An open-label study reported that ingestion of a fish oil concentrate decreased the incidence of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) surgery. However, a general cardiac surgery population involves valve and CABG surgeries. We undertook a double-blinded randomized controlled trial to examine the effectiveness of fish oil supplementation on the incidence of postsurgical AF after CABG and valve procedures. The primary end point was incidence of AF in the first 6 days after surgery. Two hundred patients were randomized to receive fish oil (providing 4.6 g/day of long-chain ω-3 fatty acids) or a control oil starting 3 weeks before surgery; 194 subjects completed the study, with 47 of 97 subjects in the control group and 36 of 97 subjects in the fish oil group developing AF (odds ratio 0.63, 95% confidence interval [CI] 0.35 to 1.11). There was a nonstatistically significant delay in time to onset of AF in the fish oil group (hazard ratio 0.66, 95% CI 0.43 to 1.01). There was a significant decrease in mean length of stay in the intensive care unit in the fish oil group (ratio of means 0.71, 95% CI 0.56 to 0.90). In conclusion, in a mixed cardiac surgery population, supplementation with dietary fish oil did not result in a significant decrease in the incidence of postsurgical AF. However, there was a significant decrease in time spent in the intensive care unit.
Atrial fibrillation (AF) is a common postoperative complication of cardiac surgery and is associated with increased length of intensive care unit (ICU) and hospital stays and an increased mortality. A previous open-label study reported that preoperative intervention with ω-3 polyunsaturated fatty acids (PUFAs) markedly decreased the incidence of postoperative AF in patients undergoing coronary artery bypass grafting (CABG) surgery by 65%. Although this demonstration of an atrial antiarrhythmic effect of ω-3 PUFAs complements reports of its ventricular antiarrhythmic action in animals and humans, the magnitude of decrease suggests a profound effect that needs to be confirmed in a randomized controlled study. Therefore, in this prospective double-blinded randomized controlled study, we examined the effect of perioperative fish oil supplementation on occurrence of AF in a general cardiac surgery population that included CABG and/or valve surgical patients.
Methods
This study was a single-center, randomized, double-blinded, placebo-controlled trial investigating the effect of ω-3 PUFA supplementation on incidence of AF after cardiac surgery. The study protocol was approved by the Royal Adelaide Hospital (Adelaide, Australia) research ethics committee and was registered with the Australian New Zealand Clinical Trials Register ( http://www.anzctr.org.au , identifier ACTRN12606000134527).
All patients >18 years of age who were accepted for cardiac surgery involving CABG and/or valve repair or replacement at the Royal Adelaide Hospital were eligible for inclusion in the study. The following exclusion criteria were used: previous diagnosis of AF or atrial flutter, antiarrhythmic drug use (class 1 or 3) within the previous 3 months, urgent surgery (<3 weeks), New York Heart Association class IV heart failure, myocardial infarction within previous 2 weeks, or any condition that might affect the ability to ingest or absorb dietary fat. To maximize differences in tissue ω-3 PUFA levels between the treatment and control groups, we also excluded patients who consumed dietary supplements rich in ω-3 oils, e.g., fish oil or flaxseed oil, or self-reported habitual consumption of ≥1 fish meal per week. All patients provided written informed consent to the study protocol. Study enrollment commenced in April 2006 and concluded in December 2009.
Patients were randomly allocated to fish oil or placebo oil (high monounsaturated sunflower oil). Group assignment was based on a computer-generated randomization list using blocks of 20 and individual allocation was by sealed envelope. The 2 oils were supplied in liquid form in 500-ml bottles (Melrose Laboratories, Pty. Ltd., Mitcham, Victoria, Australia) and were citrus flavored to increase masking. Compositions of the oils used are presented in Table 1 . Subjects were instructed to ingest oil 15 ml/day, providing eicosapentaenoic acid ∼2.7 g/day and docosahexaenoic acid ∼1.9 g/day in the fish oil group, commencing 3 weeks before their scheduled surgery date. This dose of eicosapentaenoic acid plus docosahexaenoic acid 4.5 g/day was chosen to increase rapid short-term incorporation into tissue phospholipids and maximize differences in tissue ω-3 PUFA content between the treatment and control groups. Patients were instructed to maintain their normal dietary patterns and to not consume any additional oil supplements. In the event of surgery being delayed, participants were instructed to continue with the allocated oil until surgery. Subjects continued to ingest the allocated oil for 6 days after surgery or until discharge, whichever came first. Apart from this intervention, monitoring and treatment were standard practice as determined by the attending physician.
| Fatty Acid | Fish Oil | Sunola |
|---|---|---|
| Total saturated fatty acids | 31.1 | 8.6 |
| Oleic acid (18:1ω-9) | 9.8 | 82.4 |
| Total monounsaturated fatty acids | 24.2 | 82.9 |
| Linoleic acid (18:2ω-6) | 1.8 | 7.9 |
| Arachidonic acid (20:4ω-6) | 0.9 | 0.0 |
| Total ω-6 fatty acids | 3.6 | 7.9 |
| α-Linolenic acid (18:3ω-3) | 0.8 | 0.4 |
| Stearidonic acid (18:4ω-3) | 3.1 | 0.0 |
| Eicosapentaenoic acid (20:5ω-3) | 18.3 | 0.0 |
| Docosapentaenoic acid (22:5ω-3) | 2.2 | 0.0 |
| Docosahexaenoic acid (22:6ω-3) | 13.1 | 0.0 |
| Total ω-3 fatty acids | 37.9 | 0.4 |
Blood was sampled at baseline and before surgery for fatty acid analysis. A sample of atrial appendage was obtained at the time of surgery. Collection and evaluation procedures were as described previously.
All patients underwent surgical intervention as clinically indicated. All but 1 of the procedures used cardiopulmonary “on-pump” intervention. No patient underwent concurrent atrial ablation. Postoperative management was in accordance with routine care within the institution. A minimum of 72 hours of continuous electrocardiographic monitoring was performed. After this patients underwent daily 12-lead electrocardiographic recording until discharge from the hospital with further continuous monitoring if there were any symptoms or signs to suggest AF.
To determine a clinically relevant period of atrial arrhythmia, we prospectively established an event as 1 that lasted for ≥10 minutes or that required intervention. AF was defined as an irregular rhythm with no discernable discrete atrial activation. Atrial flutter or atrial tachycardia was defined as an atrial rate >100 beats/min with discrete atrial activation with P-wave structure distinct from that of sinus rhythm. In addition, onset and termination of these latter tachycardias were scrutinized to exclude sinus tachycardia. All episodes were reviewed by 2 investigators blinded to patient treatment arm, with disagreement being resolved by consensus.
The primary outcome measurement was occurrence of sustained AF/atrial flutter (duration ≥10 minutes or requiring intervention) during the first 6 postoperative days or until discharge if this occurred first. Secondary outcomes were time to first occurrence of AF and length of time in cardiothoracic ICU and total hospital length of stay.
Logistic regression was used to compare the odds of in-hospital AF between treatment groups. A multivariate logistic regression model adjusted for potential confounding variables that were unbalanced by the randomization process (gender and surgery type) was also performed. Analysis of time to first episode of AF was performed by the Kaplan–Meier method. Cox proportional hazards regression was used to compare treatment groups and control for potential confounding effects of gender and surgery type. Length of time in the ICU and total length of stay were assessed using negative binomial regression in unadjusted models and models adjusted for gender and surgery type. Results are expressed as mean ± SD unless otherwise specified. A probability value <0.05 (2-tailed) was considered statistically significant. Analysis was performed using SAS 9.2 (SAS Institute, Cary, North Carolina) using intention-to-treat principles.
A previous open-label trial reported a 54% relative risk decrease in AF after CABG using a modified fish oil in which the fatty acids were present as ethyl esters. It was hypothesized that our study using unmodified commonly available fish oil would have a similar effect size but with a different control event rate because our study included valve procedures and CABG. Based on the ratio of CABG/aortic valve/mitral valve/combination procedures at this hospital, an overall event rate of 42% was estimated using published figures for postoperative AF rates for each procedure. In this scenario, 200 participants would provide 90% power to detect a 53% relative risk decrease with a p value <0.05.
Results
Two hundred subjects were enrolled into the study, 100 into each group. Six subjects did not have surgery (3 in each group), leaving 194 subjects (97 in each group) included in the intention-to-treat analysis ( Figure 1 ). Demographic, clinical, and surgical variables were similar in the control and fish oil groups, with the exception of gender, where more men were enrolled into the fish oil group, and surgery type, where more patients undergoing a valve procedure were enrolled into the control group ( Table 2 ).
| Variable | Control (n = 97) | Fish Oil (n = 97) |
|---|---|---|
| Age (years) | 64 ± 10 | 64 ± 11 |
| Men | 62 (64%) | 80 (82%) |
| Body mass index (kg/m 2 ) | 31 ± 6 | 30 ± 5 |
| Hypertension | 75 (77%) | 76 (78%) |
| Myocardial infarction | 34 (35%) | 34 (35%) |
| Stroke | 4 (4%) | 5 (5%) |
| Diabetes mellitus | 35 (36%) | 26 (27%) |
| Chronic obstructive pulmonary disease | 12 (12%) | 9 (9%) |
| Left ventricular ejection fraction (%) | 64 ± 13 | 65 ± 13 |
| Smoker | 67 (69%) | 80 (71%) |
| Medications | ||
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker | 57 (59%) | 53 (55%) |
| β Blockers | 38 (39%) | 42 (43%) |
| Calcium channel blocker | 39 (40%) | 34 (35%) |
| Statin | 71 (73%) | 71 (73%) |
| Aspirin | 68 (70%) | 76 (78%) |
| Clopidogrel | 17 (18%) | 17 (18%) |
| Type of surgery | ||
| Coronary artery bypass grafting only | 53 (55%) | 69 (71%) |
| Valve ± coronary artery bypass grafting | 44 (45%) | 28 (29%) |
| Time in theater (minutes) | 241 ± 63 | 225 ± 46 |
| Bypass time (minutes) | 92 ± 43 | 77 ± 29 |
| Aortic crossclamp time (minutes) | 64 ± 31 | 55 ± 22 |
The study aimed for ingestion of fish oil or control oil for 3 weeks before surgery. The surgery date varied according to availability of staff and theaters. Five subjects (1 in the control group and 4 in the fish oil group) had their surgery brought forward and did not consume any oil before surgery. When surgery was delayed, participants continued to ingest the allocated oil until surgery. Median (interquartile range) times on treatment were 22 days (18 to 28) and 21 days (13 to 35) for the control and fish oil groups, respectively (p = 0.8, Mann–Whitney U test).
There were no differences in red blood cell fatty acid levels between the intervention and control groups at baseline ( Table 3 ). At the time of surgery the fish oil group had significant increases from baseline in red blood cell eicosapentaenoic acid and docosahexaenoic acid and a significant decrease in ω-6 PUFAs, whereas there were no significant changes in the control group ( Table 3 ). The fish oil–supplemented group had significantly larger proportions of eicosapentaenoic acid and docosahexaenoic acid and a significantly lower proportion of arachidonic acid in atrial tissue than the control group ( Table 4 ).
| Control | Fish Oil | |||
|---|---|---|---|---|
| Baseline | At Surgery | Baseline | At Surgery | |
| (n = 79) | (n = 80) | (n = 78) | (n = 77) | |
| Total saturated fatty acids | 44.9 ± 0.9 | 44.8 ± 1.0 | 44.9 ± 1.1 | 45.6 ± 1.3 ⁎ |
| Oleic acid (18:1ω-9) | 13.8 ± 0.9 | 14.1 ± 1.0 | 13.9 ± 1.1 | 13.4 ± 1.3 ⁎ |
| Total monounsaturated fatty acids | 17.0 ± 0.9 | 17.4 ± 1.1 | 17.2 ± 1.2 | 16.7 ± 1.4 ⁎ |
| Linoleic acid (18:2ω-6) | 8.42 ± 1.38 | 8.40 ± 1.39 | 8.22 ± 1.44 | 7.02 ± 1.17 ⁎ † |
| Arachidonic acid (20:4ω-6) | 14.3 ± 1.1 | 14.1 ± 1.2 | 14.2 ± 1.3 | 13.0 ± 1.3 ⁎ † |
| Total ω-6 fatty acids | 28.2 ± 1.3 | 28.1 ± 1.5 | 28.0 ± 1.5 | 24.7 ± 2.1 ⁎ † |
| α-Linolenic acid (18:3ω-3) | 0.12 ± 0.05 | 0.11 ± 0.04 | 0.12 ± 0.03 | 0.10 ± 0.04 † |
| Eicosapentaenoic acid (20:5ω-3) | 0.88 ± 0.22 | 0.86 ± 0.22 | 0.91 ± 0.27 | 2.62 ± 0.86 ⁎ † |
| Docosapentaenoic acid (22:5ω-3) | 2.80 ± 0.35 | 2.76 ± 0.34 | 2.82 ± 0.37 | 3.17 ± 0.40 ⁎ † |
| Docosahexaenoic acid (22:6ω-3) | 5.08 ± 0.85 | 4.97 ± 0.83 | 5.00 ± 0.94 | 6.18 ± 1.06 ⁎ † |
| Eicosapentaenoic acid + docosahexaenoic acid | 5.96 ± 0.91 | 5.82 ± 0.94 | 5.91 ± 1.10 | 8.80 ± 1.73 ⁎ † |
| Total long-chain ω-3 fatty acids | 8.75 ± 0.95 | 8.58 ± 0.98 | 8.73 ± 1.14 | 12.0 ± 1.9 ⁎ † |
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