensity of statin treatment
(mean statin dose calculated in atorvastatin dose equivalents) in
ACS patients on admission, during hospitalization, at discharge and
at 120-day follow-up. ACS: acute coronary syndrome; LLT: lipidlowering therapy; mono: monotherapy.
174
Table 4
Lipid proﬁlea and proportion of patients who achieved the 2011 ESC/EAS targets threshold values [4].
ACS
All ACS
(n = 468)
Lipid proﬁle
(mmol/L)
LDL-C
Total cholesterol
HDL-C
Triglycerides
Non—HDL-C
Total
cholesterol/HDLC
ratio
LDL-C < 1.8 mmol/L
(< 70 mg/dL)
Distance to
1.8 mmol/L
(mmol/L)e
LDL-C < 2.5 mmol/L
(< 100 mg/dL)
Distance to
2.5 mmol/L
(mmol/L)e
Non-HDLC < 2.6 mmol/L
(< 100 mg/dL)
Stable CHD
Incident ACS (n = 362)
Recurrent ACS (n = 106)
All CHD
(n = 436)
No LLT
(n = 12)
LLT
(n = 424)
No LLT (n = 181)
LLT (n = 181)
No LLT (n = 10)
LLT (n = 96)
2.86 ± 1.12
4.74 ± 1.27
1.19 ± 0.37
1.50 (1.04, 2.03)
3.58 ± 1.23
4.29 ± 1.56
3.49 ± 1.04
5.37 ± 1.22
1.21 ± 0.39
1.51 (1.03, 2.20)
4.21 ± 1.17
4.79 ± 1.59
2.50 ± 0.97
4.41 ± 1.10
1.21 ± 0.33
1.40 (1.04, 1.85)
3.20 ± 1.06
3.83 ± 1.23
3.66 ± 1.32
5.49 ± 1.47
1.21 ± 0.59
1.88 (1.51, 2.44)
4.28 ± 1.27
5.22 ± 2.12
2.27 ± 0.87b
4.09 ± 1.09b
1.10 ± 0.34
1.54 (1.06, 2.05)
3.02 ± 1.10b
4.10 ± 1.71b
2.26 ± 0.79
4.23 ± 0.92
1.28 ± 0.38
1.26 (0.90, 1.70)
2.95 ± 0.89
3.55 ± 1.27
3.50 ± 0.63b
5.49 ± 0.71b
1.36 ± 0.29
1.15 (0.80, 1.66)
4.12 ± 0.80b
4.21 ± 1.07c
2.22 ± 0.77
4.20 ± 0.90
1.28 ± 0.39
1.26 (0.90, 1.70
2.92 ± 0.87
3.53 ± 1.27
79 (16.9)
8 (4.4)
39 (21.5)
1 (10.0)
31 (32.3)b
124 (28.4)
0c
124 (29.2)
1.35 ± 0.99
1.78 ± 0.96
1.00 ± 0.86
2.10 ± 1.11
0.86 ± 0.75b
0.80 ± 0.62
1.69 ± 0.63
0.77 ± 0.60
215 (45.9)
37 (20.4)
111 (61.3)
2 (20.0)
65 (67.7)b
295 (67.7)
1 (8.3)b
294 (69.3)
1.10 ± 0.82
1.27 ± 0.81
0.87 ± 0.80
1.51 ± 1.03
0.72 ± 0.60b
0.57 ± 0.52
1.04 ± 0.48d
0.53 ± 0.51
106/465 (22.8)
10/179 (5.6)
55 (30.4)
0
41/95 (43.2)b
161 (36.9)
1 (8.3)c
160 (37.7)
J. Ferrières et al.
Data are expressed as mean ± standard deviation, median (interquartile range) or n (%). ACS: acute coronary syndrome; CHD: coronary heart disease; EAS: European Atherosclerosis
Society; ESC: European Society of Cardiology; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; LLT: lipid-lowering therapy.
a Lipid proﬁle and lipid parameters measured within 24 hours of admission for an ACS event and at the time of latest lipid test for stable CHD.
b P < 0.0001.
c P < 0.05.
d P < 0.01.
e In patients who have not achieved the target.
Suboptimal LDL-C levels in French CHD patients
175
greatest improvement observed among patients with an incident ACS who were not on previous chronic LLT. Of the 136
patients on low-to-moderate-intensity statin treatment at
discharge, 127 (93.4%) remained on this dose, compared
with 183/314 (58.3%) patients remaining on high-intensity
statin treatment.
DYSIS II CHD
In DYSIS II CHD, 436 patients with CHD were enrolled by 27
cardiologists and general practitioners in France during 2013
and 2014. Most patients (97.2%) were on chronic LLT at the
time of the latest lipid test (Table 1). The use of chronic
non-LLT treatments was high, particularly antihypertensive
medications (97.5% of patients), with diuretics used in 27.3%
of patients (Table 2). Oral antidiabetic drugs were used in
27.5% of patients. Aspirin was used in 80.2% of patients and
a P2Y12 inhibitor in 39.2%.
Of the 424 patients on LLT, 404 (95.3%) were taking a
statin and 75 (17.7%) were taking a non-statin LLT (Table 3).
The most frequently used statin was atorvastatin (45.0% of
404 patients on statins), followed by rosuvastatin (25.5%);
the most frequently used non-statin LLT was ezetimibe
(77.3% of 75 patients on LLT). Eighty per cent of patients
were on statin monotherapy and 10.3% were on statin plus
ezetimibe (Fig. 4A). Only one-third (32.0%) of the patients
were on ≥ 40 mg/day atorvastatin dose equivalent (Fig. 4B).
The mean ± SD LDL-C concentration at the time
of the latest lipid test was 2.26 ± 0.79 mmol/L
(87.4 ± 30.5 mg/dL), and was lower among patients on
LLT (Table 4). Of the patients on LLT, 29.2% met the LDL-C
Figure 3. Percentage of ACS patients with LDL-C
value < 1.8 mmol/L (< 70 mg/dL) at admission for the index
event and at 120 days according to: A. Chronic LLT at admission;
and B. LLT treatment at admission. a With LDL-C > 1.8 mmol/L
(> 70 mg/dL). ACS: acute coronary syndrome; LDL-C: low-density
lipoprotein cholesterol; LLT: lipid-lowering therapy.
At admission, 16.9% of patients had an LDL-C value
of < 1.8 mmol/L (70 mg/dL), driven primarily by the group
on LLT (25.3%) (Fig. 3A, B; Table 4). Among patients with
a recurrent ACS, a higher number had the LDL-C value
of < 1.8 mmol/L (70 mg/dL).
At hospital discharge, 96.6% (450/466) of patients were
on statin therapy (Table 3), but nearly one-third (30.2%)
of the patients were on ≤ 20 mg/day atorvastatin dose
equivalent (Fig. 2B). The mean ± SD atorvastatin dose
equivalent increased from 22 ± 18 mg/day at admission to
49 ± 28 mg/day at discharge (Fig. 2B).
Follow-up data at 120 days were available in 333 (71.2%)
patients, at which time 95.1% (310/326 with data on medications) were still on statins. The mean ± SD atorvastatin
dose equivalent decreased to 41 ± 28 mg/day by the 120-day
follow-up (Fig. 2B) and 50.6% (80/158) achieved the LDL-C
goal (< 1.8 mmol/L [70 mg/dL]) (Fig. 3A). The percentage of
patients with LDL-C < 1.8 mmol/L (70 mg/dL) had increased
relative to those at admission in all subgroups, with the
Figure 4. A. LLT (n = 436) and B. Statin treatment in atorvastatin
dose equivalents at time of latest lipid test in 403 patients with stable coronary heart disease. Atorva: atorvastatin; LLT: lipid-lowering
therapy; mono: monotherapy.
176
Figure 5. Percentage of CHD patients who achieved the LDL-C
targets at the time of the latest lipid test. a Who had not achieved
the target. CHD: coronary heart disease; LDL-C: low-density lipoprotein cholesterol; LLT: lipid-lowering therapy.
treatment target (< 1.8 mmol/L [70 mg/dL]) and 69.3% met
the target of < 2.5 mmol/L (100 mg/dL) (Table 4 and Fig. 5).
Discussion
These French data from the multicentre, observational
DYSIS II study provide contemporary and detailed insights
into the full lipid proﬁles and patterns of use of LLT in
patients hospitalized with a new or recurrent ACS and in
patients with stable CHD in France.
Despite their generally high-risk proﬁle, half of the
patients with an incident ACS had not been taking LLT
before the event. Of note, chronic use of aspirin and
P2Y12 inhibitors was low in ACS patients with a recurrent
event. These ﬁndings highlight an opportunity to improve
the early identiﬁcation of high-risk individuals who could
beneﬁt from cholesterol-lowering medications in the
primary prevention setting. In addition, only one-third of
the patients with a recurrent ACS who were taking LLT
achieved the therapeutic LDL-C target of < 1.8 mmol/L. This
failure may reﬂect the fact that nearly three-quarters of
these patients had been on a low- or moderate-intensity
dose of statin (≤ 20 mg/day atorvastatin dose equivalent)
before the event. The mean statin dose (calculated in
atorvastatin equivalent) in patients with recurrent ACS was
only 26 ± 21 mg/day at admission, which was insufﬁcient to
adequately control their LDL-C levels. Our data also suggest
that physicians are responding by increasing the dose of LLT
during hospitalization, with patients discharged on a mean
dose of 49 ± 28 mg/day. Almost one-third (30.2%) of the
patients were discharged on ≤ 20 mg/day atorvastatin dose
equivalent. Persistence with this low-to-moderate-intensity
statin treatment at 120 days was greater than that for
high-dose statin treatment; this ﬁnding, together with low
use of combination treatment with ezetimibe (4.6%), may
explain why still only half of the patients had achieved the
LDL-C treatment goal at this time. In line with our previous
ﬁndings [10], patients with an incident ACS who were on
statin therapy before the event presented with a higher
J. Ferrières et al.
rate of non-ST-elevation ACS than patients not taking statin
therapy (44.8% vs 32.6%, respectively). While these data
are unadjusted for differences in baseline characteristics,
they support the hypothesis that chronic use of statins could
alter the presentation of ACS, resulting in fewer ST-segment
elevation myocardial infarctions, a smaller infarct size and
a lower mortality [10—12].
Three-quarters of the patients with stable CHD had
hypercholesterolaemia. A minority (28.4%) achieved the
LDL-C treatment goal of < 1.8 mmol/L (70 mg/dL). Most of
the CHD patients were taking LLT, with four out of ﬁve
patients receiving statin monotherapy, and 43.2% were on a
low- or moderate-intensity dose. Of concern, one-quarter of
the patients with CHD were being treated with rosuvastatin,
which is not indicated for secondary prevention [13]. The
mean LDL-C value in our population of stable CAD patients is
marginally lower (2.26 ± 0.79 mmol/L vs 2.5 ± 0.8 mmol/L)
than that reported in the multicentre CORONOR study [14],
conducted between 2010 and 2011 in the Nord Pas-de-Calais
administrative region of France and involving 4184 patients
with stable CAD enrolled by cardiologists. In both this study
and in the CORONOR study, the use of statins was very high
(92.7% overall in DYSIS II vs 92% in CORONOR), and a similar percentage of patients achieved the LDL-C therapeutic
target of < 2.5 mmol/L (67.7% vs 70—71% in CORONOR).
The Lipid Treatment Assessment Project (L-TAP), conducted initially in the United States between 1996 and
1997, and subsequently in nine countries in 2006 to 2007,
demonstrated improvements in the use of LLT in adult
dyslipidaemic patients [15]. Overall, 73% of patients (75%
of whom were on a statin, 8% on other LLT, and 16% on
non-pharmacological LLT) achieved the national treatment
goals in L-TAP 2, versus 38% in L-TAP, but this percentage
decreased to 67% in high-risk patients (versus 18% in L-TAP).
The European Action on Secondary and Primary Prevention
by Intervention to Reduce Events (EUROASPIRE) surveys,
which started in 1995—1996, have shown a large proportionate increase in the prescribing of LLT, most frequently
statins, and a corresponding reduction in LDL-C in patients
aged < 80 years with CHD in Europe [16]. However, the surveys also revealed that most patients were not achieving the
LDL-C treatment targets. In an analysis from EUROASPIRE IV
of nearly 8000 patients (conducted between May 2012 and
April 2013), 80.5% of the population had LDL-C ≥ 1.8 mmol/L
despite the fact that 85.7% were on statin medication,
and 65% of men and 55% of women had achieved the conservative target of < 2.5 mmol/L [16]. In a further analysis
from EUROASPIRE IV of adults aged ≤ 80 years with a ﬁrst
or recurrent CHD discharged from hospital, 90.4% were discharged on statin therapy (37.6% were on a high-intensity
statin), but this ﬁgure had dropped to 86% by the follow-up
interview (conducted at least 6 months after hospitalization), at which point 32.7% were still on a high-intensity
statin [17]. Only 19.3% of the patients achieved an LDLC value of < 1.8 mmol/L at follow-up interview. In the 332
EUROASPIRE IV patients enrolled in France, 93.1% were discharged on a statin, which is similar to the rate of 96.6% in
DYSIS II ACS. However, a greater proportion of patients in
DYSIS II ACS were discharged on high-intensity statin therapy (69.8% vs 56.9%). This difference persisted at follow-up
(59.0% vs 48.2% in EUROASPIRE IV), perhaps reﬂecting differences in the populations, geographical reach and durations
Suboptimal LDL-C levels in French CHD patients
of follow-up. Together, however, the ﬁndings from these
studies clearly demonstrate the need for better lipid control
through the use of more intensive or combination LLT.
Limitations
As an observational cohort study, this analysis is subject to
several limitations, including missing data and loss to followup. While investigators were strongly encouraged to enrol
consecutive patients to avoid selection bias, we are unable
to verify to what extent this was achieved. Some of the
subpopulations were small and the ﬁndings should be interpreted with caution. Patients who were lost to follow-up at
120 days (approximately one-quarter of the population) may
have been less compliant with their LLT than patients who
were available.
Conclusions
These data from DYSIS II highlight key areas for improvement
in the primary and secondary prevention of CHD in France
and better adherence to evidence-based clinical practice
guidelines. A sizable proportion of patients without a history of CHD − but who are at very high risk of an ischaemic
event − do not receive LLT. Among patients with CHD, higher
intensity LLT, or a combination of a statin and a non-statin
LLT, is needed to increase the achievement of LDL-C treatment targets and reduce the risk of morbidity and mortality.
Funding
177
• Linda Aissou, hôpital Avicenne, Bobigny;
• Franck Albert, centre hospitalier Louis-Pasteur, Le
Coudray;
• Denis Angoulvant, CHRU Tours, Tours;
• Emmanuel Boiffard, centre hospitalier départemental
Vendée Site de la Roche, La-Roche-Sur-Yon;
• Yves Cottin, hôpital du Bocage central, Dijon cedex;
• Nicolas Delarche, centre hospitalier de Pau, Pau;
• Raphaele Arrouasse, Philippe Le Corvoisier, hôpital HenriMondor, Creteil;
• Emile Ferrari, Hôpital Pasteur, Nice;
• Alain Furber, CHU d’Angers, Angers;
• Sylvain Ranc, Centre Hospitalier Saint-Joseph Saint-Luc,
Lyon;
• Michel Galinier, hôpital Rangueil - pôle cardiovasculaire
et Toulouse;
• Jean-Louis Georges, centre hospitalier de Versailles, Le
Chesnay;
• Christophe Piot, clinique Millenaire, Montpellier;
• Florence Leclercq, hôpital Arnaud-de-Villeneuve,
Montpellier;
• Thierry Lefevre, institut Jacques-Cartier, Massy;
• Marc Goralski, CHR De La Source, BP 6709, Orleans;
• Gilles Levy, clinique du Millénaire, Montpellier;
• Nicolas Mansencal, hôpital Ambroise-Pare, BoulogneBillancourt;
• Franck Paganelli, hôpital Nord—Pavillon Mistral, Marseille;
• François, Paillard, CHU de Rennes—hôpital Pontchaillou,
Rennes;
• Patrick Peycher, clinique Axium, Aix-en-Provence;
• Gilles Rouault, hôpital Laënnec—site de Quimper, Quimper;
• François Schiele, CHU Besançon—hôpital Jean-Minjoz,
Besancon;
• Jacques Berland, clinique Saint-Hilaire, Rouen.
This study was sponsored by Merck & Co., Inc.
Acknowledgements
Sophie Rushton-Smith, PhD (MedLink Healthcare Communications Ltd, UK) provided writing support and was funded by
the sponsors.
Disclosure of interest
J. F. Received honoraria from Aegerion, Amgen, Merck, and
Sanoﬁ.
M.V.R., D.L., V.A., B.M.A. and P.B. Full-time employees
of Merck & Co., Inc., Kenilworth, NJ, USA.
A.K.G. Received research support and honoraria for
lectures from a number of pharmaceutical companies producing lipid-lowering drugs including Merck & Co., Inc., the
sponsor of this study.
Appendix A. DYSIS II French Investigators
DYSIS II ACS (24 centres):
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
DYSIS II CHD (27 centres):
Regis Agache, cabinet médical, Billy-Montigny;
Philippe Boisson, Bedoin;
Loic Boucher, cabinet médical, Murs Erigne;
Alain Rostane, Velizy-Villacoubla;
Jean Ferrieres, CHU Rangueil, Toulouse;
Adib Dabboura, cabinet médical, Villefranche-sur-Saone;
Bernard Doucet, cabinet médical, Chambery;
Christian Duroy, cabinet médical, Laval;
Dominique Edet, Bretteville L’orgueilleu;
Ghazaleh Esna Ashari, cabinet médical, Rambouillet;
Jean Philippe Fleury, Velines;
Daniel Gombaud, cabinet médical, Angers;
Yves Bermond, Vannes;
Roland Greffe, Firminy;
Macario Sorribas, Sete;
Patrick Leprince, cabinet médical, Tours;
Jean-Louis Long, cabinet médical, Vichy;
Benaouda Mahdjoub, cabinet médical, Thouars;
Hamid Makki, cabinet médical, Chatillon-Sur-Seine;
Denis Marin, cabinet médical, Briollay;
Christophe Marocco, Les-Pennes-Mirabeau;
Jean-Luc Mougeolle, cabinet médical, Sedan;
Philippe Mureau, cabinet médical, Belabre;
Philippe Remaud, cabinet médical, Angers;
Dominique Renard, cabinet médical, Calvi;
178
• Philippe Rieu, cabinet médical, La Riche;
• Patrick Robert, cabinet médical, Laval.
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