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Cognition 6 years after surgical or medical therapy for coronary artery disease.

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Cognition 6 Years after Surgical or Medical
Therapy for Coronary Artery Disease
Ola A. Selnes, PhD,1 Maura A. Grega, MSN,2 Maryanne M. Bailey, BA,3 Luu D. Pham, MS,4
Scott L. Zeger, PhD,4 William A. Baumgartner, MD,2 and Guy M. McKhann, MD1,3,5
Objective: The choice of coronary artery bypass grafting (CABG) as an intervention for coronary artery disease has been clouded
by concerns about postoperative cognitive decline. Long-term cognitive decline after CABG has been reported, but without
appropriate control subjects, it is not known whether this decline is specific to CABG or related to other factors such as
cerebrovascular disease.
Methods: This prospective, observational study of patients with diagnosed coronary artery disease included 152 CABG and 92
nonsurgical cardiac comparison patients from one institution. The main outcome measure was within-patient change in cognitive performance for eight cognitive domains from baseline to 12- and 72-month follow-up.
Results: Mild late cognitive decline was observed for both study groups, but despite greater than 80% power to detect a 0.2
standard deviation difference, there were no statistically significant differences between the surgical and nonsurgical patients in
the degree of change from 12 to 72 months for any cognitive domain. There was also no difference between groups in the degree
of change from baseline to 72 months or in the number of patients with a Mini-Mental State Examination score in the clinically
impaired range at 72 months.
Interpretation: Late cognitive decline does occur in patients who have undergone CABG surgery, but the degree of this decline
does not differ from that observed in patients of similar age with coronary artery disease who have not undergone CABG.
Therefore, late cognitive decline after CABG is not specific to the use of cardiopulmonary bypass.
Ann Neurol 2008;63:581–590
The choice among the types of intervention for coronary artery disease is complex. Recent reports suggest
increased thrombotic complications with drug-eluting
stents. On the other hand, neurological complications
and cognitive decline have been associated with coronary artery bypass grafting (CABG) surgery. Adverse
cerebral outcomes after CABG with the use of cardiopulmonary bypass (CPB) can range from clinically apparent events such as stroke to more subtle neurological injury such as cognitive decline.1,2 A review of
contemporary studies concludes that 30 to 65% of patients have evidence of cognitive decline 1 month after
surgery.3 The cause of this early postoperative cognitive
decline has not yet been clearly established, but it has
been commonly assumed that factors associated with
the use of CPB, including hemodynamic fluctuations,
microemboli, and systemic inflammatory response,
may be responsible.
Although the early cognitive decline does appear to
improve over the first few months after surgery,4
longer term prospective follow-up studies have described subsequent late cognitive decline. In one study
of cognitive outcomes after CABG, it was reported that
42% of the patients had worse cognitive performance
at 5 years than at baseline.5 The occurrence of late cognitive decline 5 or more years after surgery has been
reported by other investigators,6 although some studies
have not found evidence of delayed decline several
years after CABG.7
If the late cognitive decline is related to the use of
CPB, one would predict that patients who have offpump surgery should not experience this late decline.
The only randomized comparison of long-term outcomes after on- and off-pump CABG surgery did not
find a difference in the incidence of late cognitive decline.8 This leaves open the possibility that the late
cognitive decline might be caused by nonspecific effects
of major surgery, anesthesia, progression of underlying
cerebrovascular disease, or normal aging.
Because most long-term studies have not included
From the 1Departments of Neurology and Surgery; 2Division of
Cardiac Surgery, Johns Hopkins University School of Medicine;
3
Zanvyl Krieger Mind/Brain Institute; 4Department of Biostatistics,
Johns Hopkins Bloomberg School of Public Health; and 5Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.
This article includes supplementary materials available via the Internet at http://www.interscience.wiley.com/jpages/0364-5134/suppmat
Received Nov 9, 2007, and in revised form Dec 18. Accepted for
publication Feb 4, 2008.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ana.21382
Address correspondence to Dr Selnes, Department of Neurology,
Reed Hall East-2, 1620 McElderry Street, Baltimore, MD 212051910. E-mail: oselnes@jhmi.edu
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
581
patients of comparable age and health status, it is not
known whether late cognitive decline may occur even
in patients who do not undergo CABG surgery. In this
study, we sought to determine whether patients undergoing CABG surgery have a greater degree of cognitive
decline over 72 months than do patients with similar
demographic and medical characteristics without surgical intervention.
Subjects and Methods
In this nonrandomized study, eligible patients completed a
medical history review and a battery of standardized neuropsychological tests on the following longitudinal schedule:
baseline, 3, 12, 36, and 72 months. The protocol was approved by the institutional review board, and subjects gave
written informed consent.
Description of Study Groups
CORONARY ARTERY BYPASS GRAFTING GROUP.
Patients scheduled to undergo elective or urgent CABG surgery with CPB at our institution between September 1997
and March 1999 were approached by the study coordinators
for enrollment into the study. Eligibility criteria included being a native English speaker, not mechanically ventilated,
able to sit upright, willing to return for follow-up, and able
to provide informed consent. These procedures have been
previously described.4,9
NONSURGICAL CARDIAC COMPARISON GROUP.
Patients under medical management for coronary artery disease (diagnosed by cardiac catheterization) were recruited
from cardiologists at our institution from September 1997
through December 2001. Eligibility criteria were the same as
described earlier, except that patients who had previous cardiac surgery were excluded. Some of the nonsurgical comparison patients had a percutaneous coronary intervention either before or after entry into the study as part of their
medical care.
Neuropsychological Tests and Questionnaires
The neuropsychological tests were selected to evaluate performance in specific areas of cognition and were structured
into eight domains. A description of each test is included in
Supplementary Appendix 1. To have a clinically meaningful
measure of the overall cognitive status of the study patients,
we also administered the Mini-Mental State Examination
(MMSE) at all time points.10 The Center for Epidemiological Studies Depression scale (CES-D)11 to measure depression and the Functional Status Questionnaire (FSQ)12 to determine physical functioning were also administered at all
study times.
Statistical Analysis
We used linear mixed models to estimate the difference between the CABG and comparison group in the mean withinsubject change in cognitive test scores from baseline (R: A
Language and Environment for Statistical Computing, Vienna, Austria; http://www.R-project.org). This method allows each person to serve as his or her own control so that
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any differences between the two groups in baseline or other
nonchanging characteristics do not bias the treatment comparison. We assumed that the average response for each
group had its own mean change from baseline to 3 months,
reflecting both learning and treatment effects, and then had
an approximately linear change from 3 to 72 months. The
average within-subject changes from baseline for each group,
as estimated by this model, are shown in Figures 1 and 2.
Because the performance on neuropsychological tests can
be influenced by education, age, and sex, we controlled for
these variables in a preliminary regression analysis. For education and age, we used regression splines with two degrees
of freedom to allow for possible nonlinear relations.
The linear mixed models account for missing data for
which the probability of being missing depends on treatment
group, time of follow-up, and other measured variables, but
not on the unobserved missing data (missing at random).
We did not distinguish deaths from refusals to participate or
losses to follow-up. Hence, the inferences here pertain to the
original cohort as if all subjects survived the follow-up period.
This study was designed to have greater than 80% power
to detect a difference in the average within-person change
from baseline between the CABG and comparison group of
0.2 population standard deviation.
Results
Subject Characteristics
We recruited 152 candidates for CABG and 92 comparison patients with coronary artery disease diagnosed
by cardiac catheterization. Table 1 summarizes baseline
characteristics for the surgical and nonsurgical patients.
Risk factors for cerebrovascular disease were common
in both study groups. The mean interval between baseline testing and the last follow-up was slightly longer
for the CABG group (6.9 years) than for the nonsurgical patients (6.3 years) ( p ⫽ 0.006). A greater proportion of the CABG patients (32%) than nonsurgical
comparison patients (20%) had surgery with general
anesthesia during the follow-up interval ( p value is not
significant). Additional interval medical history is described in Table 2.
Completeness of Follow-up
Twenty-six of the 152 CABG patients (17%) died before the 72-month visit. Contact was made with 119
patients of whom 96 (76%) completed cognitive testing at 72 months, and 23 patients refused. Seven patients were lost to follow-up. Nineteen of the 92 nonsurgical patients (21%) died before the 72-month visit.
Contact was made with 69 patients, of whom 61
(84%) completed cognitive testing and 8 refused. No
contact was made with four patients, who were therefore lost to follow-up.
There were eight patients in the comparison group
who during the course of the study follow-up had subsequently undergone CABG surgery (two before the
Fig 1. Longitudinal trends by individual cognitive domains: mean Z-scores for the eight cognitive domains and the global cognitive
domain showing trends in cognitive performance for both groups from baseline to 3-, 12-, 36-, and 72-month follow-up. The
Z-scores are standardized relative to the baseline performance of the nonsurgical cardiac patients, whose mean baseline value is
therefore zero. The Z-scores have been adjusted for age, sex, and education. Error bars indicate the limits of the 95% confidence
interval for the mean of each measure. Solid line indicates nonsurgical cardiac comparison (NSCC) group; dashed line indicates
coronary artery bypass graft (CABG) group.
12-month visit, three before the 36-month visit, and
three before the 72-month visit). These patients completed follow-up according to the study protocol and
were included in the 72-month data as nonsurgical patients under the intent-to-treat methodology. We did,
however, complete our primary statistical analysis outlined later, both with and without these eight patients,
and concluded that there were no material differences
in the study results.
Cognitive Outcomes
The mean unadjusted scores for each neuropsychological variable by study group at baseline, 12, and 72
months are presented in Supplementary Appendix 2.
Selnes et al: Cognitive Decline with CAD
583
72 months, the only domain where the two groups differed statistically significantly was Motor Speed ( p ⫽
0.04), with the nonsurgical patients showing greater
decline.
Fig 2. Changes from baseline in overall cognitive performance
by group: mean changes from baseline (with 95% confidence
intervals) for the global average of all eight cognitive domains
for the coronary artery bypass graft (CABG) group (dashed
line) and nonsurgical patients (solid line).
Although the CABG group had lower mean scores for
several of the neuropsychological tests at baseline, there
were no statistically significant differences between the
CABG group and nonsurgical patients in these unadjusted raw scores. The trends in the levels of longitudinal test performance by cognitive domain for the two
study groups are shown in Figure 1. Both groups
showed improvement from baseline to 12 months, and
this was followed by a trend of subsequent decline in
performance for all cognitive domains. The mean of
the eight cognitive domain scores is summarized in the
global domain score (see Fig 2). In Figure 2, the baseline for both groups is set at zero, to compare differences between the groups in the degree of change over
time.
Comparison of Change in Cognitive Performance
between Study Groups
The question of principal interest to this study was
whether the degree of late decline was greater in the
CABG group than in the nonsurgical group. Using the
linear mixed models described in Subjects and Methods, we compared the within-patient change in test
performance from baseline to each follow-up point for
each cognitive domain for the two study groups (Table
3). In this model, there were no statistically significant
differences in the degree of decline/change between the
two study groups from baseline to 72 months (see Fig
2). Comparing the degree of “late” decline from 12 to
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Degree of Cognitive Change from Baseline to 72
Months for Each Group
To evaluate the amount of decline in cognitive test
performance over time for the two groups, we examined change from baseline to 72 months for each cognitive domain. As seen in Figure 1, both study groups
declined in all domains except attention. For the
CABG patients, however, the only statistically significant declines were in visuoconstruction ( p ⬍ 0.01) and
executive function ( p ⫽ 0.02). For the nonsurgical
comparison group, declines were statistically significant
in visuoconstruction ( p ⬍ 0.01) and motor speed ( p ⫽
0.01). The degree of change from baseline to 72
months was relatively small for both groups, ranging
from an improvement of 0.1 to a decline of 0.3 standard deviation units.
To address the question of the magnitude of the late
decline, we compared degree of change in cognitive
performance from 12 to 72 months. With the single
exception that the nonsurgical group did not have significant decline in the cognitive domain of attention,
both groups had statistically significant decline in all
other cognitive domains ( p values ranging from
⬍0.01– 0.02). The degree of change from 12 to 72
months was of greater magnitude than that observed
from baseline to 72 months, ranging from a decline of
0.1 to a decline of 0.58 standard deviation units. There
were no group differences in the mean change in the
global score regardless of whether we also controlled
for baseline medical variables that were different between the groups.
Mini-Mental State Examination Performance
We also examined changes in scores on the MiniMental State Examination from baseline to follow-up
points for the two groups. Mean MMSE scores at baseline and at 72 months did not differ between the two
study groups (see Tables 1 and 2). At baseline, 5% of
the CABG and 6% of the nonsurgical patients had
MMSE scores below normal (⬍24) (not significant).
From baseline to 72 months, the average withinpatient change on the MMSE was a decline of 0.22 for
the CABG group and 0.16 point for the nonsurgical
patients (not significant). The majority of CABG
(57%) and nonsurgical patients (67%) had stable or
improved MMSE scores at 72 months. Six of the
CABG patients (6.3%) had a clinically meaningful decline (4 or more points)13 on the MMSE at 72 months
compared with 7 patients (11.5%) in the comparison
group. The number of patients with MMSE scores less
Table 1. Baseline Participant Characteristics
Characteristics
CABG
(n ⴝ 152)
NSCC
(n ⴝ 92)
p
Mean age ⫾ SD, yr
63.6 ⫾ 9.4
65.9 ⫾ 9.2
0.06
Mean education ⫾ SD, yr
14.0 ⫾ 4.0
14.4 ⫾ 3.4
0.47
Male sex, n (%)
115 (76)
71 (77)
0.46
White, n (%)
137 (90)
86 (93)
0.26
8 (5)
4 (4)
0.50
Carotid bruit, n (%)
26 (17)
6/33 (8)
0.04
Hypertension, n (%)
98 (65)
46 (50)
0.01
Diabetes mellitus, n (%)
45 (30)
21 (23)
0.16
Peripheral vascular disease, n (%)
25 (16)
6 (7)
0.01
Transient ischemic attack, n (%)
8 (5)
2 (2)
0.20
Myocardial infarction, n (%)
71 (47)
45 (49)
0.42
History of atrial fibrillation, n (%)
16 (10)
13 (15)
0.23
Family history of Alzheimer’s disease, n (%)
20 (13)
9 (10)
0.27
Past smoker, n (%)
106 (70)
51 (55)
0.01
Current smoker, n (%)
17 (11)
3 (3)
0.02
2.73 ⫾ 0.5
1.95 ⫾ 0.7
0.0001
30 (20)
49 (53)
0.0001
Mean number of percutaneous coronary interventions ⫾ SD
1.6 ⫾ 0.9
1.4 ⫾ 0.6
0.24
Past chest pain/angina, n (%)
121 (80)
56 (61)
0.001
56.0 ⫾ 11.1
55.8 ⫾ 9.5
0.87
27.6 ⫾ 2.4
27.9 ⫾ 2.0
0.16
Past stroke, n (%)
Mean number of diseased coronary vessels ⫾ SD
Percutaneous coronary interventions, n (%)
Mean cognitive testing time ⫾ SD, min
Functional Measures
Mean Mini-Mental State Examination score ⫾ SDa
Mini-Mental State Examination score ⬍ 24, n (%)
7 (5)
6 (6)
0.55
Mean CES-D score ⫾ SD
13.2 ⫾ 9.6
8.8 ⫾ 7.6
0.0001
CES-D score ⬎ 15, n (%)
50 (33)
14 (15)
0.002
30.6 ⫾ 5.1
33.0 ⫾ 3.9
0.0001
Mean Functional Status Questionnaire, Physical function
score ⫾ SDb
Physiological Data
Any ApoE-ε4 genotype, n (%)
38 (25)
29 (32)
0.14
Mean systolic blood pressure ⫾ SD, mm Hg
131 ⫾ 22
141 ⫾ 26
0.001
Mean diastolic blood pressure ⫾ SD, mm Hg
73 ⫾ 11
79 ⫾ 13
0.0001
Mean MAP ⫾ SD, mm Hg
92 ⫾ 13
100 ⫾ 16
0.0001
Mean heart rate ⫾ SD, beats/min
66 ⫾ 14
66 ⫾ 11
0.93
Mean pulse pressure ⫾ SD, mm Hgc
58 ⫾ 19
62 ⫾ 21
0.15
Pulse pressure ⬎ 65 mm Hg, n (%)
41 (27)
29 (33)
0.21
Selnes et al: Cognitive Decline with CAD
585
Table 1. (Continued)
Operative Data (CABG only)
Mean cardiopulmonary bypass time ⫾ SD, min
99 ⫾ 32.3
NA
—
Mean aortic cross clamp time ⫾ SD, min
68 ⫾ 24.4
NA
—
Mean number of coronary grafts placed ⫾ SD
3.1 ⫾ 0.9
NA
—
Left anterior descending graft placed, n (%)
149 (98)
NA
—
Right coronary artery graft placed, n (%)
119 (78)
NA
—
Circumflex graft placed, n (%)
110 (72)
NA
—
38 (25)
NA
—
Mean general anesthesia time ⫾ SD, min
291 ⫾ 68
NA
—
Mean lowest esophageal temperature ⫾ SD, °C
29.7 ⫾ 2.3
NA
—
69 ⫾ 6.2
NA
—
Red blood cell transfusion in first 24 hours, n (%)
54 (35)
NA
—
Inotropic support in the ICU, n (%)
80 (53)
NA
—
Mean awake time from general anesthesia ⫾ SD, hr
3.6 ⫾ 2.6
NA
—
10.3 ⫾ 10.2
NA
—
5.7 ⫾ 2.8
NA
—
Aortic disease by palpation, n (%)
Mean MAP ⫾ SD, mm Hg
ICU and Postoperative Data
Mean time to extubation ⫾ SD, hr
Mean postoperative hospital length of stay ⫾ SD, days
Mini-Mental State Examination (30 ⫽ best score), score ⬍ 24 indicative of dementia.
Beth Israel Functional Status Questionnaire, Physical functioning score (36 ⫽ best score).
c
Pulse pressure is calculated as systolic blood pressure minus diastolic blood pressure.
CABG ⫽ coronary artery bypass grafting group; NSCC ⫽ nonsurgical cardiac comparison group; SD ⫽ standard deviation; CES-D ⫽
Center for Epidemiological Study-Depression, score ⬎ 15 indicative of depressive symptoms; ApoE ⫽ apolipoprotein E; MAP ⫽ mean
arterial pressure; NA ⫽ not available; ICU ⫽ intensive care unit.
a
b
than 24 at 72 months was similar for the two groups
(see Table 2).
Discussion
This observational study compared longitudinal
changes in cognition in patients 72 months after coronary artery bypass surgery with those occurring in a
group of demographically and medically similar nonsurgical patients with coronary artery disease. Despite
evidence of mild cognitive decline in both study
groups, we found no statistically significant or clinically
meaningful differences in the degree of decline in cognitive test performance over time between the CABG
patients and the nonsurgical comparison patients.
Comparing the degree of change from 12 to 72
months, which in previous studies has been considered
as late decline, there was again no evidence of statistically significant greater late decline in the CABG group
than in the nonsurgical patients.
Relative to their baseline performance, both groups
had modest decline in performance in all cognitive domains when reevaluated at 72 months. The relatively
small change from baseline to 72 months may partially
reflect improvements from practice effects counteract-
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ing any decline in cognitive test performance that may
be expected over a 6-year follow-up period.14
In our CABG population, there are comorbidities
that might be associated with worse cognitive performance. These include greater incidence of cardiovascular risk factors, greater severity of coronary artery disease, and more surgery requiring general anesthesia
during the follow-up period. Nonetheless, despite these
factors, which might have been expected to produce
greater cognitive decline in the CABG population, no
differences between the two groups were found. On
the other hand, the CABG group had higher scores
than the nonsurgical patients on a screening measure of
depression at baseline. This difference was not statistically significant at 72-month follow-up. There is evidence from several studies, however, that improvement
in depression scores does not predict improved performance on cognitive tests.14 –16 Therefore, the lack of
greater late decline among the CABG patients cannot
be attributed to an improvement in their mood status.
Similar to the findings from this study, Newman
and colleagues5 report evidence of late cognitive decline in their prospective 5-year study. They hypothesize that the late cognitive decline might be related to
Table 2. Characteristics of the Study Population at 72 Months
Variables
CABG
NSCC
p
Died since enrollment, n (%)
26/152 (17)
19/92 (21)
0.35
Completed cognitive testing, n (%)
96/126 (76)
61/73 (84)
0.14
Refused cognitive testing, n (%)
23/126 (18)
8/73 (11)
0.12
7/126 (6)
4/73 (5)
0.62
Mean number of days since enrollment ⫾ SD
2,515 ⫾ 434
2,313 ⫾ 380
0.006
Mean number of years since enrollment ⫾ SD
6.9 ⫾ 1.2
6.3 ⫾ 1.0
0.006
Tested patient at home, n (%)
47/96 (49)
19/61 (31)
0.02
62 ⫾ 14
61 ⫾ 13
0.71
Testing Status
No contact/lost to follow-up, n (%)
Mean cognitive testing time ⫾ SD, min
n ⴝ 96
n ⴝ 61
70.99 ⫾ 9.6
71.91 ⫾ 9.7
0.56
Actively employed for wages, n (%)
39/94 (41)
15/59 (25)
0.03
Hospitalized since last visit, n (%)
53 (55)
30 (49)
0.28
Surgery with general anesthesia, n (%)
31 (32)
12 (20)
0.06
Angina/chest pain, self-report, n (%)
28 (29)
21 (34)
0.30
18/28 (64)
12/21 (57)
0.41
Seen by doctor since last visit, n (%)
94(98)
61 (100)
0.37
Electrocardiogram done, n (%)
86 (90)
57 (93)
0.30
Stress testing done, n (%)
66 (69)
43 (73)
0.35
4 (4)
1 (2)
0.35
19 (20)
13 (21)
0.48
8 (8)
5 (8)
0.61
0
8 (13)
0.0001
17 (18)
8 (13)
0.29
Cerebrovascular accident, n (%)
4 (4)
1 (2)
0.35
Currently smoking, n (%)
5 (5)
5 (8)
0.33
Cancer/cancer therapy, n (%)
14 (15)
9 (15)
0.57
Vision changes for the worse, n (%)
36 (37)
19 (31)
0.26
New diagnosis of hypertension, n (%)
Interim Medical History
Mean current age ⫾ SD, yr
If yes to chest pain, NTG used, n (%)
Myocardial infarction, n (%)
Repeat coronary angiogram, n (%)
Percutaneous coronary intervention, n (%)
New CABG surgery, n (%)
Atrial fibrillation, n (%)
13 (13)
7 (12)
0.46
New diagnosis of diabetes mellitus, n (%)
9 (9)
3 (5)
0.24
Thyroid problems, n (%)
9 (9)
8 (14)
0.27
Takes medication as prescribed, n (%)
88 (93)
57 (98)
0.12
Hormone replacement therapy, n (%)
5/24 (21)
3/16 (19)
0.60
69 (72)
42 (69)
0.40
7 (7)
10 (16)
0.06
81 (84)
47 (76)
0.13
3 (3)
4 (7)
0.26
Taking a ␤-blocker, n (%)
Taking an antidepressant, n (%)
Taking a statin, n (%)
Taking cognitive-enhancing drugs, n (%)
Selnes et al: Cognitive Decline with CAD
587
Table 2. (Continued)
Variables
CABG
NSCC
p
27.4 ⫾ 2.5
27.9 ⫾ 2.6
0.18
Functional Measures
Mean Mini-Mental Examination score ⫾ SDa
Mini-Mental State Examination score ⬍ 24, n (%)
Mean CES-D score ⫾ SD
CES-D score ⬎ 15, n (%)
b
Mean Functional Status Questionnaire, Physical
functioning score ⫾ SD
7 (7)
5 (8)
0.53
9.5 ⫾ 9.2
9.0 ⫾ 8.6
0.73
13 (13)
9 (15)
0.50
29.9 ⫾ 6.4
32.1 ⫾ 5.5
0.03
Physiologic Data
Mean systolic blood pressure ⫾ SD, mm Hg
132 ⫾ 20
136 ⫾ 20
0.29
Mean diastolic blood pressure ⫾ SD, mm Hg
71 ⫾ 10
73 ⫾ 10
0.21
Mean MAP ⫾ SD, mm Hg
91 ⫾ 11
94 ⫾ 11
0.17
Mean heart rate ⫾ SD, beats/min
65 ⫾ 10
64 ⫾ 10
0.69
Mean pulse pressure ⫾ SD, mm Hg
61 ⫾ 19
63 ⫾ 18
0.66
Pulse pressure ⬎ 65mm Hg, n (%)
42 (45)
22 (39)
0.28
c
Mini-Mental State Examination (30 ⫽ best score), score ⬍ 24 indicative of dementia.
Beth Israel Functional Status Questionnaire, Physical functioning score (36 ⫽ best score).
c
Pulse pressure is calculated as systolic blood pressure minus diastolic blood pressure.
CABG ⫽ coronary artery bypass grafting group; NSCC ⫽ nonsurgical cardiac comparison group; SD ⫽ standard deviation; NTG ⫽
sublingual nitroglycerin; CES-D ⫽ Center for Epidemiological Study-Depression, score ⬎ 15 indicative of depressive symptoms;
MAP ⫽ mean arterial pressure.
a
b
delayed effects of the CABG 5 years earlier, but because their study, as well as other 5-year studies,6 did
not include a comparison group, they could not rule
out that late cognitive decline might also occur in a
population of older patients with cardiovascular disease. The lack of any difference in the long-term cognitive trajectories between the surgery patients and
such a comparison group in our study suggests that late
cognitive decline 5 or more years after CABG is not
specific to the use of CPB.
Additional support for this interpretation comes
from studies that have compared long-term cognitive
outcomes after conventional CABG and off-pump surgery. In a recent study, van Dijk and colleagues8 com-
Table 3. Differences in Change from Baseline to 72 Months and from 12 to 72 Months between Coronary Artery
Bypass Grafting Group and Nonsurgical Cardiac Comparison Group
Cognitive
Domains
Verbal Memory
Visual memory
Visuoconstruction
Language
Motor speed
Psychomotor speed
Attention
Executive function
Global
Difference in Change from
Baseline to 72 Months
Difference in Change from
12-72 Months
Differencea (95% CI)
p
Differencea (95% CI)
p
0.01 (⫺0.23, 0.26)
0.10 (⫺0.25, 0.44)
0.02 (⫺0.24, 0.28)
⫺0.07 (⫺0.26, 0.13)
0.20 (⫺0.03, 0.43)
⫺0.10 (⫺0.32, 0.13)
⫺0.02 (⫺0.30, 0.26)
⫺0.13 (⫺0.48, 0.22)
0.02 (⫺0.15, 0.18)
0.94
0.58
0.88
0.48
0.10
0.36
0.89
0.47
0.80
⫺0.15 (⫺0.41, 0.11)
0.05 (⫺0.24, 0.35)
⫺0.08 (⫺0.35, 0.19)
⫺0.06 (⫺0.25, 0.13)
0.21 (0.00, 0.41)
⫺0.09 (⫺0.29, 0.12)
0.04 (⫺0.21, 0.29)
⫺0.07 (⫺0.42, 0.28)
⫺0.03 (⫺0.17, 0.11)
0.25
0.74
0.57
0.55
0.04b
0.37
0.76
0.70
0.67
a
Difference numbers that are positive indicate that the coronary artery bypass grafting (CABG) group has declined less than the
nonsurgical cardiac comparison group.
b
Statistically significant values.
CI ⫽ confidence interval.
588
Annals of Neurology
Vol 63
No 5
May 2008
pared cognitive outcomes 5 years after surgery in patients who had been randomized to undergo either
conventional CABG or off-pump surgery. They found
that a significant proportion of both study groups had
declined at 5 years, but there was no difference in the
incidence of decline between the two groups. They
concluded, therefore, that avoiding the use of CPB
does not materially affect cognitive outcomes 5 years
after the surgery.
The cause of the late cognitive changes after CABG
and in nonsurgical patients with cardiovascular disease
remains uncertain. There is considerable evidence in
support of the hypothesis that patients with risk factors
for vascular disease and markers of atherosclerosis have
greater rates of cognitive decline over time than do patients without such risk factors.17–21 Because both the
surgical and nonsurgical patients had one or more risk
factors for cerebrovascular disease, it is likely, therefore,
that the cognitive decline over time is related either to
normal aging in the context of cerebrovascular disease
or to progression of the underlying vascular disease
over the 6-year follow-up. This hypothesis is also supported by data from recent studies suggesting that degree of coronary atherosclerosis is predictive of greater
degree of cerebrovascular disease on magnetic resonance imaging.21–23 We did not have MRI studies in
our patients, but previous studies have shown that not
only are lacunar infarcts common before surgery in
candidates for CABG,24 but new silent infarcts occurring between 3 and 12 months after surgery are also
frequent.25
If rate of cognitive decline in elderly patients is related to vascular risk factors, one might expect that better control of such risk factors might reduce the degree
of late cognitive decline. Mullges and colleagues7 studied 52 patients more than 4 years after CABG and reported that none of the patients in this group had cognitive decline at follow-up. They hypothesized that
strict postoperative control of modifiable risk factors,
including hypertension, hyperlipidemia, and diabetes,
may explain the lack of late cognitive decline in their
group of patients. Although these findings are intriguing, prospective randomized trials with larger cohorts
would be required to test the hypothesis that better
postoperative control of risk factors for cerebrovascular
disease may attenuate the degree of late cognitive decline in patients with coronary artery disease.
It has also been suggested that there may be an increased risk for Alzheimer’s disease several years after
surgery.26 In a recent retrospective cohort study of Veterans Affairs patients with either CABG or percutaneous coronary intervention 5 years earlier, the authors
conclude that the risk for development of Alzheimer’s
disease was significantly greater among the CABG patients.27 In contrast with these findings, Knopman and
colleagues28 did not find any evidence of an association
of CABG and dementia in a case–control study from
the Mayo Clinic. In our study, we found no differences
between CABG and nonsurgical patients in the proportion of patients with Mini-Mental State Examination scores in the clinically impaired range at 72
months. Similarly, there were no differences between
the two groups in the number of patients with a meaningful decline (four points or more) from baseline to
72 months. Furthermore, as with previous studies, we
did not find a disproportionate decline in memory that
is typically associated with Alzheimer’s disease.28,29
The principal limitation of this study is that it was
not a randomized comparison of CABG patients and
nonsurgical control subjects. Such a study would not
have been ethically possible in our environment at the
time when the study was initiated. However, we compared the mean change from a person’s own baseline
level so that constant (eg, baseline) characteristics are
less likely to bias the comparison. As was the case with
previous studies reporting late cognitive decline, this
was a single-site study of relatively educated patients,
and it may not be representative of a more diverse population. Finally, in cohort studies of this duration,
there is an inevitable loss to follow-up of study participants. The statistical methods we used adjusted for
differential dropout rates that are predictable from observed variables, but not for those that cannot be observed. The loss to follow-up in this study is comparable or better than what has been reported in previous
long-term studies of cognition after CABG.5
As an observational study, there were differences in
the medical and demographic characteristics of the patients in the two study groups. Because we focused the
analysis on change from each person’s own baseline
level, we controlled for the influence of nonchanging
variables. As in every nonrandomized study, there may
remain unmeasured factors that bias the results reported.
Strengths of this study are the duration of the
follow-up (6 years), and to our knowledge, it is also the
first study to compare cognitive outcomes after CABG
with those of nonsurgical patients with coronary artery
disease. In addition to addressing the impact of aging
and cardiovascular disease on cognitive test performance over time, such comparison patients also allow
for practice effects and random errors associated with
repeated neuropsychological testing to be taken into
account.
As with previous long-term follow-up studies, we did
observe decline in cognitive test performance over the
follow-up period. However, in contrast with past work,
this study with nonsurgical patients did not find evidence of greater late cognitive decline compared with
patients undergoing CABG 6 years earlier. Late cognitive decline after CABG is therefore not specific to the
use of CPB.
Selnes et al: Cognitive Decline with CAD
589
This study was supported by the NIH (NINCDS, 35610,
[G.M.M.]), the Charles A. Dana Foundation (90030633,
[G.M.M.]), and the Johns Hopkins Medical Institution (GCRC
00052, [G.M.M.]).
We thank Drs P. Talalay, R. Gottesman, and C. Hogue for their
help during the preparation of this manuscript. L.M. Borowicz, Jr.
helped with the data collection. We also thank the cardiologists,
cardiac surgeons, and anesthesiologists at our institution and at
Johns Hopkins Bayview Medical Center who helped with this
study. Special thanks are extended to our study participants who
volunteered their time and energy to make this study possible.
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