Intermediate- and Long-Term Cognitive Outcomes After Cardiovascular Procedures in Older Adults

Approximately 200000 coronary artery bypass graft (CABG) surgeries, 50000 carotid revascularizations, 50000 cardiac valve replacements or repairs, and 10000 catheter ablations for atrial fibrillation are performed annually in U.S. adults aged 65 years or older (16). The older U.S. population also has a high rate of cognitive impairment and dementia, with a combined incidence of 77.5 cases per 1000 person-years in adults aged 72 years or older with normal cognition at baseline (7). However, great uncertainty surrounds the relationship between these cardiovascular interventions and subsequent cognitive outcomes in older patients. Most attention has addressed the possible relationship between CABG and cognitive impairment. Early studies reported a high prevalence of cognitive impairment after CABG, possibly attributable to surgical factors, such as anesthesia and cardiopulmonary bypass (8, 9). Later studies suggested that much cognitive impairment after CABG predated the procedure (10) and was related to patient factors, such as age, education, and vascular disease (8, 1114). Studies of carotid revascularization have reported mixed cognitive outcomes, with some suggesting early improvement (15). Studies of cardiac valve procedures and catheter ablation for atrial fibrillation commonly report imaging-detected cerebral emboli, but cognitive outcomes have been less clear (16, 17). However, understanding the longer-term cognitive outcomes attributable to these cardiovascular procedures in older adults has been limited because many studies had no control group, had short follow-up, had a predominance of middle-aged patients, or used surrogate outcomes for cognitive function. Meanwhile, older adults, who have the highest risk for intermediate- and long-term cognitive impairment, increasingly are having these procedures. Therefore, improved understanding of any relationship between these cardiovascular procedures and cognitive outcomes in older patients could enhance physicianpatient clinical decision making. This systematic review evaluates the evidence from randomized, controlled trials (RCTs) and prospective cohort studies on the association of coronary and carotid revascularization, cardiac valve replacement and repair, and ablation for atrial fibrillation on intermediate- and long-term cognitive outcomes in adults aged 65 years or older. We further sought to evaluate whether these associations were modified by procedural and patient characteristics and by procedure-related stroke or transient ischemic attack (TIA). Methods We followed a protocol developed with input from the Agency for Healthcare Research Quality (AHRQ) and the Coverage and Analysis Group at the Centers for Medicare & Medicaid Services (CMS) (Supplement). The full technical report, which incorporated AHRQ, CMS, peer, and public review, is available on the CMS Web site (www.cms.gov/Medicare/Coverage/DeterminationProcess/Downloads/id97ta.pdf). Supplement. Evidence-based Practice Center Systematic Review Protocol Data Sources We searched the MEDLINE, Cochrane Library, Scopus, and ClinicalTrials.gov databases using a combination of search terms for cognitive function, cardiovascular procedures of interest, and study design (Supplement). We also reviewed reference lists of eligible studies, relevant review articles, and articles suggested by experts. We included only studies published from 1990 to January 2015 to reasonably reflect current clinical practice. Study Selection We included English-language RCTs, controlled clinical trials, and prospective cohort studies. Eligible studies predominately consisted of adults aged 65 years or older. They also reported clinically diagnosed cognitive impairment (such as dementia or mild cognitive impairment) or results of neuropsychological tests (such as Trail Making Test B) or global cognitive screening tests (such as the Mini-Mental State Examination) at least 3 months after coronary or carotid artery revascularization, cardiac valve replacement or repair, or ablation for atrial fibrillation. Clinically diagnosed cognitive impairment must have been based on an assessment of symptoms, function, and formal neuropsychological testing. Treatment group cognitive outcomes must have been compared with those in a control group. The Supplement shows the detailed eligibility criteria. Two reviewers independently examined titles, abstracts, and full articles for eligibility and resolved discrepancies by discussion and consensus. Data Extraction and Quality Assessment For each article, 1 reviewer extracted details on study design, patient characteristics, cardiovascular procedure characteristics, and cognitive outcomes, and a second reviewer checked accuracy. Using Cochrane Collaboration (for trials) and AHRQ (for prospective cohort studies) criteria (18, 19), 2 reviewers rated individual-study risk of bias as low, moderate, high, or unknown (Appendix Tables 1 and 2). For trials, ratings were based on adequacy of randomization and allocation concealment, masking, accounting for attrition bias, use of intention-to-treat analyses, and selectiveness of outcome reporting. For prospective cohort studies, ratings were based on similarity of prognostic factors between comparison groups, accounting for attrition bias, masking, and selectiveness of outcome reporting. Following AHRQ Effective Health Care Program methods (20), 2 reviewers graded the strength of evidence (SOE) for the association of each treatment comparison with subsequent cognitive outcomes as high, moderate, low, or insufficient based on risk of bias, consistency, precision, and directness (Appendix Table 3). We resolved discrepancies in risk-of-bias ratings and SOE grades by discussion and consensus. Appendix Table 1. Risk of Bias in RCTs Appendix Table 2. Risk of Bias in Prospective Cohort Studies Appendix Table 3. Strength of Evidence Appendix Table 3.Continued Data Synthesis and Analysis We used Review Manager, version 5.2 (Cochrane Collaboration), to estimate relative risks and 95% CIs for the incidence of dichotomous outcomes and standardized mean differences and 95% CIs for continuous outcomes. We did not pool results between studies because no 2 studies had clinically similar patient populations, cardiovascular procedure and control groups, and definitions of cognitive outcomes. Role of the Funding Source This review was nominated to AHRQ by the CMS and was funded by AHRQ. Staff at AHRQ and CMS helped to develop and refine the scope of the study and reviewed the draft AHRQ report. Results Twenty-five reports of 21 unique studies (17 RCTs and 4 prospective cohort studies) met eligibility criteria (Figure) (2145). Sixteen of these reports studied CABG; 2 studied cardiac valve replacement, including 1 study of CABG combined with cardiac valve replacement; and 3 studied carotid revascularization. Figure. Summary of evidence search and selection. * Some references were identified in several databases. Sixty-five additional references were identified by hand searching; 61 of them were excluded at the title and abstract review stage, and 4 were excluded after full-text review. Ninety studies were identified from ClinicalTrials.gov. Among studies not already included in the review, 2 seemed possibly eligible: 1 (NCT02108093) that was still enrolling patients and the other (NCT01743456) that is listed as completed but for which no results appear reported. Included 21 unique studies. We rated risk of bias as high in 3 studies, moderate in 11, and unclear in 7. Eighty percent of study patients were men, and mean age was 68 years (mean age was between 65 and 69 years in all but 4 studies). In the 6 studies that reported education, patients completed a mean of 11 years (range, 7 to 14). Few patients had a history of stroke (study range, 0% to 8%; 10 studies) except in the 3 carotid revascularization studies (range, 50% to 100%). All studies reported baseline results for individual neuropsychological tests (such as attention, memory, and executive functioning). Five studies excluded patients with baseline dementia (39, 40), abnormal baseline cognitive screening (25, 26, 30, 39, 40), or a learning disorder (36, 40). Among included patients, mean baseline scores in individual studies were similar to estimated age-based norms for IQ and global cognitive screening tests, but more than half of studies reported mean baseline scores in the impaired range for at least 1 neuropsychological test, most frequently with impairment in timed tests. All studies reported follow-up results for individual neuropsychological tests. Twelve studies reported incident cognitive impairment as defined by a composite of neuropsychological test results (definitions differed in every study [Appendix Table 4]), but none reported incidence of mild cognitive impairment or dementia. Only 2 studies reported cognitive outcomes more than 1 year after the procedure. Appendix Table 4. Individual Study Definitions of Incident Cognitive Impairment Based on Combining Results of Individual Neuropsychological Tests Coronary Artery Revascularization CABG Versus Medical Management One prospective cohort study (n=326) compared on- or off-pump CABG versus medical management in older adults with catheter-proven coronary artery disease (Table 1) (2729). It found that both the CABG and medical groups had small to moderate improvements in memory versus baseline at 1 year and no changes versus baseline at 6 years for all neuropsychological tests measured. Further, there were no between-group differences at any follow-up or in change from baseline to any follow-up. Risk of bias for this study was high due to important baseline differences between treatment groups and substantial loss to follow-up. The higher dropout rates in the CABG group could have biased the results if they were related to cognitive decline. We rated SOE as insufficient because of these limitations and the absence of corroborating studies. Table 1. Cor