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Ann Thorac Surg 2008;85:60-64. doi:10.1016/j.athoracsur.2007.08.068
© 2008 The Society of Thoracic Surgeons
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Original Articles: Cardiovascular

Cognitive Outcomes Five Years After Not Undergoing Coronary Artery Bypass Graft Surgery

Diederik van Dijk, MD, PhDa,*, Karel G.M. Moons, PhDa,e, Hendrik M. Nathoe, MD, PhDb, Egidius H.L. van Aarnhem, MDc, Cornelius Borst, MD, PhDb, Annemieke M.A. Keizer, PhDd, Cor J. Kalkman, MD, PhDa, Ron Hijman, PhDd, Octopus Study Group*

a Department of Anesthesiology, University Medical Center Utrecht, Utrecht, the Netherlands
b Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
c Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht, the Netherlands
d Department of Psychiatry, University Medical Center Utrecht, Utrecht, the Netherlands
e Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands

Accepted for publication August 15, 2007.

* Address correspondence to Dr van Dijk, University Medical Center Utrecht, Division of Perioperative and Emergency Care (Mail stop Q.04.2.313), PO Box 85500, Utrecht, 3508 GA, the Netherlands (Email: d.vandijk{at}umcutrecht.nl).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
 References
 
Background: Patients with coronary artery disease who underwent coronary artery bypass graft surgery have a high risk of cognitive decline 5 years after the procedure. It is conceivable that this is not caused by the operation, but by natural aging.

Methods: Psychologists repeatedly administered a battery of seven neuropsychological tests with eight main variables to 112 subjects without known coronary artery disease, with a time interval of 5 years. Cognitive decline was defined as deterioration in performance beyond normal variation in at least two of the eight main variables. The incidence of cognitive decline in the control subjects was compared with the incidence of cognitive decline in the 281 participants of the Octopus Study, who underwent coronary artery bypass graft surgery 5 years earlier. Patients and control subjects were age-matched.

Results: After 5 years, cognitive outcome could be determined in 99 of 112 control subjects (88%) and 240 of 281 coronary artery bypass graft surgery patients (85%). Cognitive decline was present in 82 (34.2%) of 240 coronary artery bypass graft surgery patients and in 16 (16.2%) of 99 control subjects (crude odds ratio, 2.69; 95% confidence interval, 1.48 to 4.90). However, after correction for differences in age, sex, education, and baseline comorbidity between the patients and the control subjects, the odds ratio was 1.37 (95% confidence interval, 0.65 to 2.92).

Conclusions: We were unable to demonstrate that patients who underwent coronary artery bypass graft surgery have more cognitive decline after 5 years than control subjects without coronary artery disease.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
 References
 
Coronary artery bypass grafting (CABG) effectively relieves angina, but can be complicated by short-term and long-term postoperative cognitive decline [1–3]. Two recent studies in 261 and 281 patients reported a 42% and 34% incidence of cognitive decline, respectively, 5 years after CABG [2, 3]. Cognitive decline after CABG has been attributed to the use of cardiopulmonary bypass [4, 5]. The Octopus Study, however, allocated patients to CABG with or without cardiopulmonary bypass and found no benefit of avoiding cardiopulmonary bypass. At 5 years the incidence of cognitive decline was 33% after off-pump CABG and 35% after on-pump CABG [3].

This result raised the hypothesis that the high incidence of long-term postoperative cognitive decline after CABG may be less related to the use of cardiopulmonary bypass or any other feature of the operation, but merely reflects normal aging [6]. This prompted us to appreciate the long-term cognitive status of CABG patients relative to the natural change in cognitive function with time. We therefore compared the 5-year neuropsychological performance of the CABG patients who were included in the Octopus Study with the cognitive status of similarly aged control subjects who had not undergone CABG.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Footnotes
 Acknowledgments
 References
 
Patients
Between March 1998 and August 2000, 281 patients suffering from coronary artery disease underwent CABG with or without cardiopulmonary bypass in the Octopus Study. The main results have been reported elsewhere [3, 7]. Because no difference in the incidence of cognitive decline was found between patients operated on with or without cardiopulmonary bypass (35% and 33%, respectively, at 5-year follow-up), all 281 CABG patients were regarded as one group in the present study.

To measure the natural variation in performance and practice effects during repeated neuropsychological testing, we have also studied a group of 112 control subjects. They were recruited between April 2000 and March 2001 through an advertisement in a local newspaper, age-matched to the CABG patients included in the Octopus Study, but not suffering from coronary artery disease [8]. The natural variation in cognitive performance observed in these control subjects during a short period of 3 months has been reported elsewhere [8].

To evaluate the difference in long-term cognitive decline between CABG patients and subjects who did not undergo CABG, we now compared neuropsychological test performance at 5-year follow-up between both cohorts. The study was approved by the medical ethics committees of the participating centers.

Design
The present study was a nonrandomized age-matched cohort study comparing long-term cognitive outcomes of CABG patients and control subjects without coronary artery disease.

Outcome Measure (Cognitive Decline)
The CABG patients and the control subjects underwent the same cognitive assessment at two points in time, with an interval of 5 years. For the CABG patients, the neuropsychological test battery was administered on the day before and 5 years after their surgery. Patients and control subjects underwent additional assessments 3 and 12 months after baseline assessment; the results of these latter two assessments have been reported elsewhere [7, 8].

The test battery comprised seven neuropsychological tests with eight main variables and was executed by trained psychologists. Testing procedures were similar for control subjects and patients [8]. In accordance with the Statement of Consensus on Assessment of Neurobehavioral Outcomes after Cardiac Surgery, the test battery included tests for motor skills, verbal memory capacity, and attention [9]. Each test yielded one or more variables, with different ranges per variable. Eight main variables were chosen a priori to be used in the analysis. The cognitive domains that were covered, the tests, and the eight main variables are listed in the Results section.

To determine the presence of cognitive decline, each individual’s performance on the neuropsychological tests at 5-year follow-up was compared with his or her performance on the same tests 5 year earlier. Cognitive decline was defined as deterioration beyond the normal variation in cognitive performance. The normal variation in performance was measured in a short interval of 3 months in the control population (baseline assessment and 3-month follow-up). To define cognitive decline at 5 years in both the patients and the control subjects, the scores of the eight main variables were first standardized using the formula of reliable change (RC) as proposed by Jacobson and Truax [10]:


Formula

The practice effect is the control subjects’ mean improvement from baseline to 3 months after baseline. The SDdiff is the standard deviation of the control subjects’ mean 3-month performance minus baseline performance. Patients and control subjects were considered as experiencing cognitive decline at 5-year follow-up if they had either an overall mean RC score equal to or less than –1.96, or an RC score equal to or less than –1.96 in two or more main variables.

Patients and control subjects who had experienced a stroke and subjects unable to undergo testing because of Alzheimer’s disease were also considered to have cognitive decline.

Data Analysis
Incidences of cognitive decline after 5 years in patients and control subjects were compared using the odds ratio and 95% confidence interval, with adjustment for possible remaining differences in age between the two groups. Multivariable logistic regression analysis was used to correct for other baseline differences between the patients and the control subjects, and thus for potential confounding. We considered the following potential confounders: female sex, years of education, diabetes, hypertension, and pulmonary disease. All reported probability values are two-sided.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Footnotes
 Acknowledgments
 References
 
Baseline Characteristics and Completeness of Follow-Up
The baseline characteristics of the patients and control subjects, and potential confounders, are summarized in Table 1. The age-matched control group comprised more females than the patient group, was better educated, and had less diabetes, hypertension, and pulmonary disease.


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  		Table 1 Baseline Characteristics of the Patients and the Control Subjects a
 
After 5 years, 2 of the 112 control subjects had died (2%) and 107 could be contacted by telephone. The other 3 were lost to follow-up. Four of the 107 remaining control subjects had undergone a coronary intervention. Cognitive follow-up could be completed in 99 of the 112 control subjects (88%). From the CABG patients, 260 were alive (93%) and 259 of them could be contacted by telephone. Cognitive status could be determined in 240 patients (85%). Five patients were unable to undergo neuropsychological testing because of severe dementia (n = 3) or because of a stroke (n = 2). They were thus considered to have cognitive decline. Reasons for failed neuropsychological follow-up are in Table 2.


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  		Table 2 Reasons for Failure of Neuropsychological Assessment
 
Outcomes
The raw data of the neuropsychological tests at baseline and 5-year follow-up are listed in Table 3. The incidence of cognitive decline was 34.2% in the CABG group and 16.2% in the control group. The crude odds ratio without adjustment for age was 2.69 (95% confidence interval, 1.48 to 4.90), and after adjustment for age, 2.59 (95% confidence interval, 1.39 to 4.82). After additional correction for other baseline differences, the odds ratio was 1.37 (95% confidence interval, 0.65 to 2.92; Table 4).


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  		Table 3 Neuropsychological Tests at Baseline and 5-Year Follow-up a
 

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  		Table 4 Crude and Adjusted Odds Ratio for Cognitive Decline After 5 Years Between Coronary Artery Bypass Graft Patients and Control Subjects
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Footnotes
 Acknowledgments
 References
 
We have compared the incidence of long-term (5 years) cognitive decline in CABG patients and age-matched control subjects who did not undergo CABG. We were unable to demonstrate a statistically significant difference in cognitive decline at 5-year follow-up between the two groups (odds ratio, 1.37; 95% confidence interval, 0.65 to 2.92).

This study compared the 5-year cognitive outcome of CABG patients to that of "healthy" control subjects. In 2001, Newman and colleagues [2] reported an alarming 42% incidence of cognitive decline 5 years after CABG, but this was an uncontrolled study. The results of the present study indicate that long-term cognitive decline also frequently occurs in similarly aged subjects who did not undergo CABG. This suggests that cognitive decline in CABG patients, as detected with repeated neuropsychological testing, is also partly the result of natural aging [6]. Despite the fact that the subjects in the control group had no coronary artery disease, we were unable to show that they had statistically significantly less cognitive decline than the CABG patients.

Several groups have recently suggested that the previously reported cognitive decline during the early postoperative period after CABG is transient and reversible [11, 12]. This has even led to the question of whether postoperative cognitive decline exists or whether it is a consequence of inadequate or misinterpreted neuropsychological test batteries [13]. It is therefore obvious that non-CABG control groups are needed for interpreting longitudinal changes in cognitive performance after CABG [8, 11, 14]. Selecting an appropriate control group, however, is difficult. Studies using control groups consisting of patients with coronary artery disease who did not undergo CABG have also suggested that undergoing CABG is not a major determinant of unfavorable neuropsychological outcome [15–17]. Two trials evaluated cognitive performance in patients randomized to CABG or percutaneous coronary intervention, and both failed to demonstrate a difference between the two patient categories [16, 17]. A study comparing patients with coronary disease with healthy control subjects indicated that the patients have a higher risk of cognitive impairment even before they undergo coronary revascularization [15]. This is confirmed by other studies reporting that cardiovascular risk factors predict lower performance on neuropsychological tests [18, 19]. Diffusion-weighted magnetic resonance imaging has shown new ischemic lesions in 11% to 15% of patients who underwent coronary angiography [20]. We therefore deliberately selected control subjects who were not suffering from coronary artery disease and who were unlikely to undergo a coronary intervention. As expected, the patients with coronary artery disease in the present study had a lower cognitive performance than the age-matched control subjects at baseline and at 5-year follow-up. However, the amount of decline in cognitive function after a period of 5 years was not statistically different between the patients with coronary artery disease and the control subjects, despite the fact that the patients had undergone CABG.

It is possible that the confidence interval of the adjusted odds ratio would not have included 1 (statistically significant) if the number of subjects had been greater. However, both the patient group and the control group are larger than in any study on long-term postoperative cognitive decline reported so far. Also, the loss to follow-up (12% in the control subjects and 15% in the CABG patients) is satisfactory compared with all other studies reporting long-term cognitive outcomes [2, 21]. The control subjects, although age-matched, were better educated. This appeared to have a strong influence on their risk of cognitive decline. The initially better cognitive outcome in the control subjects largely disappeared after correcting for this confounder.

In conclusion, we were unable to demonstrate that patients who underwent CABG have more cognitive decline after 5 years than control subjects without coronary artery disease.


   Appendix
 
The members of the Octopus Study Group were University Medical Center, Utrecht: Egidius E. H. L. van Aarnhem, Cornelius Borst, Johan J. Bredée, Lex A. van Herwerden, Erik Buskens, Jan C. Diephuis, Diederik Van Dijk, Frank D. Eefting, Diederick E. Grobbee, Ron Hijman, Peter P. T. de Jaegere, Erik W. L. Jansen, René S. Kahn, Johannes T. A. Knape, Cor J. Kalkman, Annemieke M. A. Keizer, Jaap R. Lahpor, Karel G. M. Moons, Hendrik M. Nathoe, and Pieter S. Stella; Isala Clinics, Zwolle: Arno P. Nierich, Harry Suryapranata, and Willem J. L. Suyker; Antonius Hospital, Nieuwegein: Wim-Jan van Boven and Sjef M. P. G. Ernst.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
References
 
This study was supported by a grant from the International Anesthesia Research Society (IARS).


   Footnotes
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Footnotes
Acknowledgments
 References
 
* The members of the Octopus Study Group are listed in the Appendix. Back


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Footnotes
 Acknowledgments
 References
 

  1. Van Dijk D, Keizer AMA, Diephuis JC, Durand C, Vos LJ, Hijman R. Neurocognitive dysfunctions following coronary artery bypass surgery: a systematic review J Thorac Cardiovasc Surg 2000;120:632-639.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  3. 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.[Abstract/Free Full Text]
  4. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgeryMulticenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996;335:1857-1863.[Abstract/Free Full Text]
  5. Lund C, Hol PK, Lundblad R, et al. Comparison of cerebral embolization during off-pump and on-pump coronary artery bypass surgery Ann Thorac Surg 2003;76:765-770.[Abstract/Free Full Text]
  6. Morris JC. Mild cognitive impairment and preclinical Alzheimer’s disease Geriatrics 2005;60(6 Suppl):9-14.[Medline]
  7. Van Dijk D, Jansen EWL, Hijman R, et al. Cognitive outcome after off-pump and on-pump coronary bypass surgery: results from a randomized study JAMA 2002;287:1405-1412.[Abstract/Free Full Text]
  8. Keizer AM, Hijman R, Kalkman CJ, Kahn RS, van Dijk D. The incidence of cognitive decline after (not) undergoing coronary artery bypass grafting: the impact of a controlled definition Acta Anaesthesiol Scand 2005;49:1232-1235.[Medline]
  9. Murkin JM, Newman SP, Stump DA, Blumenthal JA. Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery Ann Thorac Surg 1995;59:1289-1295.[Free Full Text]
  10. Jacobson NS, Truax P. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research J Consult Clin Psychol 1991;59:12-19.[Medline]
  11. McKhann GM, Grega MA, Borowicz Jr LM, et al. Is there cognitive decline 1 year after CABG?Comparison with surgical and nonsurgical controls. Neurology 2005;65:991-999.[Abstract/Free Full Text]
  12. Rosengart TK, Sweet JJ, Finnin E, et al. Stable cognition after coronary artery bypass grafting: comparisons with percutaneous intervention and normal controls Ann Thorac Surg 2006;82:597-607.[Abstract/Free Full Text]
  13. Hanning CD. Postoperative cognitive dysfunction Br J Anaesth 2005;95:82-87.[Free Full Text]
  14. Selnes OA, Pham L, Zeger S, McKhann GM. Defining cognitive change after CABG: decline versus normal variability Ann Thorac Surg 2006;82:388-390.[Free Full Text]
  15. Rosengart TK, Sweet J, Finnin EB, et al. Neurocognitive functioning in patients undergoing coronary artery bypass graft surgery or percutaneous coronary intervention: evidence of impairment before intervention compared with normal controls Ann Thorac Surg 2005;80:1327-1334.[Abstract/Free Full Text]
  16. Wahrborg P, Booth JE, Clayton T, et al. Neuropsychological outcome after percutaneous coronary intervention or coronary artery bypass grafting: results from the Stent or Surgery (SoS) Trial Circulation 2004;110:3411-3417.[Abstract/Free Full Text]
  17. Hlatky MA, Bacon C, Boothroyd D, et al. Cognitive function 5 years after randomization to coronary angioplasty or coronary artery bypass graft surgery Circulation 1997;96(Suppl):II-11-II-14.
  18. Aleman A, Muller M, De Haan EH, Van der Schouw YT. Vascular risk factors and cognitive function in a sample of independently living men Neurobiol Aging 2005;26:485-490.[Medline]
  19. Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive decline in middle-ages adults Neurology 2001;56:42-48.[Abstract/Free Full Text]
  20. Bendszus M, Stoll G. Silent cerebral ischaemia: hidden fingerprints of invasive medical procedures Lancet Neurol 2006;5:364-372.[Medline]
  21. Selnes OA, Royall RM, Grega MA, Borowicz Jr LM, Quaskey S, McKhann GM. Cognitive changes 5 years after coronary artery bypass grafting: is there evidence of late decline? Arch Neurol 2001;58:598-604.[Abstract/Free Full Text]

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