Download - American Heart Journal

Renal function, atherothrombosis extent, and outcomes
in high-risk patients
Raphaelle L. Dumaine, MD, a Gilles Montalescot, MD, PhD,a Ph. Gabriel Steg, MD, b E. Magnus Ohman, MD, c
Kim Eagle, MD, d and Deepak L. Bhatt, MD, MPHe on behalf of the REACH Registry Investigators Paris, France;
Durham, NC; Ann Arbor, MI; and Boston, MA
Background Although prior data showed an association between chronic kidney disease (CKD) and atherothrombotic
events, little is known about the risk profile and specific outcomes of atherothrombotic outpatients with CKD.
Methods
More than 69,000 outpatients at risk of atherothrombotic events were enrolled in the REACH Registry. Creatinine
clearance (CrCl) was available for 51,208 patients divided into 4 groups: normal (CrCl ≥90 mL/min, n = 13,949), mild (6089 mL/min, n = 19,474), moderate (30-59 mL/min, n = 15,883), and severe CKD (CrCl <30 mL/min, n = 1902). Baseline
characteristics, number of arterial beds overtly affected, medications, overall mortality, cardiovascular death, myocardial infarction,
stroke, congestive heart failure, peripheral arterial events, and bleeding events were assessed according to renal function.
Results
The number of arterial beds affected increased with severity of CKD. However, patients with severe CKD were less
likely to receive medications of proven benefit. Severe CKD was an independent correlate of all-cause mortality, cardiovascular
mortality, myocardial infarction, congestive heart failure, peripheral arterial revascularization, or amputation.
Conclusion
One third of outpatients at risk for atherothrombotic events have moderate to severe CKD. They are less
likely to receive beneficial therapies despite a higher atherothrombotic burden and worse outcomes. (Am Heart J
2009;158:141-148.e1.)
Since the first publication by Lindner et al,1 the
development of accelerated atherothrombosis in patients
with severe chronic kidney disease (CKD) has been well
documented: clinical trials and registries show an association between CKD and adverse cardiovascular (CV) events
among both community-based 2,3 and hospitalized
unstable patients.4-6 However, little is known about the
risk profile, medical management, and outcomes of
atherothrombotic outpatients with CKD.
The objectives of this study are to assess the prevalence
of CKD in patients presenting with risk factors or
manifestations of atherothrombotic disease and to
describe according to renal function the number of arterial
beds involved and type of atherothrombosis, the quality of
care delivered, and the prognosis of these patients.
From the
a
Pitié-Salpêtrière University Hospital, Paris, France,
b
Bichat-Claude Bernard
University Hospital, Paris, France, cDuke University, Durham, NC, dUniversity of Michigan
Cardiovascular Center, Ann Arbor, MI, and eVA Boston Healthcare System and Brigham
and Women's Hospital, Boston, MA.
See Appendix (available online) for a complete listing of REACH Registry Investigators.
Submitted December 10, 2008; accepted May 2, 2009.
Reprint requests: Gilles Montalescot, MD, PhD, Institut de Cardiologie, CHU PitiéSalpêtrière, 47 boul de l'Hôpital, 75013 Paris, France.
E-mail: [email protected]
0002-8703/$ - see front matter
© 2009 Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2009.05.011
Methods
Study design
The REACH Registry is an international, prospective, observational registry designed to provide up to 24 months of clinical
follow-up. The design and methodology of the REACH Registry
have been published previously.7,8 Briefly, consecutive eligible
outpatients aged 45 years, with established coronary artery
disease (CAD), cerebrovascular disease (CVD), or peripheral
arterial disease (PAD), or with at least 3 atherothrombotic risk
factors were enrolled.
Documented CAD consisted of ≥1 of the following criteria:
stable angina or history of unstable angina with established CAD,
history of percutaneous or surgical myocardial revascularization,
or previous myocardial infarction (MI). Documented CVD
consisted of a hospital or neurologist report with the diagnosis of
transient ischemic attack or ischemic stroke. Documented PAD
consisted of one or both criteria: current intermittent claudication
with ankle brachial index (ABI) of <0.9 or a history of intermittent
claudication together with a previous and related percutaneous or
surgical intervention, including amputation. The risk factors
consisted of those that were documented in the medical record
or for which patients were receiving treatment at the time of study
enrolment: treated diabetes mellitus, diabetic nephropathy, ABI of
<0.9, asymptomatic carotid stenosis of ≥70%, carotid intima media
thickness exceeding twice that of adjacent sites, systolic blood
pressure of ≥150 mm Hg despite therapy for at least 3 months,
hypercholesterolemia treated with medication, current smoking of
at least 15 cigarettes per day, men aged ≥65 years, or women aged
≥70 years. Patients already in a clinical trial, hospitalized patients,
142 Dumaine et al
or those who might have difficulty returning for a follow-up visit
were excluded from enrolment.
Study sample and data source
A total of 69,055 patients were enrolled in 5,473 sites in 44
countries worldwide between December 2003 and June 2004.
Creatinine clearance (CrCl) was available in 51,208 patients.
Estimates of CrCl were made using the Cockcroft-Gault
equation.9 Patients were classified as follows: normal (≥90 mL/
min), mildly impaired (60-89 mL/min), moderately impaired (3059 mL/min), and severely impaired CrCl (<30 mL/min), as
defined by the Kidney Disease Outcome Quality Initiative.10
Data regarding baseline characteristics, treatment strategies
during follow-up as well as clinical end points were collected
centrally using a standardized international case report form
completed at the study visit. The protocol of the REACH Registry
was submitted to the institutional review board in each country
according to local requirements, and signed informed consent
was obtained for all patients. The protocol of the present study
was submitted to and approved by the REACH Publication
Committee in May 2005 before all data were collected.
Sources of funding
The REACH Registry is sponsored by sanofi-aventis (Paris,
France), Bristol-Myers Squibb (Princeton, NJ), and the Waksman
Foundation (Tokyo, Japan). The sponsors provide logistical
support. All the publication activity is controlled by the REACH
Registry Global Publication Committee (see Appendix for
details). The REACH Registry enforces a no-ghost-writing policy.
All manuscripts in the REACH Registry are prepared by
independent authors who are not governed by the funding
sponsors and are reviewed by an academic publication
committee before submission. The funding sponsors have the
opportunity to review manuscript submissions but do not have
authority to change any aspect of a manuscript.
The authors are solely responsible for the design and conduct
of this study, all study analyses, the drafting and editing of the
article, and its final contents.
Statistical analysis
Continuous variables are expressed as mean (SD). Categorical
variables are expressed as frequencies and percentages. Comparisons between categorical variables were performed using the
Pearson χ2 test. For continuous variables, regression analysis was
performed to test linear trend between the 4 CrCl groups.
Multivariable logistic regression was used for the analysis of 1-year
clinical end points, adjusting for clinical differences in atherothrombotic risk factors at baseline: CrCl subgroups, age (as
continuous variable), gender, hypertension, diabetes, smoking
status, and hypercholesterolemia. Statistical significance was
considered as a 2-tailed probability of <.05. Statistical analysis was
performed using SAS Software v8 (SAS Institute Inc, Cary, NC).
Results
Demographics
Table I presents baseline characteristics of the patients.
Normal CrCl was present in less than one third of the
overall population (n = 13,949; 27.2%). Advanced CKD
American Heart Journal
July 2009
was present in more than one third of the population
(34.7%), combining moderate CKD in 15,883 (31.0%)
patients and severe CKD in 1902 (3.7%) of the patients. A
small majority of patients had mildly reduced renal
function, representing 38.0% (n = 19,474) of the population. Chronic kidney disease severity increased with age
and social isolation (Table I).
Except for age and hypertension, other traditional
atherothrombotic risk factors were less frequent as CKD
severity increased; patients with the worst renal function
were more often female, nonsmokers, had a lower body
mass index (BMI), waist circumference, and weight, and
were less likely to be treated for diabetes or dyslipidemia
(all P < .0001). However, the number of patients with
diabetic nephropathy and stage 2 hypertension (blood
pressure ≥160/100 mm Hg) was more frequent as CKD
severity increased (Table II).
Other CV events such as a history of congestive heart
failure (CHF), supraventricular tachyarrhythmias, aortic
valve stenosis, or abdominal aortic aneurysm were all
more frequent as CKD severity increased (all P <
.0001) (Table I).
Atherothrombotic disease burden and location
The extent and severity of vascular disease increased
with CKD severity: history of atherothrombotic event at
any location, low ankle brachial index (ABI) (<0.9), and
asymptomatic carotid stenosis were more frequent as
CKD increased (Table II, all P < .05).
Atherothrombotic disease screening was not systematically performed among all these high-risk patients; as
CKD severity increased, there was a stepwise decrease in
the evaluation of ABI (not done in 58.7% vs 59.2% vs 60.1%
vs 61.0% among patients with CrCl ≥90 60-89, 30-59, <30
mL/min, respectively) as well as screening for significant
carotid stenosis (not done in 48.9% vs 48.6% vs 48.9% vs
51.2%, respectively) (Table II, P < .0001 for all).
The number of arterial beds affected by atherothrombotic disease was greater with increasing CKD severity
(Table II). Most patients had an atherothrombotic event in
a single territory, CAD being the most prevalent atherothrombotic location across all CrCl subgroups.
Medications according to renal function
Statins, other lipid-lowering therapies, β-blockers, and
angiotensin-converting enzyme (ACE) inhibitors were all
administered less frequently as renal dysfunction
increased (P < .0001 for all, Figure 1). There was a
stepwise decrease in the use of aspirin as renal dysfunction increased (71.5%, 69.2%, 64.6%, 61.5% among
patients with CrCl ≥90, 60-89, 30-59, <30 mL/min,
respectively, P < .0001), as opposed to a stepwise increase
in the use of other antiplatelet therapies (22.9%, 24.9%,
25.7%, 27.1%, among patients with CrCl ≥90, 60-89, 3059, <30 mL/min respectively, P < .0001). Oral anticoagulants were used more frequently as CKD severity
American Heart Journal
Volume 158, Number 1
Dumaine et al 143
Table I. Baseline characteristics on inclusion
CrCl (mL/min) (n = 51 208)
≥90 (n = 13 949) 60–89 (n = 19 474) 30–59 (n = 15 883) <30 (n = 1902) P (for trend)
Mean age ± SD (y)
≥75 y old (%)
Female (%)
Weight (kg, mean ± SD)
Height (m, mean ± SD)
BMI⁎ male (kg/m2, mean± SD)
BMI⁎ female (kg/m2, mean ± SD)
Waist circumference among men
(cm, mean ± SD)
Waist circumference among women
(cm, mean ± SD)
Social isolation (%)
Social position (%)
Full-time employment
Part-time employment
Unemployed
Retired
Incapacity
History of CHF (%)
History of AF/flutter (%)
History of aortic valve stenosis (%)
History of abdominal aortic aneurysm (%)
Physical and biologic
characteristics on inclusion
SBP (mm Hg, mean SD)
DBP (mm Hg, mean ± SD)
Albuminuria† (mg/L, mean ± SD)
61.0 ± 8.7
5.9
25.7
93.7 ± 20.3
1.7 ± 0.1
30.9 ± 5.8
34.4 ± 7.5
105.9 ± 16.0
68.1 ± 8.2
20.6
32.6
78.7 ± 14.6
1.7 ± 0.1
27.3 ± 4.0
29.2 ± 5.5
98.4 ± 13.4
75.2 ± 7.7
54.9
48.1
69.3 ± 13.7
1.6 ± 0.1
25.5 ± 3.9
26.2 ± 4.9
95.0 ± 14.0
78.0 ±10.1
67.6
62.4
63.2 ± 15.3
1.6 ± 0.1
24.5 ± 4.5
24.6 ± 5.1
92.6 ± 15.9
<.0001
<.0001
<.0001
<.0001
<.0001
<.0001
<.0001
105.2 ± 18.2
96.4 ± 16.4
90.3 ± 15.6
86.1 ± 14.8
<.0001
15.7
18.7
25.2
28.9
<.0001
34.2
6.3
6.3
41.6
9.1
12.2
7.8
2.3
1.4
15.2
6.7
6.4
64.7
4.4
12.4
9.8
2.9
2.4
5.1
4.6
7.5
76.9
2.8
18.4
14.1
4.3
3.5
4.6
2.7
8.4
75.1
5.8
29.5
16.4
5.2
4.6
<.0001
<.0001
<.0001
<.0001
137 ± 19
80 ± 11
103.5 ± 507.2
137 ± 19
79 ± 11
81.8 ± 312.0
138 ± 20
76 ± 11
135.3 ± 485.0
138 ± 21
74 ± 12
388.2 ± 1003.8
.14
<.0001
<.000
<.0001
AF, Atrial fibrillation; SBP, systolic blood pressure; DBP, diastolic blood pressure.
⁎ Calculated as weight in kilograms divided by the square of height in meters.
† Albuminuria was available in 9480 patients.
increased (10.2%, 11.6%, 15.0%, 15.1% from normal to
severe CKD, respectively, P < .0001). By contrast with βblockers and ACE inhibitors, other antihypertensive
therapies—including angiotensin II receptor blockers
(ARBs), diuretics, and calcium-channel blockers—were
all prescribed more frequently with increasing CKD
severity (all P < .0001, Figure 1). Nitrates were also used
more frequently as renal function decreased (21.7%,
24.6%, 28.3%, 31.9% from normal to severe CKD
respectively, P < .0001).
Medications according to atherothrombotic extent
In all grades of CrCl, there was a significant increase in
the use of antiplatelet therapy with the extent of
atherothrombotic disease (Figure 2). When stratifying by
the number of vascular beds involved and by renal
function, prescription of at least 1 antiplatelet agent was
similar across CrCl subgroups in patients who only had
risk factors and no prior manifestation of atherothrombosis. However, in patients with atherothrombotic disease in
1 or 2 locations, there was a stepwise decrease in the use
of antiplatelet therapy with increasing of CKD severity. In
patients with 3 atherothrombotic locations, these differences were no longer observed (Figure 2).
Parallel to the decreased use of antiplatelet agents, there
was a stepwise increase in the use of oral anticoagulant
medication with the extent of atherothrombotic disease.
Oral anticoagulant medication was used more frequently
as CKD severity increased, except in polyvascular patients
in whom the use of oral anticoagulants was similar,
irrespective of the level of renal function (20.8%, 20.7%,
25.1%, 22.5%, among patients with CrCl ≥90, 60-89, 3059, <30 mL/min, respectively, P = not significant).
The stepwise decrease in the prescription of statins with
the increase of CKD severity was observed irrespective of
the number of beds affected (data not shown).
Use of other medications of proven benefit increased
with the number of atherothrombotic beds affected
among all CrCl subgroups: β-blockers (eg, among patients
with severe CKD, β-blockers were prescribed among
34.9%, 48.5%, 56.7%, 51.0%, of patients with no, 1, 2, or 3
atherothrombotic locations, respectively, P < .001), at
least 1 antiplatelet agent (53.2%, 78.6%, 81.3%, 88.2%), or
double antiplatelet therapy (2.4%, 13.4%, 19.3%, 22.0%)
(P < .001 for all).
These medications of proven benefit, however,
remained significantly less prescribed among patients
with the most severe CKD compared with patients with
American Heart Journal
July 2009
144 Dumaine et al
Table II. Atherothrombotic characteristics on inclusion
CrCl (mL/min) (n = 51 208)
≥90 (n = 13 949) 60–89 (n = 19 474) 30–59 (n = 15 883) <30 (n = 1902) P (for trend)
Atherothrombotic risk factors
≥65 y old, men (%)
≥70 y old, women (%)
Current smoker (%)
Treated diabetes (%)
Diabetic nephropathy (%)
Yes
Unknown
History of hypertension (%)
BP >140/90 mm Hg (%)
Hypertension stage 1 (160/100 > BP >
140/90 mm Hg)
Hypertension stage 2
(BP ≥160/100 mm Hg)
Treated hypercholesterolemia (%)
ABI <0.9 (%)
Yes
Unknown
Asymptomatic carotid stenosis ≥70%
Yes
Unknown
Carotid intimal-media thickness
(mm, mean ± SD)
ABI (mean ± SD)
Ischemic disease history (%)
TIA
Ischemic stroke
Stable angina
Unstable angina
MI
PCI
CABG
Lower limb artery angioplasty
or bypass grafting
Lower limb amputation
Carotid surgery
No. of atherothrombotic locations
0 (risk factor only)
1
2
3
Location of atherothrombotic disease
Risk factors only
CAD only
CVD only
PAD only
CAD + CVD
CAD + PAD
CVD + PAD
CAD + CVD + PAD
32.3
23.1
21.8
48.9
67.8
50.2
15.2
40.2
90.0
79.4
9.8
39.3
84.8
86.4
8.1
42.3
<.0001
<.0001
<.0001
<.0001
<.0001
12.8
18.5
82.1
9.9
19.0
81.1
12.5
19.4
84.6
21.6
17.8
88.6
32.4
33.0
33.0
29.7
16.7
16.0
16.5
19.4
78.5
74.3
70.0
65.7
8.4
58.7
9.0
59.2
11.1
60.1
13.6
61.0
3.7
48.9
1.3 ± 0.7
4.6
48.6
1.3 ± 0.6
5.9
48.9
1.5 ± 0.7
7.3
51.2
1.5 ± 0.7
.17
0.9 ± 0.2
0.9 ± 0.2
0.9 ± 0.2
0.8 ± 0.2
<.0001
10.0
16.1
29.7
13.8
33.8
28.4
19.4
5.4
12.1
19.7
30.6
12.9
31.4
26.4
20.3
6.1
15.1
22.5
30.6
11.9
30.6
22.9
21.6
6.8
17.0
22.5
32.4
13.0
33.9
19.4
23.6
8.8
<.0001
<.0001
.02
<.0001
<.0001
<.0001
<.0001
<.0001
1.6
3.2
1.7
4.2
1.8
5.7
2.9
6.1
<.0001
<.0001
<.0001
22.0
64.9
11.9
1.3
18.5
66.7
13.3
1.5
17.9
63.3
16.8
2.0
15.8
61.8
19.8
2.7
22.0
48.3
13.0
3.7
6.7
4.3
0.9
1.3
18.5
46.1
16.3
4.3
7.8
4.4
1.2
1.5
17.9
41.5
17.3
4.5
10.2
5.1
1.5
2.0
15.8
39.7
16.8
5.3
11.3
7.5
1.0
2.7
<.0001
<.0001
<.0001
<.0001
<.0001
<.0001
BP, Blood pressure; TIA, transient ischemic attack; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.
better renal function, especially in patients with atherothrombosis in 1 or 2 locations. At the 2 extremes of
atherothrombotic extent, that is, among patients with risk
factors only or among patients with 3 diseased locations,
prescription patterns changed: β-blockers were prescribed more frequently as CKD severity increased (eg,
among patients with risk factors only, 27.5%, 28.4%,
30.4%, 34.9% in subgroups with CrCl ≥90, 60-89, 30-59,
<30 mL/min, respectively, P = .001), and antiplatelet
therapy administration did not differ across all CrCl
subgroups (54.2%, 55.0%, 54.7%, 53.2% from normal to
severe CKD severity, respectively, P = .86).
American Heart Journal
Volume 158, Number 1
Figure 1
Main medications used depending on renal function. RX, Therapies;
HTN, antihypertensive.
Figure 2
Antiplatelet therapy prescription stratified by number of atherothrombotic beds affected and creatinine clearance subgroups.
One-year atherothrombotic and bleeding events
There was an increase in the risk of mortality from any
cause, CV death, nonfatal MI, and amputation with
increase in CKD severity (Figure 3). There was also a
trend toward an increase in non-fatal stroke as renal
function decreased, without reaching significance (Figure
3). Finally, hospitalization for CHF occurred more
frequently with worsening of CKD (3.7%, 3.0%, 4.1%,
6.2% from normal to severe CKD, respectively, P < .001).
Bleeding leading to hospitalization and transfusion was
also significantly more frequent as renal function worsened (0.9%, 0.8%, 1.0%, 1.4% from normal to severe CKD
respectively, P = .04).
Dumaine et al 145
Figure 3
Main adverse atherothrombotic events involving the 3 arterial beds at
1 year among creatinine clearance subgroups.
Figure 4
Association between severe chronic kidney disease and adverse
outcomes at 1-year follow-up. *Adjusted risk of outcome for severely
impaired creatinine clearance versus normal renal function as detailed
in the Methods section.
In multivariate analysis, severe CKD was independently
associated with all-cause mortality, as well as CV mortality
(Figure 4). Severe CKD was also an independent correlate
of several other end points at 1-year follow-up: nonfatal
MI, hospitalization for CHF, as well as PAD revascularization and amputation. In addition, the lowest quartile of
CrCl was independently associated with bleeding leading
to hospitalization and/or transfusion (Figure 4).
Moderately and severely impaired renal functions
were independently correlated with the triple composite end point including CV death/MI/stroke (OR 1.89,
95% CI 1.53-2.34, for CrCl <30 mL/min; OR 1.17, 95% CI
1.01-1.34, for CrCl 30-59 mL/min compared with CrCl
≥90 mL/min). Similarly, decreased renal function was
146 Dumaine et al
also an independent correlate for the quadruple end
point of CV death/MI/stroke/hospitalization (OR 1.54,
95% CI 1.33-1.78, for CrCl <30 mL/min; OR 1.11, 95% CI
1.02-1.21, for CrCl 30-59 mL/min compared with CrCl
≥90 mL/min).
Discussion
Prior US community-based studies have demonstrated a
graded association between the risk of adverse CV
outcomes and renal dysfunction.2,3 The present study
builds on these results and provides extensive information from the largest database available regarding the
prevalence of CKD among stable outpatients with or at
risk of atherothrombosis. Associations are also highlighted between renal function and number and type of
arterial beds affected, risk profile, medical management,
and clinical outcomes among this broad population of
>51,000 outpatients.
In the current REACH Registry population, prevalence
of CKD is high, and less than one third of this population
at risk of atherothrombotic events has normal CrCl levels.
Most of these stable outpatients already have mild CKD,
and more than one third have more severe CKD. In the
large US community-based Kaiser Permanente Renal
Registry,3 16.8% of the population had moderate CKD
and 0.8% had severe CKD after exclusion of kidney
transplant recipients or patients receiving maintenance
dialysis at entry. In comparison, among the present
population, there is a 2-fold increase in the prevalence
of CKD with 31.0% and 3.7% of patients having moderate
and severe CKD, respectively. These frequencies are as
high as those observed among prospective4 or retrospective studies5,6 of patients hospitalized for acute
coronary syndromes. This might reflect the strength of
the link between the degree of renal dysfunction and the
level of the “vascular risk” of the atherothrombotic
patient. This emphasizes the need to incorporate renal
function evaluation in the management of any patient
with atherothrombosis risk or manifestation, including
stable outpatients.
As severity of CKD increases, there is a stepwise
increase in the risk of prior manifestation of atherothrombosis in any of the 3 main arterial beds (CAD, CVD, PAD).
Distribution of atherothrombosis locations is similar
among all CrCl subgroups, with CAD as the most prevalent
location, then CVD, and finally PAD. There is a gradation
in the number of arterial beds affected with the severity of
CKD; prevalence of prior manifestations in multiple
locations of atherothrombosis is almost 2-fold higher in
patients with severe CKD than in patients with normal
CrCl. Despite the high atherothrombotic risk of these
patients, screening for assessment of significant carotid
stenosis or abnormal ABI is not performed in most
patients; half of the patients did not undergo assessment
for significant carotid stenosis, and in 60% of patients, ABI
American Heart Journal
July 2009
was not estimated. As albuminuria quantification is usually
recommended among hypertensive or diabetic patients,
to stratify the risk and guide the “aggressivity” of the
medical management, discovery of advanced renal dysfunction in a patient at risk of atherothrombosis should be
interpreted as an additional major risk factor, leading to a
more systematic assessment of the whole arterial bed.
Patients with the most severe CKD are also at higher risk
of further atherothrombotic events at 1-year follow-up. Of
these outpatients, severe CKD is not only independently
associated with CV events such as CV death, MI, or acute
coronary syndromes, as in previous observations,2,3 but is
also an independent correlate of PAD revascularization,
amputation, CHF, or significant bleeding. The risk of heart
failure was mainly observed in CAD patients with marked
renal dysfunction, a triple association of serious concern.
Medical management was different depending on the
number of arterial beds affected as well as renal function.
The lower prescription of ACE inhibitors among patients
with renal dysfunction was in part counterbalanced by an
increase of ARB's prescription among these patients.
Overall, other medications of proven benefit in different
settings of atherothrombosis such as antiplatelet therapies, statins, and β-blockers, were prescribed less
frequently among patients with CKD. Some confounders
may explain in part this observation, for instance, more
limited financial resources among patients with CKD who
are more likely to be unemployed or retired. However, the
same underutilization has been previously observed in
other settings, for instance, among patients with acute
coronary syndromes during their inhospital stay4,6,11; in
this setting, underutilizations of these medications may
have been related in part to unstable hemodynamics,
comorbidities, and a higher propensity for bleeding.
Overall, even if confounders may explain in part the
lower prescription of beneficial therapies, the present
observation in stable outpatients underscores the need for
optimization of prevention of atherothrombotic events
among CKD patients. Interestingly, when stratifying by
the extent of arterial disease, in each CrCl subgroup, there
was a stepwise increase in the prescription of β-blockers,
antiplatelet therapy, and ACE inhibitors as the number of
arterial beds involved increased. This may be related to
the larger number of physicians involved in the patient's
care when several atherothrombotic locations are
involved, or the higher concern from the physician in
charge as atherothrombotic events increase in frequency
and diversity.
The use of oral anticoagulants increased gradually
with the number of arterial beds affected and the
increase of CKD severity. This may relate in part to the
higher incidence of atrial fibrillation observed with
increasing severity of CKD. The large prescription of
oral anticoagulants may partly explain the decrease in
prescription of antiplatelet agents, as the gradual
increase in oral anticoagulant prescription with renal
American Heart Journal
Volume 158, Number 1
function decrease is paralleled by a gradual decrease in
administration of antiplatelet agents. The association
between this treatment strategy and the observed
increased risk of bleeding in the CKD population
warrants further specific investigation.
The observed underuse of statin therapy among patients
with CKD, irrespective of the number of arterial beds
affected, remains challenging as there is no definitive
restriction in the use of statins among patients with CKD.
The “paradoxical” association of lower cholesterol levels
among patients with severe CKD and poor outcomes has
been previously reported; poor outcome does not seem to
relate to low cholesterol levels per se but to associated bias
such as concomitant systemic inflammation and malnutrition.12 Statin therapy has proven to be of benefit in
patients with nonsevere CKD,13-15 but not in patients on
chronic haemodialysis.16,17 This suggests that statin
therapy may be beneficial in CKD patients, at least when
started early enough in the evolution of the disease.18 The
results of the ongoing SHARP randomized trial (ClinicalTrials.gov number, NCT00125593)19 of simvastatin in
addition to ezetimibe versus placebo in a large population
of patients with mild to severe CKD is awaited to draw
more definitive conclusion.
The present analysis has several limitations. Most of
them are inherent to the nature of a registry. Data
collection and patients' recruitment may have been biased
by unknown cofounders, highly dependent on the
investigating center. However, the large size of the current
international multicenter registry may have diluted these
potential biases. Despite the diversity and extent of
recruitment worldwide, some important ethnic groups,
including African and Chinese populations, were underrepresented in the REACH Registry. The present findings
may thus not be extrapolated to these particular groups.
While it can be argued that, at times, absolute differences
between CrCl subgroups represented only a few percentages, it is noteworthy that these differences are
significant, repeated among almost all studied end point,
and particularly marked when the subgroup of patients
with the worst renal function is compared with patients
with normal renal function.
In conclusion, CKD is frequent among stable outpatients
at high atherothrombotic risk, with one third of this
population presenting with moderate to severe kidney
dysfunction. There is a gradual association between CKD
severity and the number of arterial atherothrombotic beds
affected, translating into a higher risk of atherothrombotic
events among patients with severe CKD, particularly in
patients with disease in 3 arterial beds.
Despite this association between CKD and atherothrombotic events, patients with renal dysfunction are less likely
to undergo extensive vascular risk assessment and to
receive beneficial therapies, especially if they present with
limited atherothrombotic disease. Focus should be made
toward greater screening for CKD among patients at high
Dumaine et al 147
atherothrombotic risk and optimization of medical management to improve primary and secondary prevention.
Acknowledgements
We thank the REACH Editorial Support Group for
providing editorial help. The REACH Registry is endorsed
by the World Heart Federation. Statistical evaluations
were performed by Alain-Jean Richard, Sanofi-Aventis,
Paris, France.
Disclosures
Dr R. Dumaine had full access to the data of the
present study and takes responsibility for the integrity of
the data and accuracy of the data analysis. The authors
are fully responsible for the content and editorial
decisions for this manuscript.
Dr Dumaine has no disclosure information to declare.
Dr Montalescot discloses the following relationships:
Grant support – sanofi-aventis (Paris, France), Eli Lilly
(Indianapolis, IN), Guerbet (Villepinte, France), Pfizer
(New York, NY), and Bristol-Myers Squibb (New York,
NY); Consulting fees – sanofi-aventis, Eli Lilly, BristolMyers Suibb, Merck Sharpe & Dohme (Whitehouse
Station, NJ), Proctor & Gamble (Cincinnati, OH), AstraZeneca (London, United Kingdom), GlaxoSmithKline
(Uxbridge, United Kingdom), Medicines Company (Parsippany, NJ), and Schering-Plough (Kenilworth, NJ);
Lecture fees – sanofi-aventis, Eli Lilly, Bristol-Myers Squibb,
Merck Sharpe & Dohme, GlaxoSmithKline and Nycomed
(Zurich, Switzerland).
Dr Steg discloses the following relationships: Research
Grant – sanofi-aventis; Speakers bureau – BoehringerIngelheim (Ingelheim, Germany), Bristol-Myers Suibb,
GlaxoSmithKline, Nycomed, sanofi-aventis, Servier (Suresnes, France), ZLB-Behring (King of Prussia, PA);
Consulting/advisory board – AstraZeneca, BoehringerIngelheim, Bristol-Myers Suibb, GlaxoSmithKline, Merck
Sharpe & Dohme, Nycomed, sanofi-aventis, Servier,
Takeda (Osaka, Japan), The Medicines Company.
Dr Ohman discloses the following relationships: Grant
support – Bristol-Myers Squibb, sanofi-aventis, ScheringPlough, Millennium Pharmaceuticals (Cambridge, MA), Eli
Lilly, Berlex (Wayne, NJ); Consulting fees – Inovise
(Beaverton, OR) and Savacor (Los Angeles, CA); Shareholder – Inovise, Savacor and Medtronic (Minneapolis,
MN); Speaker's Bureau – CV Therapeutics (Palo Alto, CA)
and Schering Plough.
Dr Eagle discloses the following relationships: Grant
support – Biosite (San Diego, CA), Bristol-Myers Squibb,
Cardiac Sciences (Bothell, WA), Blue Cross Blue Shield of
Michigan (Detroit, MI), Hewlett Foundation (Menlo Park,
CA), Mardigian Fund (Detroit, MI), Pfizer, sanofi-aventis,
Varbedian Fund (Ann Arbor, MI); Consulting fees – NIH
NHLBI (Bethesda, MD), Pfizer, sanofi-aventis, Robert
Wood Johnson Foundation (Princeton, NJ).
148 Dumaine et al
Dr. Bhatt discloses the following relationships:
Research Grants (directly to the institution) – Bristol
Myers Squibb, Eisai (Tokyo, Japan), Ethicon (Somerville,
NJ), sanofi-aventis, The Medicines Company; Honoraria
(currently donated to non-profits) – Astra Zeneca,
Bristol Myers Squibb, Centocor (Horsham, PA), DaiichiSankyo (Tokyo, Japan), Eisai, Eli Lilly, GlaxoSmithKline,
Millennium, Paringenix (Tucson, AZ), PDL (Incline
Village, NV), sanofi-aventis, Schering Plough, The
Medicines Company, TNS Healthcare (London, United
Kingdom); Speaker's bureau (not current, over 2 years
ago) – Bristol Myers Squibb, sanofi-aventis, The Medicines Company; Consultant/Advisory Board (currently
donated to non-profits) – Astra Zeneca, Bristol Myers
Squibb, Cardax (Aiea, HI), Centocor, Cogentus (Menlo
Park, CA), Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson (Raritan, NJ), McNeil
(Raritan, NJ), Medtronic, Millennium, Otsuka (Tokyo,
Japan), Paringenix, PDL, Portola (San Francisco, CA),
sanofi-aventis, Schering Plough, The Medicines Company, TNS Healthcare, Vertex (Cambridge, MA); Expert
testimony regarding clopidogrel (the compensation was
donated to a non-profit organization).
References
1. Lindner A, Charra B, Sherrard DJ, et al. Accelerated atherosclerosis in
prolonged maintenance hemodialysis. N Engl J Med 1974;290:
697-701.
2. Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney function
as a risk factor for atherosclerotic cardiovascular outcomes in the
community. J Am Coll Cardiol 2003;41:47-55.
3. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the
risks of death, cardiovascular events, and hospitalization. N Engl J
Med 2004;351:1296-305.
4. Dumaine R, Collet JP, Tanguy ML, et al. Prognostic significance of
renal insufficiency in patients presenting with acute coronary
syndrome (the Prospective Multicenter SYCOMORE study). Am J
Cardiol 2004;94:1543-7.
5. Gibson CM, Dumaine RL, Gelfand EV, et al. Association of
glomerular filtration rate on presentation with subsequent mortality
in non ST-segment elevation acute coronary syndrome; observations
in 13,307 patients in five TIMI trials. Eur Heart J 2004;25:
1998-2005.
American Heart Journal
July 2009
6. Santopinto JJ, Fox KA, Goldberg RJ, et al. Creatinine clearance and
adverse hospital outcomes in patients with acute coronary syndromes:
findings from the global registry of acute coronary events (GRACE).
Heart 2003;89:1003-8.
7. Bhatt DL, Steg PG, Ohman EM, et al. International prevalence,
recognition, and treatment of cardiovascular risk factors in outpatients
with atherothrombosis. JAMA 2006;295:180-9.
8. Ohman EM, Bhatt DL, Steg PG, et al. The REduction of Atherothrombosis for Continued Health (REACH) Registry: an international,
prospective, observational investigation in subjects at risk for
atherothrombotic events-study design. Am Heart J 2006;151:786.
e1-786.e10.
9. Cockcroft DW, Gault MH. Prediction of creatinine clearance from
serum creatinine. Nephron 1976;16:31-41.
10. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification
of chronic kidney disease: a position statement from Kidney Disease:
Improving Global Outcomes (KDIGO). Kidney Int 2005;67:2089-100.
11. Berger AK, Duval S, Krumholz HM. Aspirin, beta-blocker, and
angiotensin-converting enzyme inhibitor therapy in patients with endstage renal disease and an acute myocardial infarction. J Am Coll
Cardiol 2003;42:201-8.
12. Liu Y, Coresh J, Eustace JA, et al. Association between cholesterol level
and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 2004;291:451-9.
13. MRC/BHF Heart Protection Study of cholesterol lowering with
simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:7-22.
14. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and
stroke events with atorvastatin in hypertensive patients who have
average or lower-than-average cholesterol concentrations, in the
Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm
(ASCOT-LLA): a multicentre randomised controlled trial. Lancet
2003;361:1149-58.
15. Tonelli M, Moye L, Sacks FM, et al. Pravastatin for secondary
prevention of cardiovascular events in persons with mild chronic renal
insufficiency. Ann Intern Med 2003;138:98-104.
16. Wanner C, Krane V, März W, et al. Atorvastatin in patients with type
2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;
353:238-48.
17. Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and
cardiovascular events in patients undergoing hemodialysis. N Engl J
Med 2009;360:1395-407.
18. K/DOQI Workgroup. K/DOQI clinical practice guidelines for
cardiovascular disease in dialysis patients. Am J Kidney Dis 2005;45:
S1-S153.
19. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP).
Kidney Int Suppl 2003;84:S207-10.
American Heart Journal
Volume 158, Number 1
Appendix A. REACH Registry Global
Publication Committee
Mark Alberts, MD, Northwestern University Medical
School, Chicago; Deepak L. Bhatt, MD, VA Boston
Healthcare System and Brigham and Women's Hospital,
Boston, Massachusetts(chair); Ralph D'Agostino, MD,
Boston University, Boston; Kim Eagle, MD, University of
Michigan, Ann Arbor, Michigan; Shinya Goto, MD, Tokai
University School of Medicine, Isehara, Kanagawa, Japan;
Alan T. Hirsch, MD, Minneapolis Heart Institute Foundation and Division of Epidemiology and Community Health,
University of Minnesota School of Public Health, Minneapolis; Chiau-Suong Liau, MD, PhD, Taiwan University
Hospital and College of Medicine, Taipei; Jean-Louis Mas,
MD, Centre Raymond Garcin, Paris, France; E. Magnus
Ohman, MD, Duke University Medical Center, Durham,
NC; Joachim Röther, MD, Klinikum Minden, Minden,
Germany; Sidney C. Smith, MD, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina; P.
Gabriel Steg, MD, Hôpital Bichat-Claude Bernard, Paris,
France (chair); Peter W. F. Wilson, MD, Emory University
School of Medicine, Dept of Medicine, Cardiology
Division Atlanta, Georgia.
National Coordinators
Australia: Christopher Reid, Victoria. Austria: Franz
Aichner, Linz; Thomas Wascher, Graz. Belgium: Patrice
Laloux, Mont-Godinne. Brazil: Denilson Campos de
Albuquerque, Rio de Janeiro. Bulgaria: Julia Djorgova,
Dumaine et al 148.e1
Sofia. Canada: Eric A. Cohen, Toronto, Ontario. Chile:
Ramon Corbalan, Santiago. China: Chuanzhen LV,
Frederiksberg. Finland: Ilkka Tierala, Helsinki. France:
Jean-Louis Mas, Patrice Cacoub and Gilles Montalescot,
Paris. Germany: Klaus Parhofer, Munich; Uwe Zeymer,
Ludwigshafen; Joachim Röther, Minden. Greece: Moses
Elisaf, Ioannina. Interlatina (Guatemala): Romulo Lopez,
Guatemala City. Hong Kong: Juliana Chan, Shatin. Hungary: György Pfliegler, Debrecen. Indonesia: Bambang
Sutrisna, Jakarta. Israel: Avi Porath, Beer Sheva. Japan:
Yasuo Ikeda, Tokyo. Lebanon: Ismail Khalil, Beirut.
Lithuania: Ruta Babarskiene, Kaunas. Malaysia:
Robaayah Zambahari, Kuala Lumpur. Mexico: Efrain
Gaxiola, Jalisco. The Netherlands: Don Poldermans,
Rotterdam. Philippines: Maria Teresa B. Abola, Quezon
City. Portugal: Victor Gil, Amadora. Romania: Constantin Popa, Bucharest. Russia: Yuri Belenkov and Elizaveta
Panchenko, Moscow. Saudi Arabia: Hassan ChamsiPasha, Jeddah. Singapore: Yeo Tiong Cheng, Singapore.
South Korea: Oh Dong-Joo, Seoul. Spain: Carmen Suarez,
Madrid. Switzerland: Iris Baumgartner, Bern. Taiwan:
Chiau-Suong Liau, Taipei. Thailand: Piyamitr Sritara,
Bangkok. United Arab Emirates: Wael Al Mahmeed, Abu
Dhabi. United Kingdom: Jonathan Morrell, Hastings. Ukraine: Vira Tseluyko, Kharkov. United States:
Mark Alberts, Chicago, IL; Robert M. Califf, Durham, NC;
Christopher P. Cannon, Boston, MA; Kim Eagle, Ann
Arbor, MI; Alan T. Hirsch, Minneapolis, MN.
The list of REACH Registry investigators is accessible
online at www.reach-registry.org.