Fish Oil Supplementation Does Not Affect Cognitive Outcomes in Cardiac Surgery Patients in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Trial

Abstract

Background

Cognitive decline has been reported following cardiac surgery, leading to great interest in interventions to minimize its occurrence. Long-chain n–3 (ω-3) polyunsaturated fatty acids (PUFAs) have been associated with less cognitive decline in observational studies, yet no trials have tested the effects of n–3 PUFAs on cognitive decline after surgery.

Objective

We sought to determine whether perioperative n–3 PUFA supplementation reduces postoperative cognitive decline in patients postcardiac surgery.

Methods

The study comprised a randomized, double-blind, placebo-controlled, multicenter, clinical trial conducted on cardiac surgery recipients at 9 tertiary care medical centers across the United States. Patients were randomly assigned to receive fish oil (1-g capsules containing ≥840 mg n–3 PUFAs as ethyl esters) or placebo, with preoperative loading of 8–10 g over 2–5 d followed postoperatively by 2 g/d until hospital discharge or postoperative day 10, whichever came first. Global cognition was assessed using in-person testing over 30 d with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (primary outcome), Mini-Mental State Exam (secondary outcome), and Trails A and B (secondary outcome) tests. All end points were prespecified. Statistical methods were employed, including descriptive statistics, logistic regression, and various sensitivity analyses.

Results

A total of 320 US patients were enrolled in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Cognitive Trial (OCT), a substudy of OPERA. The median age was 62 y (IQR 53, 70 y). No differences in global cognition were observed between placebo and fish oil groups at day 30 (P = 0.32) for the primary outcome, a composite neuropsychological RBANS score. The population demonstrated resolution of initial 4-d cognitive decline back to baseline function by 30 d on the RBANS.

Conclusion

Perioperative supplementation with n–3 PUFAs in cardiac surgical patients did not influence cognition ≤30 d after discharge. Modern anesthetic, surgical, and postoperative care may be mitigating previously observed long-term declines in cognitive function following cardiac surgery. This trial was registered at clinicaltrials.gov as NCT00970489.

Introduction

Cognitive decline has been reported as a potential consequence of cardiac surgery, with seminal research suggesting neuropsychological decline in the months postsurgery (1). These past observations have led to interest in new therapies to prevent cognitive decline (2) and advances in anesthetic, surgical, and postoperative care (3, 4). Long-chain n–3 PUFAs, derived from fish and seafood, have been of particular interest. The brain is particularly rich in the n–3 PUFA DHA, the most abundant fatty acid in neural membranes (5). In experimental studies (6), n–3 PUFAs have physiologic effects that may arrest the deterioration of cognition in the setting of insults. These effects include maintaining membrane integrity and neuronal function of phospholipids and improving endothelial function. These effects also include mediating processes such as inflammation and oxidative stress (5) by giving rise to newly identified metabolites such as monoepoxide derivatives, resolvins, and protectins that actively resolve inflammation in response to acute injury. In observational studies of community-dwelling older adults, consumption of fish and dietary n–3 PUFAs is associated with less cognitive impairment and decline (7, 8). Few randomized trials have tested this hypothesis and with mixed results (9, 10). To our knowledge, no prior clinical trials have evaluated the effects of n–3 PUFAs on cognitive decline in patients undergoing cardiac surgery. In addition, the contemporary rates of sustained cognitive decline following cardiac surgery in current patient care, compared to historical studies, are not well established (11–16).

To investigate these important questions, we conducted a substudy embedded within a randomized, double-blind, placebo-controlled clinical trial to determine whether perioperative n–3 PUFA supplementation reduces cognitive decline among patients undergoing cardiac surgery (the clinical trial in question was primarily focused on atrial fibrillation and secondarily on cognition). We hypothesized that individuals receiving n–3 PUFA supplementation would experience less cognitive decline over a 30-d period compared to controls.

Methods

Study design and patients

The Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Cognitive Trial (OCT) was a prespecified substudy embedded within the OPERA trial, an investigator-initiated, double-blind, placebo-controlled, randomized clinical trial (17). This substudy, conducted in 9 medical centers in the United States, tested the hypothesis that perioperative n–3 PUFA supplementation would reduce decline in cognition in patients undergoing cardiac surgery ≤30 d after discharge. Details of the OPERA clinical trial have been published (17).

General inclusion criteria included age ≥18 y, cardiac surgery scheduled on the following day or later, and the presence of sinus rhythm on the screening electrocardiogram. Exclusion criteria included regular use of fish oil, known allergy or intolerance to fish oil or olive oil (placebo), current pregnancy, existing or planned cardiac transplant or use of ventricular assist device, or being unable or unwilling to provide informed consent. Patients were not excluded due to prior cognitive impairment, as is often the case in studies on cognitive outcomes. This study was approved by institutional review boards (IRBs) including and notably the Vanderbilt IRB, the IRB of record for the OPERA cognitive substudy.

Intervention

Patients were block randomized to receive 1-g n–3 PUFA capsules containing ≥840 mg EPA (∼465 mg) plus DHA (∼375 mg) as ethyl esters (Omacor, Pronova BioPharma) or matched placebo (olive oil), stratified by enrolling medical center and planned valve surgery (yes or no). Study drugs were identical in appearance and specially coated to minimize taste differences. Investigators, patients, and clinicians were blinded to treatment assignment.

Patients received a total preoperative loading dose of 10 g divided over 3–5 d (or 8 g divided over 2 d), including the morning of surgery (17). For each patient, the loading dose was divided over the maximum number of days possible, based on the dates of enrollment and planned surgery. Flexibility in the loading days maximized generalizability by allowing enrollment of most patients undergoing cardiac surgery. Following cardiac surgery, patients received 2 g/d until hospital discharge or postoperative day 10, whichever occurred sooner, at which time administrative censoring occurred for in-hospital follow-up. A comprehensive description of the study intervention is available elsewhere (17).

End points

Description of cognitive tests

At baseline enrollment in the cognitive substudy (∼1 d prior to surgery) and at 4 and 30 d after surgery, trained research personnel performed in-person assessments of cognition. All evaluators were trained during a face-to-face 1–2-d training experience led by a licenced psychologist (JCJ). Evaluators were blinded.

At baseline, 4 d, and 30 d, cognitive testing was performed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), a cognitive battery assessing immediate and delayed memory, attention, visuospatial construction, and language (18). Visual attention was assessed using the Trail Making Test A (Trails A) (19), executive function was assessed using the Trail Making Test B (Trails B) (19) and global cognition was assessed using the Mini-Mental State Exam (MMSE) (20). These tests were chosen as they are widely used in outcome investigations and have strong psychometric properties (21–25).

Our prespecified primary outcome was the RBANS normalized global index score (mean 100, SD 15), which reflects overall RBANS performance (18). We assessed the difference-in-difference (DID) in the RBANS normalized global score between baseline and postoperative scores over 30 d in the n–3 PUFA group relative to the placebo group. Additional cognitive outcomes included differences in impairment rates on the RBANS, Trails A and B, and MMSE over 30 d.

Other data and risk factors

Data were collected on demographics, cardiovascular risk factors, and clinical factors including comorbid conditions, medical and surgical history, anthropometry, medication use, and laboratory measures. Surgical and anesthetic details of the cardiac procedure as well as daily follow-up, medications, and discharge information were recorded. Additionally, plasma phospholipid n–3 PUFA fatty acid concentrations were obtained and were calculated using a standard formula: EPA + DHA = 22:5n–3 + 22:6n–3.

Statistical analysis

Descriptive statistics related to cognitive functioning at baseline, day 4, and day 30 were calculated. Analyses were conducted as intention-to-treat, including all eligible patients according to treatment assigned at randomization (referred to as “treatment”). In order to utilize information from all 3 in-person cognitive assessments (baseline, and 4 and 30 d postoperation), we used multivariable generalized least squares (GLS) regression for longitudinal analyses. Models featured an unstructured correlation matrix. Multivariable GLS models included a variable for randomization, a variable for time point, and an interaction term for treatment multiplied by each time point. The interaction term represents a DID estimate: the absolute difference in outcome between postoperative and baseline measurements in the n–3 PUFA group relative to the placebo group. Missing RBANS global score outcome data were singly imputed if 60% or more of RBANS component measures were completed. All models included the following covariates: age, logistic EuroSCORE (24), heart failure (yes or no), BMI, ejection fraction, history of atrial fibrillation arrhythmia (yes or no), and baseline use of statins (yes or no) and benzodiazepines (yes or no). Continuous covariates were entered in models with restricted cubic splines and 3 knots. Covariates with missing data were singly imputed for all multivariable models.

Sensitivity analyses were performed for each of the models. The same DID interaction terms were adjusted for the same covariates as the main models. In the first sensitivity analysis, we log-transformed each outcome by taking the natural log. The resulting multivariable GLS model DID term indicated the percentage (rather than absolute) change in outcome between postoperative and baseline measurements in the n–3 PUFA group relative to the placebo group. In a second sensitivity analysis, we dichotomized outcomes into “impaired” (compared to “nonimpaired”) based on widely used clinical thresholds: for RBANS global, score <78; MMSE, <24; and Trails B, <36 (25). We used logistic regression with Huber-White robust covariance to perform longitudinal models. The DID term indicated difference in impairment status between postoperative and baseline measurements in the n–3 PUFA group relative to the placebo group.

A sample size of 668 observations, including 292 at baseline, 210 at 4 d, and 192 at 30 d, would detect a clinically meaningful DID of 7 RBANS points with 2-sided α = 0.05 and 83% power. All analyses were evaluated at 2-tailed α = 0.05 and were performed using R version 3.0.1 (cran.r-project.org), with the exception of OR calculations which were done using SAS.

Results

Enrollment and study completion rates

Between August 2010 and June 2012, 445 patients were enrolled across North American sites in the OPERA trial (17). Of these, 320 met the cognitive substudy selection criteria (Figure 1). Ineligible patients were most often excluded because they were not enrolled in a US center (70.6%) and the US center did not perform cognitive testing (5.3%).

FIGURE 1.

CONSORT diagram showing screening, randomization, and follow-up for OCT, a substudy of OPERA. CONSORT, Consolidated Standards of Reporting Trials; OCT, Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation Cognitive Trial; OPERA, Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status.

Baseline characteristics of patients

Baseline characteristics by group are shown in Table 1 and are presented as number and percentage for categorical variables and median and IQR for continuous variables. Across the entire population, median age at baseline was 62 y (IQR: 53, 70 y); 226 patients were men (71%) and valve surgery was planned in 150 patients (48%). The median logistic EuroSCORE was 3.54 (IQR 1.72, 7.98). Baseline characteristics, including baseline neuropsychological test scores, were evenly matched between groups.

TABLE 1.

Baseline demographic and in-hospital data of participants in the OPERA Cognitive Trial¹

Demographics	n	Placebo (n = 161)	n	n–3 PUFA (n = 159)
Age	161	61.0 (52.0, 72.0)	159	62.0 (54.0, 69.5)
Male sex, % (n)	161	70 (112)	159	72 (114)
Race, % (n)	161		159
White		86 (138)		87 (139)
Black, African-American, or African-European, %		12 (20)		11 (17)
Asian		0 (0)		0 (0)
Native Hawaiian/Pacific Islander		0 (0)		1 (1)
American Indian/Alaska Native		1 (1)		1 (1)
Other		1 (2)		1 (1)
Level of education, % (n)	151		156
Some high school		14 (21)		10 (15)
High school graduate		32 (50)		32 (50)
Some college or vocational school		23 (35)		33 (52)
College graduate		15 (23)		17 (27)
Graduate degree		17 (26)		8 (12)
EuroSCORE	161	3.370 (1.720, 7.540)	159	4.00 (1.715, 8.585)
Planned valve surgery, % (n)	159	48 (76)	156	47 (74)
Hypertension, % (n)	161	76 (123)	158	77 (122)
Dyslipidemia, % (n)	156	72 (112)	154	66 (101)
Diabetes mellitus, % (n)	161	37 (60)	158	34 (53)
Cerebrovascular disease, % (n)	160	12 (20)	158	7 (11)
Chronic obstructive pulmonary disease, % (n)	161	16 (26)	159	19 (31)
Chronic renal failure, % (n)	161	13 (21)	159	5 (8)
Prior myocardial infarction, % (n)	160	29 (47)	157	29 (45)
Prior cardiac surgery, % (n)	161	11 (18)	159	15 (24)
Coronary bypass, % (n)	161	7 (12)	159	4 (7)
Valve surgery, % (n)	161	5 (8)	159	9 (14)
Other cardiac surgery, % (n)	161	2 (3)	159	6 (9)
Prior arrhythmias, % (n)	150	19 (28)	142	18 (26)
Atrial fibrillation, % (n)	25	72 (18)	24	67 (16)
Congestive heart failure, % (n)	160	32 (52)	158	28 (44)
Ejection fraction	160	57.50 (50.00, 61.25)	158	59.00 (50.00, 61.75)

¹Binary and categorical data are expressed as % (n) and continuous data are expressed as median (IQR). OPERA, Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation.

Primary outcomes analysis

Table 2 shows the unadjusted mean cognitive test scores at baseline and at postoperative day 30 for the n–3 PUFA and placebo groups. The RBANS score increased from baseline to 30 d in both the treatment group (82.97 and 88.69, respectively) and in the placebo group (84.38 and 88.10), the adjusted DID of 1.03 (95% CI, –1.01, 3.07; P = 0.32) was not statistically significant. Mean MMSE was relatively stable at nearly 28 across treatment groups and across time. Trails A also increased from baseline to 30 d in the n–3 PUFA group (43.99 and 46.42) and in the placebo group (44.96 and 48.64). Trails B increased from 45.63 to 48.42 in the n–3 PUFA group and from 47.23 to 50.23 in the placebo group. Higher scores across all cognitive tests of interest reflect better performance. Table 3 displays the frequency of impaired compared to nonimpaired cognitive scores (across each cognitive domain) by the n–3 PUFA and placebo groups through to the 30-d follow-up. Wide variability in results was observed and no consistent patterns of impairment between groups were observed.

TABLE 2.

Cognitive test scores (RBANS, MMSE, and Trails A and B) between PUFA and placebo groups: day 0 versus day 30¹

	n–3 PUFA (n = 159)			Placebo (n = 161)				Adjusted difference-in-difference (95% CI)
Cognitive measure	Unadjusted mean, day 0	Unadjusted mean, day 30	Unadjusted difference in means, day 30 – 0	Unadjusted mean, day 0	Unadjusted mean, day 30	Unadjusted difference in means, day 30 – 0	Unadjusted difference-in-difference,n–3 PUFA (day 30 – 0) – placebo (day 30 – 0)	n–3 PUFA (day 30 – 0) – placebo (day 30 – 0)	Adjusted P value
RBANS	82.97 ± 12.16	88.69 ± 11.92	5.72	84.38 ± 11.95	88.10 ± 11.72	3.72	2.00	1.03 (–1.01, 3.07)	0.32
MMSE	27.71 ± 3.16	27.80 ± 3.16	0.10	27.90 ± 2.16	27.94 ± 3.14	0.05	0.05	0.22 (–0.55, 1.00)	0.57
Trails A	43.99 ± 10.91	46.42 ± 11.94	2.44	44.96 ± 11.44	48.64 ± 11.36	3.68	–1.24	–1.35 (–4.51, 1.80)	0.40
Trails B	45.63 ± 11.96	48.42 ± 14.49	2.79	47.23 ± 11.46	50.23 ± 11.54	3.00	–0.21	–1.30 (–4.48, 1.87)	0.42

¹Unadjusted mean is followed by ± SD. Test scores are depicted at baseline (day 0, immediately prior to surgery) and day 30. Multivariable models adjusted for: age entered continuously with restricted cubic splines and 3 knots, heart failure indicator, BMI entered continuously with restricted cubic splines and 3 knots, ejection fraction entered continuously with restricted cubic splines and 3 knots, prior arrhythmia atrial fibrillation indicator, statin indicator, and benzodiazepine indicator. MMSE, Mini-Mental State Exam; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; Trails A and B, Trailmaking Tests A and B.

TABLE 3.

Rates (%) of cognitive impairment by group (PUFA and placebo) across cognitive tests (day 0, day 4, day 30)¹

	Day 0		Day 4		Day 30
Treatment group	Placebo, n = 161	PUFA, n = 159	Placebo, n = 161	PUFA, n = 159	Placebo, n = 161	PUFA, n = 159
RBANS	27	24	44	48	9	12
Trails A	20	21	33	30	14	12
Trails B	17	18	37	29	9	14
MMSE	5	5	13	9	15	13

¹Data (shown for placebo and PUFA groups respectively, chronologically from left to right, at baseline, day 4, and day 30) refer to percentages of impairment across all tests in the cognitive battery on the RBANS, Trails A and B, and MMSE, respectively. Impairment was defined in a manner consistent with standard convention, as follows: RBANS: <78 on the RBANS global score, Trails A and B: T-scores <36, MMSE: <24. MMSE, Mini-Mental State Exam; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; Trails A and B, Trailmaking Tests A and B.

Multivariable model results

Figure 2 displays adjusted DID estimates representing the change in the n–3 PUFA group from baseline to 30 d postoperation relative to the change in the placebo group during the same time period. The RBANS global score changed ∼1 point, though this change was neither clinically nor statistically significant (P = 0.32). MMSE, Trails A, and Trails B scores also did not show clinically or statistically significant changes (MMSE DID = 0.22 and P = 0.58; Trails A DID = –1.35 and P = 0.40; Trails B DID = –1.30 and P = 0.42).

FIGURE 2.

These data represent the results of the RBANS (A), with a population age-adjusted mean (±SD) of 100 ± 15 and lower scores indicating worse global cognition; MMSE (B); Trails A scores (C); and Trails B scores (D). The total number of observations for each of these cognitive tests at each time point is listed at the bottom of each graph. In each graph a similar pattern appears for both the intervention (n–3 PUFA) and placebo groups, namely an initial decline in cognitive performance followed by a recovery to baseline function by postoperative day 30. There were no clinically meaningful or statistically significant differences between groups. DID, difference-in-difference; MMSE, Mini-Mental Status Examination; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; Trails A and B, Trailmaking Tests A and B.

Change in PUFA concentration

Mean plasma phospholipid n–3 PUFA concentrations at baseline were 4.187 (SD = 1.14) in the placebo group and 4.226 (SD = 1.01) in the n–3 PUFA group. On the morning of cardiac surgery, these concentrations essentially stayed the same in the placebo group (4.252, SD = 1.08), while increasing by 38.59% in the PUFA group.

Discussion

The OPERA trial provides 2 key findings. First, we demonstrate no evidence of significant persistent cognitive decline over 30 d among contemporaneous patients undergoing cardiac surgery. Second, no significant differences were seen by treatment on a composite measure of neuropsychological functioning or other individual cognitive measures over 30 d.

These findings contrast with a limited number of reports of long-term cognitive decline following cardiac (1) or other major surgery (26). Notably, most of these cohorts enrolled patients as long as a decade ago, compared to our enrollment between 2010 and 2012. Over this time, a number of advances in clinical care have occurred, including improvements in surgical, anesthetic, and neuroprotective strategies (27). These advances may have reduced long-term cognitive insults of cardiac surgery. Consistent with our findings, a number of investigations have demonstrated that cardiac surgery is not a cause of significant cognitive decline (28–30). Our findings provide important empirical evidence supporting this idea.

Our investigation does not support a benefit of perioperative n–3 PUFA supplementation on cognitive functioning in cardiac surgery patients ≤30 d postdischarge and, indeed, raises questions about the presence of cognitive decline in such patients. While fish and dietary n–3 PUFAs have been linked to lower incidence of cognitive decline in healthy ambulatory adults (7, 31–33), n–3 PUFA supplementation has shown mixed effectiveness in influencing cognition in patients and randomized trials have generally been negative (9, 10, 34–36). A few small-scale investigations have suggested that ingestion of n–3 PUFAs may slow memory decline in individuals with dementia, while potentially improving cognition in individuals with Alzheimer disease (37, 38).

The current investigation is the first to our knowledge to evaluate the effectiveness of short-term PUFA administration in a medical or surgical population at risk for cognitive decline. In this negative study, no differences on a composite measure of cognition were observed between PUFA and placebo groups at day 4 or day 30, suggesting that in this 9-center RCT, fish oil consumption did not impact cognitive functioning. Interestingly, we also found that neuropsychological test scores at day 30 were comparable to those obtained immediately prior to surgery, supporting the idea that cardiac surgery itself is not a cause of cognitive decline (30).

Our findings are consistent with findings from other randomized trials, which have largely failed to show any association between fish oil supplementation and cognitive outcomes (35, 39–41). These previous trials have typically involved elderly cohorts experiencing clear decline. In contrast to individuals with dementia, survivors of cardiac surgery display highly variable cognitive trajectories which may include improvement (28). In our patients, trajectories of improvement were the primary pattern observed and improvement happened equally in patients receiving a placebo. Reasons for this improvement are unclear but could be due to the postoperative mood states of patients, having survived major surgery, being superior (42). Alternatively, it could also be a function of practice effects (43). The RBANS battery has alternate forms (A and B) and form A was employed both at baseline and at 30-d follow-up, which may have resulted in artificially elevated 30-d test scores.

While our investigation found that fish oil does not influence cognition after cardiac surgery, there are ≥2 primary alternative explanations for this negative finding that do not rule out the potential therapeutic value of fish oil. As previously mentioned, relatively few of our patients displayed cognitive decline between baseline and 30-d follow-up and, instead, demonstrated cognitive improvement. The nutritional dynamics involved in accelerating cognitive improvement are potentially very distinct from those involved in slowing decline and it seems likely that fish oil does not enhance cognitition (44, 45). It may also be the case that taking fish oil for up to a maximum of 10 d is not sufficient to influence cognitive functioning, although there exists no clear guidance with regard to what an adequate duration represents. In a majority of the >30 studies of fish oil supplementation in dementia, interventions lasted for between 2 and 4 y and, even in these instances were only rarely effective (46).

While the development of cognitive decline and cognitive impairment after elective cardiac surgery has been long been identified as a public health concern in need of prevention, a spate of recent investigations have suggested that cognitive impairment after coronary artery bypass grafting may be the exception rather than the rule (29, 47–50). We found, consistent with recent evidence from cardiac surgery cohorts (28) but different to findings in medical and surgical intensive care cohorts (51–53), that the cognitive decline common at 3 d postdischarge had largely resolved at 1-mo follow-up. One possible explanation could involve resolution of the short-term effects of benzodiazepines (54).

Impairment was relatively common but not at rates that significantly exceeded those prior to surgery. These findings have potentially significant implications. Patients are often very concerned about undergoing cardiac surgery due in large part to the potential for adverse long-term neurologic outcomes. Based on these data and evidence emerging from other studies, they can be advised that this risk is likely to be quite low.

Our investigation has a variety of strengths and weaknesses. The strengths of the study include a large sample, the use of a detailed neuropsychological testing battery, and the involvement of multiple medical centers. This study also has a number of limitations. First, PUFA supplementation was time limited and the total dose that intervention patients received was small. Thus, it may not have been of a sufficient magnitude to arrest decline in the small subset of patients who are at risk for decline. Second, our battery was not designed to assess all neuropsychological domains comprehensively. It is possible that there are specific subdomains of cognitive functioning that were affected by PUFAs that were not captured by our outcome tools. Third, more dietary information at baseline might have allowed for a richer understanding of our sample. While we did discover that our patients had low concentrations of EPA + DHA, these concentrations were not so low as to reflect deficiency; thus it may be that our interventions were ineffective as patients has relatively little “room” to improve such concentrations in the context of supplementation. Finally, our sample consisted of relatively few elderly participants. Thus we were unable to examine whether supplementation might be capable of slowing postdischarge cognitive decline in them.

In conclusion, in the OPERA trial, no differences in cognitive functioning existed between individuals receiving placebo compared to PUFA supplementation and no persistent decline occurred. Future investigations should focus on exploring other interventions that have the potential to impact cognition in cardiac patients postsurgery, while also trying to determine—with the use of larger cohorts—whether cognitive decline is indeed consistently observed after cardiac surgery (our study suggested it is not). Such efforts are important, as the general public may well currently share the perception that cardiac surgery is potentially to be avoided due to dire neuropsychological sequelae. If cognitive outcome studies using PUFA supplementation are to be conducted, investigators should consider more prolonged PUFA treatment, while also potentially focusing on patients deficient in DHA + EPA.

Notes

OPERA was an investigator-initiated, not-for-profit trial sponsored by the OPERA Investigators, who had full responsibility for study planning and conduct, curation of the study data base, and discretion on data utilization, analysis, and publication. Financial support was provided by the National Heart, Lung, and Blood Institute, National Institutes of Health (RC2-HL101816), GlaxoSmithKline, Sigma Tau, and Pronova BioPharma, which also provided the study drug. The funding organizations had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

Abbreviations used: DID, difference-in-difference; GLS, generalized least squares; IRB, institutional review board; MMSE, Mini-Mental State Exam; OCT, Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation Cognitive Trial; OPERA, Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; RCT, randomized control trial; Trails A, Trail Making Test A; Trails B, Trail Making Test B.