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Coronary bypass surgery and long-term cognitive decline.

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Edward L. Baker, MD, MPH
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follow-up of psychological distress, social functioning, and coping
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toxic encephalopathy. J Occup Environ Med 1998;40:801– 807.
North Carolina Institute for Public Health
University of North Carolina at Chapel Hill
Chapel Hill, NC
DOI: 10.1002/ana.21394
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Coronary Bypass Surgery
and Long-Term Cognitive
Over the past decade, numerous studies have established a link between cardiovascular disease and the
risk for dementia and rate of cognitive decline in older
adults. Although originally hypothesized to be due to
cerebral atherosclerotic disease and changes in white
matter, more recent studies have suggested that cardiovascular disease may promote ␤-amyloid deposition in
the brain, thus increasing the risk for Alzheimer’s disease (AD) as well.1 These intriguing findings have
raised the question of whether the prevention or treatment of cardiovascular disease protects against the development of dementia. Observational studies and
some trials have suggested that treating hypertension,
hyperlipidemia, diabetes, and depression all may reduce
risk or improve the symptoms of cognitive impairment.
Balancing these observations has been increasing
concern that one of the most common treatments for
coronary artery disease, coronary artery bypass graft
surgery (CABG), may impair cognition, and that these
deleterious effects may persist many years after the
CABG. Newman and colleagues2 were among the first
to address this question and studied the cognitive effects of CABG among 261 patients by comparing performance on cognitive function tests up to 5 years after
CABG with scores obtained before surgery. These results showed significant cognitive declines at 5 years in
nearly half of patients. The results have concerned
many about the possibility that CABG may significantly reduce the risk for cognitive decline. There are
potential mechanisms for a direct effect of CABG on
cognitive function such as hypoperfusion, microemboli, arrhythmias, and anesthetic effects.3 However, the
study had no control group, making it impossible to
know what would have happened to cognitive function
in the absence of CABG surgery. This is an important
limitation, and it perhaps should have tempered some
of the alarmed reactions to this study. Without a control group, it was impossible to tease apart the effect of
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
CABG from likely effects of underlying cardiovascular
disease and other associated risk factors in an aging cohort. Other studies of the long-term effect of CABG
on cognitive function have been conflicting, but results
were difficult to interpret because most of these also do
not include a comparison group.4,5
Selnes and colleagues have been conducting a 5-year
observational study to better address this important
question. They previously have reported the 1- and
3-year outcome results,6,7 and in this issue of Annals,
they report the eagerly anticipated 5-year results.8 The
investigators studied 152 patients who received CABG.
They also studied 92 “control” patients with documented cardiovascular disease but who were treated
medically or with percutaneous stents to examine what
cognitive changes might be expected in the absence of
CABG. Patients received baseline, 3-, 12-, 36-, and 72month cognitive assessments with a comprehensive
neuropsychological battery. Both groups showed improvement from baseline to 12 months, then had a
slight decline in performance over the subsequent 4
years. After 72 months of follow-up, there were no statistically significant differences in the rate of cognitive
decline or in incidence of clinically significant impairment between patients who had CABG and patients
with cardiovascular disease who did not have CABG.
The use of a control group is a major advance over
previous research in this area. However, there are several
issues to consider in the interpretation of the study’s results. Although the study was powered to detect 0.2standard deviation differences in cognitive test scores, it
is difficult to assess whether a smaller difference between
the groups was present. Another concern is the loss to
follow-up rate, which was about 35% in both groups.
Although the authors used state-of-the-art statistical approaches to handle missing data, the statistical models
assume subjects lost to follow-up are missing at random.
This is almost certainly not the case. Many studies have
shown that those who drop out, die, or are lost to
follow-up are the patients with more severe underlying
disease, lower functional status, and with greater comorbidities. Thus, missing data are generally informative,
and it is likely that patients lost to follow-up in this
study were at greater risk for poor cognitive outcomes.
Finally, although the use of a control group is laudable,
it is impossible to find the perfect control group. One
cannot know for sure whether the control group was really at similar risk for cognitive decline. For example, it
is possible that patients who do not have surgery, either
because they decline it or their physicians recommend
against it, are at different risk for poor cognitive outcomes. Indeed, the authors found that at baseline, there
were differences in demographics and in comorbidities
among those who received and did not receive CABG.
Although many of these differences were no longer evident at the end of the study, the issue of residual con-
Annals of Neurology
Vol 63
No 5
May 2008
founding remains. Although almost impossible to conduct, a randomized, controlled trial is the only approach
that can assure that there is no baseline difference in
cognitive risk between those treated surgically or medically. The one randomized, controlled trial that compared cognitive function among those assigned to offpump CABG or to on-pump CABG surgery did not
find a difference in cognitive testing after 5 years.9
Despite these issues, this study is extremely important because it is one of the few to include a nonsurgery comparison group with known cardiovascular disease. It would be helpful to have these findings
replicated in other large cohorts of elders with high
rates of CABG and longitudinal cognitive assessments.
Even without this, however, this study should add reassurance to the concern of long-term cognitive sequelae of CABG. In an age of adverse events that are
uncovered often belatedly, it is comforting to reconsider the assumed cognitive deleterious effects from a
common and efficacious treatment for heart disease.
Kristine Yaffe, MD,1 and
Kenneth E. Covinsky, MD, MPH2
Departments of 1Psychiatry, Neurology, and
Epidemiology and 2Medicine and Division of
University of California, San Francisco
San Francisco Veterans Affairs Medical Center
San Francisco, CA
1. Launer LJ. Demonstrating the case that AD is a vascular disease:
epidemiologic evidence. Ageing Res Rev 2002;1:61–77.
2. Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal
assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 2001;344:395– 402.
3. Newman MF, Mathew JP, Grocott HP, et al. Central nervous
system injury associated with cardiac surgery. Lancet 2006;368:
694 –703.
4. Stygall J, Newman SP, Fitzgerald G, et al. Cognitive change 5
years after coronary artery bypass surgery. Health Psychol 2003;
22:579 –586.
5. Mullges W, Babin-Ebell J, Reents W, Toyka KV. Cognitive performance after coronary artery bypass grafting: a follow-up study.
Neurology 2002;59:741–743.
6. Selnes OA, Grega MA, Borowicz LM Jr, et al. Cognitive changes
with coronary artery disease: a prospective study of coronary artery bypass graft patients and nonsurgical controls. Ann Thorac
Surg 2003;75:1377–1386.
7. Selnes OA, Grega MA, Borowicz LM Jr, et al. Cognitive outcomes three years after coronary artery bypass surgery: a comparison of on-pump coronary artery bypass graft surgery and nonsurgical controls. Ann Thorac Surg 2005;79:1201–1209.
8. Selnes OA, Grega MA, Bailey MM, et al. Cognition 6 years after
surgical or medical therapy for coronary artery disease. Ann Neurol 2008;63:581–590.
9. van Dijk D, Spoor M, Hijman R, et al. Cognitive and cardiac
outcomes 5 years after off-pump vs on-pump coronary artery bypass graft surgery. JAMA 2007;297:701–708.
DOI: 10.1002/ana.21396
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terms, decline, long, bypass, surgery, coronary, cognitive
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