Purpose Results of a systematic review and meta-analysis of published data on use of ascorbic acid to prevent postoperative atrial fibrillation (POAF) after cardiac surgery are presented.
Methods MEDLINE and other sources were searched for reports on trials evaluating the effects of preoperative and/or postoperative use of ascorbic acid in patients undergoing cardiac surgery. For each study selected for meta-analysis, an assessment for risks of methodological bias was performed. Data on POAF frequency and length of stay (LOS) outcomes were pooled and analyzed via random-effects modeling.
Results The 11 identified studies involved patients receiving coronary artery bypass grafts with or without valve replacement; both i.v. and oral ascorbic acid formulations were used. Analysis of pooled outcomes data on treatment and control groups indicated that ascorbic acid prophylaxis was associated with reductions in POAF frequency (odds ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), intensive care unit (ICU) LOS (difference in means, −0.24 day; 95% CI, −0.45 to −0.03 day), and total hospital LOS (difference in means, −0.94 day; 95% CI, −1.65 to −0.23 day). Significant statistical, methodological, and clinical heterogeneity were observed.
Conclusion A meta-analysis revealed that, compared with use of a placebo or a nonplacebo control, perioperative administration of ascorbic acid to patients undergoing cardiac surgery was associated with a reduced frequency of POAF and a shorter ICU LOS and total hospital LOS.
The prevalence of postoperative atrial fibrillation (POAF) after cardiac surgery is 20–40%, depending on the procedure; these figures apply to both coronary artery bypass grafting (CABG) and valve replacement surgery populations.1 POAF typically occurs within the first four days after a procedure, with the highest frequency on postoperative days 2 and 3. Despite POAF typically being self-limiting, prolonged intensive care unit (ICU) and hospital length of stay (LOS) can be seen; stroke risk might also be elevated.2,3 POAF can also lead to increased hospital costs and long-term mortality.4,5
Excessive production of reactive oxidant species (ROS) after surgery has been proposed as a mechanism of POAF development.6–8 Ascorbic acid (vitamin C) has been shown in animal models to be a scavenger of oxygen radicals while reducing markers of oxidative stress9; thus, it has the potential to attenuate this pathway and prevent POAF and its sequelae. Studies evaluating the ability of antioxidant strategies, such as ascorbic acid administration, to prevent POAF have been performed, with varying levels of efficacy reported.9–14
Recent systematic reviews have suggested that perioperative use of antioxidant supplementation may prevent POAF.15–17 Since the publication of these studies, results of a number of additional trials examining the impact of ascorbic acid on POAF frequency as well as ICU and hospital LOS have become available.18–21 Given this influx of new data, an updated systematic review is warranted. Also, the additive and comparative effects of ascorbic acid in relation to other proven therapies such as amiodarone, magnesium, sotalol, and statins are unknown. The objective of the study described here was to perform a systematic review and meta-analysis evaluating the impact of ascorbic acid on the frequency of POAF and on ICU and hospital LOS after cardiac surgery.
This systematic review and meta-analysis of published data from randomized controlled clinical trials (RCTs) conducted in subjects undergoing cardiac surgery conformed to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance.22
Study selection and inclusion criteria
A systematic literature search of MEDLINE, the Scopus database (Elsevier B.V., Amsterdam, Netherlands), and the Cochrane Central Register of Controlled Trials was performed; the search covered the period from database inception (the 1940s for MEDLINE and 1960 and 1966 for the Scopus and Cochrane databases, respectively) through April 30, 2016. The following Medical Subject Headings and keywords were used: vitamin C, ascorbic acid, ascorbate, cardiac surgical procedures, cardiac surgery, and coronary artery bypass graft. Citations were limited to those with data published in English. A manual search of references from included studies and previously conducted systematic reviews was also performed. To be included, the population evaluated in a study must have been adult patients (≥18 years of age) undergoing cardiac surgery (CABG, valve replacement, or both) who received perioperative ascorbic acid supplementation. Studies evaluating procedures with and without use of a cardiopulmonary bypass pump (“on-pump” and “off-pump” procedures) were included. Only RCTs that compared ascorbic acid with a placebo or other control were included in the review.
Postoperative atrial fibrillation (POAF) occurs after 20–40% of cardiac surgical procedures.
Excessive production of reactive oxidant species after cardiac surgery has been proposed as a mechanism of atrial fibrillation development.
A meta-analysis of randomized controlled trials showed that ascorbic acid reduced the frequency of POAF by 56% and reduced the mean total hospital length of stay by almost one full day.
The optimal timing, dose, and route of administration of ascorbic acid for patients undergoing cardiac surgery have not been determined.
Through use of a standardized data abstraction tool, two reviewers independently collected data. Disagreements were resolved through discussion or triage to a third reviewer. The following information was obtained from each trial: author identification, year of publication, study design and methodological quality criteria, source of study funding, study population (including study inclusion and exclusion criteria), sample size, duration of patient follow-up, ascorbic acid regimen used (route, dosing regimen, and total cumulative dose given), type of surgery performed (CABG, valve, or combination surgery), and pertinent efficacy endpoints. Outcomes of interest included development of de novo POAF, as well as ICU and total hospital LOS. One investigator was responsible for all subsequent data entry.
We assessed the quality of included studies using the Cochrane Collaboration’s tool for assessing risk of bias.23 We assessed each randomized trial for the following criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Information from the published articles as well as from publicly available trial registries was used to assess risk of bias. Each item was given a designation of high, low, or unclear risk of bias.
Data on the frequency of POAF were pooled and reported as an odds ratio (OR) with associated 95% confidence interval (CI) using a random-effects model.24 Continuous outcomes (ICU and total hospital LOS) were pooled and reported as mean differences (MDs) with 95% CIs, also using a random-effects model. We also conducted a cumulative meta-analysis whereby studies were pooled chronologically by year of publication (starting with the earliest).
Statistical heterogeneity was addressed using the Cochran chi-square p value and the value I2 (which assesses the degree of inconsistency across studies and ranges from 0% to 100%, with a higher percentage representing a higher likelihood of the existence of true heterogeneity as opposed to chance).25 A Cochran p value of <0.10 was considered significant for the presence of heterogeneity, which translates roughly to an I2 value of 50%. Visual inspection of funnel plots (all analyses) and Egger’s weighted regression tests (in analyses including more than 10 studies) were performed to assess for the presence of publication bias.26 Analyses were performed using Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, NJ). Unless otherwise specified, the a priori level of significance was 0.05.
Our literature search resulted in 272 nonduplicate citations; of these citations, 234 were excluded (Figure 1). The remaining 38 citations underwent full-text review, and of these, 27 were excluded. A total of 11 studies met our inclusion criteria (Tables 1 and 2).9–14,18–21,27
Each trial enrolled patients undergoing CABG, with 2 studies allowing valve replacements.12,21 Four studies included on-pump procedures exclusively10,11,18,27; in 3 studies, data on pump use were not reported,9,14,19 and in 4 studies 50–92% of procedures were on-pump procedures.12,13,20,21 In 3 studies, only i.v. ascorbic acid was given throughout the study period11,20,27; in 1 study, an i.v. dose was given the evening before surgery, with oral doses administered thereafter21; and in the remainder of the evaluated studies, an oral formulation of ascorbic acid was used exclusively. In most of the studies, ascorbic acid administration was started the night before the surgery,9,10,12–14,19,20,27 but in a few investigations the first dose was given within a few hours before the procedure.11,18,21 Treatment continued for four days after surgery in 1 study21 and for five days in the remainder of the studies. Ascorbic acid was compared with placebo use in 7 studies11–13,19–21,27 and with a nonplacebo control in the rest.9,10,14,18 In all 11 studies, data on POAF were reported, with both ICU and hospital LOS data reported in 8 studies.
A few of the studies exclusively enrolled patients taking preoperative β-blockers10,11,14,17; in other studies, the rate of preoperative β-blocker use was variously reported as ranging from 54% to 86%. Reported rates of postoperative use of β-blockers ranged from 70% to 100%, although postprocedural use was not reported in most studies. In one study, low use of preoperative amiodarone (1.9%) was reported27; in another study, rates of postoperative amiodarone use in the treatment and placebo groups were 27% and 38%, respectively.12 In the remainder of the evaluated studies, patients receiving antiarrhythmic drugs (including amiodarone) were excluded or postoperative antiarrhythmic use was not reported. Preoperative statin use ranged from 18% to 20% in one study17 to nearly 100% in another.18 Postoperative statin use followed a similar trend. In most studies, information on preoperative or postoperative statin use was not provided.9–11,13,14,19,20
Risk of bias
Four of the 11 studies11–13,21 (36%) were determined to have posed a generally low overall risk of bias. In the remaining 7 studies, a risk of bias was present because of uncertainty in one or more domains stemming from lack of reporting or an insufficient amount of detail to make a clear determination. One study did not involve random sequence generation or blinding of participants.9 In all of the included studies, it was unclear whether or not blinding of outcome assessments occurred. There were a number of instances of uncertainty regarding the allocation concealment and blinding procedures as well. One study was primarily published in a language not known to the authors19; thus, most of the risk-of-bias domains could not be evaluated. Summary data on the risk of bias, by domain, can be found in Figure 2.
POAF frequency and LOS
When results of the 11 studies were pooled, perioperative supplementation of ascorbic acid was associated with a significantly reduced frequency of POAF relative to placebo use (OR, 0.44; 95% CI, 0.32 to 0.61; I2 = 25%)(Figure 3). No significant publication bias was noted (Egger’s p = 0.13). Comparable results were obtained in focused analyses of data from studies involving the use of only i.v. ascorbic acid (OR, 0.48; 95% CI, 0.31 to 0.74) and those involving only oral use of ascorbic acid (OR, 0.40; 95% CI, 0.25 to 0.64). Similarly, the calculated treatment effect was essentially the same in studies that enrolled only patients undergoing CABG alone (OR, 0.43; 95% CI, 0.28 to 0.67) and those that enrolled patients undergoing CABG with valve surgery (OR, 0.43; 95% CI, 0.27 to 0.67).
After results of the seven relevant studies were pooled, ascorbic acid use was associated with a reduction in ICU LOS, although appreciable statistical heterogeneity was seen (MD, −0.309 day; 95% CI, −0.484 to −0.134 day; I2 = 55.6)(Figure 4, panel A). Visual inspection of the corresponding funnel plot suggested a low likelihood of publication bias. The differences in ICU LOS between treatment and control groups were similar in studies in which ascorbic acid was given orally only (MD, −0.24 day; 95% CI, −0.51 to 0.03 day) and those in which it was given intravenously only (MD, −0.25 day; 95% CI, −0.73 to 0.23 day), although in neither case was the difference significant (data not shown in Figure 4). Analysis of the pooled data indicated that in studies involving only patients undergoing CABG alone, the difference in ICU LOS in ascorbic acid–treated versus control group patients (MD, −0.30 day; 95% CI, −0.53 to −0.07 day) was greater than that in studies involving patients undergoing CABG and valve surgery (MD, −0.01 day; 95% CI, −0.26 to 0.25 day) (data not shown in Figure 4).
Compared with use of a placebo or nonplacebo control, use of ascorbic acid was associated with a significant reduction in total hospital LOS (MD, −1.225 day; 95% CI, −1.887 to −0.564 day; I2 = 79.1%) (Figure 4, panel B), although significant heterogeneity was again seen. Visual inspection of the corresponding funnel plot suggested a low likelihood of publication bias. Relative to use of a placebo or nonplacebo control, treatment with i.v. ascorbic acid was associated with a greater reduction in hospital LOS (MD, −1.87 days; 95% CI, −2.56 to −1.18 days) than oral ascorbic acid treatment (MD, −0.58 day; 95% CI, −1.85 to −0.80 day) (data not shown in Figure 4). The type of surgery was not appreciably associated with hospital LOS; the calculated CI for the difference in mean values between the treatment and control groups was wider when we analyzed only data on patients undergoing both CABG and valve surgery (MD, −1.11 days; 95% CI, −5.01 to 2.78 days) as opposed to CABG alone (MD, −0.83 day; 95% CI, −1.60 to −0.06 day) (data not shown in Figure 4).
Overall, the meta-analysis demonstrated that the addition of ascorbic acid supplementation to the perioperative care of patients undergoing cardiac surgery significantly reduces the odds of POAF. The beneficial effects were similar whether ascorbic acid was given intravenously or orally and whether patients underwent CABG only or both CABG and valve surgery. The durations of both ICU and total hospital LOS were also shortened, by about a quarter day and a full day, respectively. These findings provide clinicians with another option for preventing the common and troublesome complication of POAF in cardiac surgery patients.
The mechanisms underlying the development of POAF after cardiac surgery are likely to be multifactorial and remain incompletely understood. Atrial dilation, a known consequence of structural changes in patients with hypertension and ischemic heart disease, results in myocyte hypertrophy, fibrosis, and altered protein distribution.28–30 These alterations may also be the result of atrial stretch due to fluid accumulation and can lead to the development of atrial fibrillation. Inflammation has long been thought to play a major role in the genesis of POAF.31 Studies have shown higher circulating levels of the inflammatory markers interleukin-6, C-reactive protein, and tumor necrosis factor α in association with POAF in patients undergoing CABG32; however, all of the pertinent published evidence does not support these findings.12,33 Additional potential mechanisms of POAF development include autonomic stimulation, systemic neurohormonal inflammation, and oxidative stress.6,7,34
The ROS that result from oxidative stress after cardiac surgery may be involved with the genesis and perpetuation of POAF.7,9,35 Oxidative damage caused by ischemia or reperfusion injury is known to occur in patients undergoing cardiopulmonary bypass. Thus, it has been hypothesized that administration of an antioxidant such as ascorbic acid may attenuate these responses, resulting in a lower frequency of POAF.8,36,37 In fact, animal models have shown that reduced atrial ascorbic acid levels are seen in concert with increased atrial oxidative stress.9 Supplemental ascorbic acid has been shown to be a scavenger of oxygen radicals whose effects include reducing markers of oxidative stress.9,38 These effects may result from either a reduction in peroxynitrite accumulation or preservation of intracellular ascorbate levels.9 Thus, there is mechanistic substantiation for a reduced frequency of POAF in association with ascorbic acid use.
Guidelines published in 2014 by the American Association for Thoracic Surgery do not contain recommendations about use of ascorbic acid for prevention of POAF.39 Those guidelines recommend that patients receiving β-adrenergic blockers prior to surgery continue to receive them postoperatively (a class I recommendation) and that i.v. magnesium supplementation be considered when the serum magnesium level is low (a class IIb recommendation). For patients with factors that put them at intermediate-to-high risk for POAF development—such as higher age, history of atrial fibrillation, left ventricular dysfunction, chronic pulmonary obstructive disease, and diabetes mellitus—administration of postoperative amiodarone can be considered.2,39–41 Despite evidence supporting preoperative and postoperative administration of amiodarone for preventing POAF, its use in clinical practice is limited by concerns about toxicity.42,43 The studies included in our meta-analysis support this limited use, with one study revealing infrequent amiodarone use (1.9%)27 and another indicating that 27–38% of patients were treated with postoperative amiodarone.12 Most studies in our meta-analysis involved only patients receiving preventive β-adrenergic blockers17; in other studies, β-blocker use was reported in about three quarters of study participants.9,12,13,18,27 A few of the evaluated studies indicated high use of postoperative statins,12,17,18,27 whose usefulness in lowering POAF risk is uncertain.44,45 Differing utilization rates for preventive strategies in the included studies introduced appreciable clinical heterogeneity into our findings.
Other potential sources of heterogeneity among the studies in our meta-analysis included differing surgical populations, surgical techniques, and doses and routes of ascorbic acid administration. While most of the studies enrolled patients undergoing CABG only, others included individuals receiving CABG and valve surgery. Although the type of surgery did not affect the association between ascorbic acid treatment and the reduction of POAF frequency, the reduction in ICU LOS was greater in patients undergoing CABG only versus patients receiving CABG and valve surgery; total hospital LOS did not differ significantly by surgery type. Relative to on-pump procedures, off-pump CABG has been associated with fewer postoperative complications,46 although this finding has been debated.47 While most studies included in our meta-analysis enrolled patients undergoing on-pump procedures exclusively, some included studies also enrolled patients undergoing off-pump procedures (the percentages varied). Quantifying the effect of differential utilization of on- versus off-pump CABG on ascorbic acid C effectiveness in POAF prevention was not possible. While data analysis according to route of ascorbic acid administration did not affect our findings with regard to POAF frequency or ICU LOS, i.v. administration correlated with greater reductions in total hospital LOS than oral administration. A firm recommendation on the best route of ascorbic acid administration cannot be made until comparative studies are performed. Taken together, these differences in study characteristics may explain the appreciable statistical heterogeneity seen in a few of our analyses.
Our findings are similar to those of previously published systematic reviews.15–17 The earliest review, by Harling et al.,15 pooled findings from studies of both ascorbic acid and vitamin E that were published through 2011. While POAF risk was lower with use of these antioxidants, sufficient data were not available to permit evaluation of the effects of ascorbic acid alone. Two other meta-analyses published in 2014 indicated significant reductions in POAF associated with use of ascorbic acid versus use of placebo or nonplacebo controls,16,17 but those analyses (by Violi and colleagues17 and Ali-Hassan-Sayegh and colleagues16) included only 4 and 5 studies involving ascorbic acid use, respectively. Our systematic review located and included 11 studies of ascorbic acid—to our knowledge, the largest body of evidence on this subject compiled to date. Moreover, Violi et al. and Ali-Hassan-Sayegh et al. did not systematically assess the risk of bias in individual studies. Despite these differences, the overall findings of those investigators and our findings were similar, although we saw a larger effect on POAF than has been previously demonstrated.
The safety of ascorbic acid administration in cardiac surgery patients should be considered when evaluating whether it should be clinically utilized. Unfortunately, the general tolerability of the ascorbic acid regimen used was rarely reported in the included studies. Sadeghpour and colleagues21 reported that patients receiving ascorbic acid were significantly less likely than placebo recipients to experience postoperative complications, such as death, impaired renal function, and infection (p = 0.042 for all comparisons). Colby and colleagues12 stated that no adverse events attributable to ascorbic acid use were reported. The good overall tolerability is not surprising in light of previous research yielding similar safety results with ascorbic acid treatment for other conditions.48,49
The results of our meta-analysis must be considered within the context of its potential limitations. As with any systematic review, there is a risk of publication bias. Because of the low number of included studies, we were only able to assess the risk of publication bias in the POAF frequency analysis, which found that the risk was not significant (p = 0.13). This is not a surprising finding given the breadth of our literature search. Our findings are also limited by the high degree of statistical heterogeneity in the analyses conducted. As previously discussed, there were also fair amounts of methodological heterogeneity (seen in the risk-of-bias assessment) and clinical heterogeneity (e.g., differences in study populations and dosages). Such heterogeneity potentially limits the applicability of our findings, since the population most likely to benefit from ascorbic acid use for POAF prevention is unknown and the optimal dosage and route of administration of ascorbic acid are unclear.
A meta-analysis revealed that, compared with use of a placebo or a nonplacebo control, perioperative administration of ascorbic acid to patients undergoing cardiac surgery was associated with a reduced frequency of POAF and a shorter ICU LOS and total hospital LOS. The comparative efficacy of ascorbic acid as well as its optimal dosage and route of administration require further investigation.
Dr. Baker’s contribution to this research was funded, in part, by the Connecticut Institute for Clinical and Translational Science (CICATS) at the University of Connecticut. The authors have declared no potential conflicts of interest.
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of CICATS. The study results were presented as a poster at the European Society of Cardiology Congress 2015, London, England, August 29, 2015.
- Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.