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Tex Heart Inst J. 2007; 34(3): 268–274.
PMCID: PMC1995047
Oral Ascorbic Acid in Combination with Beta-Blockers Is More Effective than Beta-Blockers Alone in the Prevention of Atrial Fibrillation after Coronary Artery Bypass Grafting
Masoud Eslami, MD, Roya Sattarzadeh Badkoubeh, MD, Mehdi Mousavi, MD, Hassan Radmehr, MD, Mehrdad Salehi, MD, Nafiseh Tavakoli, MD, and Mohamad Reza Avadi, PhD
Departments of Cardiovascular (Drs. Eslami and Mousavi) and Cardiac Surgery (Drs. Radmehr, Salehi, Sattarzadeh Badkou-beh, and Tavakoli), Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran 14197–33141; and R & D Department, (Dr. Avadi) Hakim Pharmaceutical Co., Tehran 11365–5465; Iran
Because adrenergic beta antagonists are not sufficient to prevent atrial fibrillation after coronary artery bypass grafting, this prospective, randomized trial was designed to evaluate the effects of ascorbic acid as an adjunct to β-blockers.
Fifty patients formed our ascorbic acid group, and another 50 patients formed our control group. All patients were older than 50 years, were scheduled to undergo coronary artery bypass grafting, and had been treated with β-blockers for at least 1 week before surgery. The mean age of the population was 60.19±7.14 years; 67% of the patients were men. Patients in the ascorbic acid group received 2 g of ascorbic acid on the night before the surgery and 1 g twice daily for 5 days after surgery. Patients in the control group received no ascorbic acid. Patients in both groups continued to receive β-blockers after surgery. Telemetry monitoring was performed in the intensive care unit, and Holter monitoring was performed for 4 days thereafter.
The incidence of postoperative atrial fibrillation was 4% in the ascorbic acid group and 26% in the control group (odds ratio, 0.119; 95% confidence interval, 0.025–0.558, P = 0.002). We conclude that ascorbic acid is effective, in addition to being well-tolerated and relatively safe. Therefore, it can be prescribed as an adjunct to β-blockers for the prophylaxis of post-bypass atrial fibrillation.
Key words: Adrenergic beta-antagonists, anti-arrhythmia agents/administration & dosage, ascorbic acid/administration & dosage/therapeutic use, atrial fibrillation/drug therapy/prevention & control, clinical trials coronary artery bypass/adverse effects
With the exception of sinus tachycardia, atrial fibrillation is the most frequent arrhythmia that follows coronary artery bypass grafting (CABG).1–3 The reported incidence of atrial fibrillation after CABG varies widely depending on the particular definition used, the mode of postoperative monitoring of the patients, and the profile of the patients who undergo CABG.3,4 The incidence of post-CABG atrial fibrillation varied between 17% and 33% in studies that included 300 or more patients.2,3,5 Patients undergoing combined CABG and valve surgery have a higher incidence of postoperative atrial fibrillation than do patients undergoing CABG alone.2–4,6 Atrial fibrillation after CABG is self-limited in most cases2—80% of patients return to sinus rhythm within 1 to 3 days after initiation of digoxin or β-blocker therapy.1 However, patients who develop postoperative atrial fibrillation have significantly higher 30-day and 6-month mortality rates.7
Multiple randomized studies have shown the consistent prophylactic effectiveness of β-adrenergic blockers,1–4,8 and all patients without contraindications should receive β-blockers before and after cardiac surgery.4,9 However, β-blockers alone are not sufficient to prevent post-CABG atrial fibrillation,9 and the administration of antiarrhythmic drugs may be ineffective and even harmful, possibly due to pro-arrhythmic and other side effects.
Currently, the role of inflammation and oxidative stress on electrical remodeling is under investigation.10 Therapeutic approaches that target inflammation and oxidative stress may exert favorable effects on atrial electrical remodeling.11 Ascorbate may attenuate electrical remodeling and may decrease the incidence of postoperative atrial fibrillation.12 The aim of this study was to evaluate the efficacy of combination therapy with β-blockers and ascorbic acid in achieving further reduction of post-CABG atrial fibrillation, in comparison with β-blocker therapy alone.
Patients scheduled to undergo isolated CABG from December 2003 through August 2005 were screened for participation in this prospective, randomized trial. Inclusion criteria were: age >50 years and treatment with β-blockers (atenolol, propranolol, or metoprolol) for a target heart rate of about 60–70 beats/min, at least 1 week before surgery. Those included had to give informed, written consent. One hundred patients entered the study: 50 patients were randomly assigned to the ascorbic acid group (those who were to receive combination therapy with β-blockers and ascorbic acid), and the other 50 were assigned to the control group (those who were to receive β-blocker therapy alone). The mean age of the population was 60.19±7.14 years, and 67% were men. Baseline and perioperative characteristics were similar in the ascorbic acid and control groups (Table I).
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TABLE I. Baseline and Perioperative Characteristics of Patients
Excluded from the study were patients who had a history of atrial fibrillation, medication with class I and III antiarrhythmic agents or digoxin, a permanent or temporary pacemaker, any degree of atrioventricular block or bradycardia with a heart rate of <50 beats/min, end-stage renal disease, severe pulmonary disease (pneumonia or chronic obstructive pulmonary disease), or severe hepatic disease (cirrhosis or fulminant hepatitis).
Echocardiography (Hewlett-Packard, Image Point HX; now a part of Philips Medical; Bothell, Wash) was performed before surgery by a single investigator in a blinded fashion. The 2-dimensional echocardiogram was used to obtain measurement of diastolic left atrial diameter at the level of the aortic root by means of electronic calipers. Left ventricular diameters at end-systole and end-diastole were measured via M-mode echocardiography at the tip of the mitral valve. Left ventricular ejection fractions were estimated by study of the apical 2- and 4-chamber views.
Hypertension was defined as a systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90 mmHg, or as a history of treatment for hypertension. Hyper-cholesterolemia was defined as low-density lipoprotein levels >100 mg/dL, and all patients with hypercholester-olemia were prescribed lovastatin (≥20 mg/day) at least 1 week before surgery. Cigarette smoking was defined as the consumption of at least 3 cigarettes per day during the preceding 3 months.
Patients in the ascorbic acid group were given 2 g of effervescent ascorbic acid tablets (Hakim Pharmaceutical Co.; Tehran, Iran) on the night before surgery, followed by 1-g doses twice daily for 5 days after surgery. Before surgery, patients in both the control and ascorbic acid groups were treated with β-blockers (atenolol, propranolol, or metoprolol), and after surgery, the β-blockers were continued in both groups. Other medications were prescribed according to clinical indications in both groups.
Patients underwent CABG on standard cardiopulmonary bypass with myocardial protection provided by the perfusion of blood cardioplegic solution. Patients were initially monitored in the cardiothoracic intensive care unit (ICU) before their transfer to a nursing ward. Holter monitoring (Novacor, Vista Access; Rueil-Malmaison, France) was performed for 4 days after the transfer of patients to nursing wards. All of the Holter recordings were examined by a single investigator who had been blinded to patients' group assignments. In addition to the Holter recordings, standard 12-lead electrocardiography was recorded on the day of surgery and on postoperative days 1 and 5.
The primary endpoints in our study were the detection of an episode of atrial fibrillation lasting >10 minutes or the requirement for urgent intervention due to atrial fibrillation (profound symptoms of atrial fibrillation or of hemodynamically unstable situations due to atrial fibrillation).
Our hospital's ethics committee approved our study.
Statistical Analyses
Clinical data were evaluated using SPSS version 11.5 statistical software (SPSS Inc.; Chicago, Ill). Continuous variables are expressed as mean±standard deviation.
The univariate association between qualitative vari-ables was evaluated by the χ2 test or Fisher's exact test, if needed. Student's t test was used for 2-group comparisons of continuous parametric data; the Mann-Whitney test was used for nonparametric 2-group comparison.
Binary logistic regression analysis with the backward Wald method was performed to determine the independent predictors of atrial fibrillation. Independent variables for the multivariate model were selected from those identified in a review of the literature. These variables were as follows: age, sex, and left ventricular ejection fraction <0.30. Also included were variables that had an association of P <0.1 with atrial fibrillation in the univariate model; ascorbic acid medication could therefore be included in the model. P values of <0.05 were considered statistically significant.
Sample size was derived from the assumptions that the baseline incidence of post-CABG atrial fibrillation in the control population (treated with β-blockers) would be 25% to 30%9 and that ascorbic acid, as an adjunct to β-blockers, could result in a 20% decrease in atrial fibrillation.12 With an α error of 0.05, a β error of 0.2, and a power of 80%, approximately 50 patients per group were needed.
The baseline and perioperative characteristics of patients in the ascorbic acid and control groups appear in Table I. Tables II and III show the results of univariate analysis of risk factors for postoperative atrial fibrillation.
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TABLE II. Univariate Analysis of Some Significant Predictors of Post-CABG Atrial Fibrillation (Qualitative Data)
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TABLE III. Univariate Analysis of Some Significant Predictors of Post-CABG Atrial Fibrillation (Quantitative Data)
The overall incidence of postoperative atrial fibrillation in the ascorbic acid group was 4%, versus 26% in the control group (χ2 = 9.49; P = 0.002; odds ratio, 0.119; 95% confidence interval, 0.025–0.558).
The logistic regression analysis (Table IV) demonstrated that ascorbic acid in combination with β-blockers was the most significant independent predictor of a reduction of post-CABG atrial fibrillation. Also, male sex seemed to be a significant predictor of post-CABG atrial fibrillation in our multivariate model.
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TABLE IV. Results of the Final Step of Binary Logistic Regression Analysis with Backward Wald Model of Important Factors Affecting Atrial Fibrillation after Coronary Artery Bypass Surgery
Atrial fibrillation developed at a mean of 2.53±0.83 days after surgery. Figure 1 shows the time course of atrial fibrillation's onset in the ascorbic acid and control groups.
figure 2FF1
Fig. 1 Day of onset of postoperative atrial fibrillation in patients treated with ascorbic acid in combination with β-blockers (ascorbic acid group) versus patients treated with β-blockers alone (control group).
The mean hospital stay after operation was 6.8±3.3 days, and the mean ICU stay was 2.43±1.54 days. The mean hospital stay after operation was 8.9±3.9 days in atrial fibrillation patients and 6.5±3.1 days in sinus rhythm patients (P = 0.02, Mann-Whitney test). The mean ICU stay was 3.23±1.92 days in those who experienced atrial fibrillation and 2.33±1.45 in those who experienced sinus rhythm (P = 0.09, Mann-Whitney test).
Adverse cerebral events (including nonfatal stroke or transient ischemic attack) occurred in 4 patients (2 in the ascorbic acid group and 2 in the control group). Two of these 4 patients had atrial fibrillation.
Carnes and colleagues12 prescribed prophylactic supplemental ascorbic acid to a series of 1st-time bypass patients on the evening before surgery and as soon as it was possible for oral administration to resume thereafter. The results, when analyzed as a univariate predictor, showed that ascorbate treatment had a significant effect (P = 0.048) on reducing post-CABG atrial fibrillation. Multivariate analysis demonstrated that β-blocker prophylaxis had the most protective effect (84% risk reduction; P = 0.007) and that ascorbate usage alone also had a clearly beneficial effect (66% risk reduction; P = 0.09). In another study,11 oral ascorbic acid reduced early recurrence rates after electrical cardioversion of persistent atrial fibrillation, and it attenuated associated low-level inflammation.
Because most studies have demonstrated the consistent effectiveness of β-blockers as prophylaxis,1–4 we decided to supplement β-blockers with ascorbic acid. Our univariate and multivariate analyses of our results have confirmed that the combination of ascorbic acid and β-blockers was more effective than β-blockers alone in reducing post-CABG atrial fibrillation. The 26% incidence of post-CABG atrial fibrillation in our control population (treated with β-blockers alone) was very similar to the historical incidence of 25% to 30% in other patients so treated.9
Possible Mechanisms
Several studies13 support the role of inflammation in the genesis of atrial fibrillation after surgery. The perioperative period is characterized by acute ischemic reperfusion injury and delayed inflammatory response, which together result in a net depletion of plasma antioxidants.14 Ascorbate as an antioxidant possibly prevents the effects of the oxidative stress, which is triggered by heightened sympathetic tone and ischemia/reperfusion injury after cardiac surgery.12 Carnes and colleagues12 showed that atrial ascorbate levels are reduced after rapid atrial pacing. Treatment with ascorbate attenuates electrical remodeling that results from short-term rapid atrial pacing.15 The beneficial effects of supplemental ascorbic acid are likely attributable to the preservation of intra-cellular ascorbic acid levels, which minimizes the peroxynitrite (ONOO)-mediated injury12 that is associated with human atrial fibrillation.16
The efficacy of β-blockers might be due in part to their ability to blunt the effects of high sympathetic tone after cardiac surgery17 and in part to their role in minimizing calcium overload. Such overload may help to initiate atrial arrhythmias.12,18 In this manner, the combination of β-blockers and ascorbic acid could well have cumulative beneficial effects.
Time of Atrial Fibrillation Onset and Duration of Hospitalization and Intensive Care Unit Care
In our study, the time of onset for atrial fibrillation was consistent with that reported in the medical literature. The highest incidence of atrial fibrillation onset falls on postoperative days 2 and 3,1–3,9 with fewer patients developing atrial fibrillation either early (<10% on the 1st postoperative day)3 or late (≥4 days after surgery).4
As we expected, atrial fibrillation remained an important factor for length of hospitalization after operation (P = 0.022), and ICU stay tended to be longer in the atrial fibrillation group (P = 0.09). Even when uncomplicated, atrial fibrillation requires additional medical treatment and prolonged stays both in the hospital3 (by 2–4 days2) and in the ICU.3 It has been estimated that patients who experience atrial fibrillation accrue $10,000 to $11,000 in additional hospital charges.19 In our study, postoperative hospital and ICU stays tended to be lower in those patients treated with ascorbic acid in combination with β-blockers than in those treated with β-blockers alone (P = 0.47 and P = 0.22, respectively; Table I), but the correlation was not statistically significant. Our study was underpowered to evaluate ICU and hospital stay in the ascorbic acid and control groups, because it was designed primarily to evaluate ascorbic acid as an adjunct to β-blockers in the prevention of post-CABG atrial fibrillation.
Atrial fibrillation can increase the risk of stroke,3,4 hypotension, and pulmonary edema.4 Because our study population was small and had a low complication rate, we could not draw definite conclusions about the ability of the ascorbic acid and β-blocker combination to reduce such complications.
Other Predictors of Atrial Fibrillation
Men are more likely to develop atrial fibrillation after CABG than are women.3,4,9 In our study, univariate analysis showed a trend toward a higher incidence of atrial fibrillation in men (19.4% vs 6.1% in women, P = 0.08). The multivariate model (Table IV) confirmed that male sex is a significant predictor of post-CABG atrial fibrillation (P = 0.045). Hormonal effects on autonomic tone and sex differences in ion-channel expression may explain this disparity.3,20
Old age is the independent risk factor most often reported for post-CABG atrial fibrillation.1–4,9 The prevalence of atrial fibrillation in postoperative cardiac patients younger than 40 years of age is as low as 3.7%,1 but the incidence increases by at least 50% per decade as patients progress beyond the 4th decade.21 In our study, patients with atrial fibrillation tended to be older, but not significantly so (P = 0.16). Aging causes cardiac dilatation, atrial fibrosis, myocardial atrophy, and a decrease in conduction tissue.22
Various studies have found associations between the post-CABG atrial fibrillation and the following factors: hypertension,3,4,9 smoking,9 statin use,13 absence of pre-operative treatment with angiotensin-converting enzyme inhibitors,12 previous congestive heart failure,3,4 previous myocardial infarction,3,12 cardiomegaly,2 low body mass index (BMI), large body surface area,3 aortic cross-clamp time,3,4 mechanical ventilation longer than 24 hours,3,9 and postoperative treatment with inotropic agents.3,12 Our study did not show any statistically significant association between these factors and the incidence of post-CABG atrial fibrillation (Tables II and III), nor was our study sufficiently powered to evaluate the role of other predictors of atrial fibrillation. However, failure to identify a preoperative risk factor for postoperative atrial fibrillation is not unusual.9
Study Limitations
Left atrial enlargement3,12 is a possible predictor of atrial fibrillation. However, left atrial enlargement was not prevalent in our population because we excluded patients with significant valvular heart disease or a history of valve operations.
Digoxin increases tachycardia-induced remodeling of the atria,15 so preoperative use of digoxin may increase the incidence of postoperative atrial fibrillation.2,3,12 For this reason, we did not include patients who had received digoxin preoperatively. We also excluded some other possible predictors of postoperative atrial fibrillation—most notably, a history of atrial fibrillation.3,4,12 Because of mandatory β-blocker use in the design of our study, we also did not include patients with chronic obstructive pulmonary disease2,3,9,12 and respiratory compromise—including postoperative pneumonia,3,4,9 bradycardia,3 and atrioventricular block (any of which may increase the incidence of postoperative atrial fibrillation).
With a larger sample size, we could have explored adequately the impact of our ascorbic acid and β-blocker combination upon such outcomes as morbidity and death, length of stay in the hospital and ICU, total hospital cost, cerebrovascular accidents, the duration of atrial fibrillation, and initial ventricular rate response.
Conclusion
Ascorbic acid is an inexpensive, effective, and well-tolerated treatment, and it is relatively safe. Therefore, ascorbic acid supplementation in preoperative and postoperative CABG regimens, as an adjunct to β-blockers, can be recommended for the prevention of post-CABG atrial fibrillation.
Footnotes
Address for reprints: Mehdi Mousavi, MD, No. 18 Moini Ave., Rajai Shahr, Karaj 3146734811, Iran. E-mail: mmoosavi/at/razi.tums.ac.ir
This study was supported in part by a research grant from Tehran University of Medical Sciences.
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