N-acetyl cysteine for the conversion of atrial fibrillation into sinus rhythm aftercardiac surgery: A prospective, randomized, double-blind, placebo-controlledpilot study

Mehmet Ozaydin a,⁎, Dogan Erdogan a, Habil Yucel a, Oktay Peker b, Atilla Icli a, Selahaddin Akcay a,Mustafa Etli b, Betul M. Ceyhan c, Recep Sutcu c, Ercan Varol a, Abdullah Dogan a, Turhan Yavuz b

a Department of Cardiology, Suleyman Demirel University, Isparta, Turkeyb Department of Cardiovascular Surgery, Suleyman Demirel University, Isparta, Turkeyc Department of Biochemistry, Suleyman Demirel University, Isparta, Turkey

a r t i c l e i n f o

Article history:Received 20 June 2012Accepted 15 September 2012Available online 3 October 2012

Keywords:N-acetyl cysteineCardiac surgeryAtrial fibrillation

There are two strategies for the treatment of postoperative atrialfibrillation (POAF): Sinus rhythm (SR) restoration and ventricularrate control. SR restoration decreases the time to cardioversion,maintains sinus rhythm for longer periods and decreases the lengthof hospitalization [1–3]. Moreover, warfarin should be commenced inthe case of POAF lasting ≥48 h, which is a problematic conditionin this patient group [3]. Therefore, there is a trend toward SR restorationover heart rate control in current guidelines and treatment algorithms.However, available rhythm control agents have significant sideeffects and they are not very effective [1–4]. Recent investigationshave suggested that POAF may be associated with oxidative stress[5–9] and anti-oxidants showed conflicting results for the preventionof atrial fibrillation (AF) in the previous studies [10–17]. However, tothe best of our knowledge, no previous study evaluated the efficacy ofanti-oxidant N-acetyl cysteine (NAC) on the conversion of POAF intoSR. Therefore, we aimed to compare the efficacy of combination ofamiodarone plus NAC and amiodarone plus saline on converting POAFinto SR in this prospective, randomized, double-blind, placebo-controlled study.

A total of 400 consecutive patients undergoing coronary by-passgraft (CABG), valve surgery or both from February 2007 to September2011 were screened and thosewith AF were detected (n=75). Patientswith the indication of urgent cardioversion, class III or IV heart failure,pregnancy, hyperthyroidism, uncorrected QT interval N500 ms, heartrate b50/bpm, implanted pace-makers, hepatic disease, a history oftorsades de pointes, sick sinus syndrome or second or third degreeatrioventricular block, left atrial diameter N55 mm, ejection fractionb0.25, sepsis, inflammatory disease, reversible causes of AF, beingalready on anti-arrhythmics or NAC, age b18 and an AF episode lasting≤5 min were excluded. Thirteen patients were excluded due to an AFepisode≤5 min (n=8), hyperthyroidism(n=2), already beingonNAC(n=2), and declining to participate (n=1) and the remaining 62patients with POAF lasting N5 min were included (Fig. 1). Twelve-leadECGwas taken every morning routinely and when the patients had any

symptoms suggesting dysrhythmia. AF was defined as an irregularrhythmwith the absence of discrete P-waves. Two-blinded cardiologistsreviewed the ECGs. Patients were assigned to NAC plus amiodarone(n=29); or saline plus amiodarone (n=33) groups. Therapy wasinitiated as soon asAF episode lastingN5 minwasdetected. Amiodaronewas given in both groups for 1 month (intravenously for the first 24 hand then orally for the rest). It was administrated at a dose of 150 mgbolus followed by infusion 15 mg/kg for the first 24 h, followed by800 mg/d for the first week, 600 mg/d for the second week, 400 mg/dfor the third week and 200 mg/d for the fourth week. N-acetyl cysteine(Asist amp, Husnu Arsan Co., Turkey) was given at a dose of 100 mg/kgintravenous bolus infusion for 30 min and 25mg/kg intravenous bolusinfusion for 48 h. In the control group, saline was infused on top ofamiodarone to serve as placebo. The infusion rate and duration wassimilar for saline and NAC. Computer-generated randomization assign-ment was kept in a sealed envelope. Cardiac surgery residents notinvolved in the study opened the envelope and assigned the patients.Staff nurses not involved in the study prepared and administeredamiodarone and study agents. Patients were monitored for 48 h withcontinuous monitoring for the observation of conversion into SR.Patients whose rhythm converted into SR within 48 h were accepted asresponders and those without conversion were accepted as non-responders. Any time when patients had severe symptoms, highventricular rate causing hemodynamic compromise, heart failure ormyocardial ischemia, they underwent electrical cardioversion (EC).Ventricular rate control with beta-blockers or non-dihidropiridinecalcium antagonists was allowed. Electrical cardioversion was per-formed in the fasting state. Propofol was administered for sedation. Rwave-synchronized monophasic direct-current shocks were deliveredin all patients with the step-up protocol of 200, 300, and 360 J withanterolateral approach. Successful cardioversion was defined as thepresence of sinus rhythm lasting≥1 min after the shock. If unsuccessful,2 anteroposterior shocks of 200 and 360 J were applied. Warfarin wasgiven in all the patients to achieve an international normalized ratio of2.0 to 3.0 for four weeks if AF persisted ≥48 h. Heparin was given untilthe international normalized ratio reached to 2.0 to 3.0. A transesopha-gial echocardiography was performed to rule out the possibility ofthrombus in left atrium or left atrial appendage before EC for patientswith POAF lasting ≥48 h. No EC was performed in patients with atrialthrombus. A transthoracic echocardiogram was performed preopera-tively. All surgical procedures were performed in similar fashion in bothgroups. The studyprotocol conforms to the ethical guidelines of the1975Declaration of Helsinki as reflected in a priori approval by theinstitution's human research committee.

Primary endpointwas the conversion rate of POAF into SR for at least1 min within 48 h of the treatment. Secondary endpoints were time toconversion, requirement of EC, cumulative incidence of conversionincluding successful EC procedure attempts and association of oxidativestatus and inflammation markers on the conversion into SR.

Preoperative oxidative status and inflammation markers weremeasured and their relations to sinus rhythm restoration wereevaluated. Total antioxidant capacity (TAC) and total oxidative stress(TOS) were used as markers of oxidative status; and white blood count

⁎ Corresponding author at: Kurtulus Mah, 122. cad. Hatice Halici apt. no: 126, 32040,Isparta, Turkey. Tel.: +90 532 413 9528; fax: +90 246 218 0163.

E-mail address: mehmetozaydin@hotmail.com (M. Ozaydin).

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(WBC) was used as a marker of inflammation. TAC and TOS levels weredeterminedwith newmethods using spectrophotometric kit (Rel AssayDiagnostics, Turkey) [18,19]. The results of TAC and TOS were expressedasmmol Trolox equivalent/L andmmol H2O2 equivalent/L, respectively.The ratio of TOS to TAC was accepted as oxidative stress index.

Continuous variables were expressed as mean±SD and categoricalvariables were expressed as frequency (%). Categorical variables werecompared with chi square test. Kolmogorov–Smirnov test was used totest the distribution of numeric variables and variables with normaldistribution were compared with Student t-test and those withoutnormal distributionwere expressed asmedian andwere comparedwithMann–Whitney U test. Predictors of conversion were determined bylogistic regression analysis. The strength of association betweenvariables and occurrence of successful conversion into SR wasrepresented by odds ratios (ORs) and their accompanying 95%confidence intervals (CIs). Factors with p value b0.10 with univariateanalysis were entered in themultivariate model. Kaplan–Meier analysiswith Log-Rank test was used to compare the probability of conversioninto SR. Calculation of the number of patients needed was based on theassumption of 80% and 40% chance of conversion of POAF into SR in NACgroup and in saline group, respectively. To detect a significance with analpha level of 0.05 and a power of 0.80, 28 patientswere required in eachgroup. A two sided p value b0.05 was considered significant. SPSS 11.0version (Chicago, IL, USA) was used for statistical analyses. The authorsof this manuscript have certified that they comply with the Principles ofEthical Publishing in the International Journal of Cardiology.

Preoperative and postoperative characteristics, procedural profileand levels of the markers of oxidative status and inflammation weresimilar between two groups (All p values N0.05; Table 1). Conversionrate into SR was higher in NAC group compared to saline group

(89.7% vs. 57.6%; p=0.02). Kaplan–Meier analysis showed thatprobability of conversion was higher in the NAC group compared tosaline group (pb0.0001 with Log-Rank test; Fig. 2). No recurrencewas detected in either group after restoration of SR duringhospitalization. Time to conversion was lower in NAC groupcompared with saline group [3 h (0.3–26) vs. 20 h (8–36);(pb0.0001)]. Requirement for EC was higher in saline groupcompared to NAC group (0% vs. 24.2%; p=0.005). No EC wasrequired in NAC group, however; it was required in eight patients inthe saline group. Cumulative incidence of conversion into SRincluding successful EC attempts was also higher in NAC groupcompared with saline group (89.7% vs. 66.7%; p=0.03). Incidence ofliver enzyme elevation was similar between the two groups (BothpN0.05). No other side effects attributable to amiodarone or NACwere detected (Table 2). Significant differences between patientsconverting and not converting into SR were observed in thefollowing parameters: Randomization group, preoperative oxidativestress index and age (All p values pN0.05; Table 3). Univariatepredictors of conversion included preoperative oxidative stressindex, age and NAC group vs. saline group. Multivariate independentpredictors of conversion included preoperative oxidative stressindex, age and NAC group vs. saline group (Table 4).

Main findings: when NAC is added to amiodarone in patients withPOAF, it may facilitate reversion to SR, decrease time to conversionand lower requirement of EC.

Postoperative atrial fibrillation is a common health care problemand its incidence continues to increase despite the use of currentlyavailable prophylactic agents and contemporary surgical techniques[3]. The rhythm can be converted into SR by EC or by pharmacolo-gical agents. The EC is rarely required and since anesthesia is needed,

Assessed for eligibility (n = 75 )

Excluded (n = 13)

Not meeting inclusion criteria

(n = 12)

Declined to participate (n = 1 )

Analysed (n = 29)

Excluded from analysis (n = 0)

Lost to follow-up (n = 0)

Discontinued intervention (n = 0)

Lost to follow-up (n = 0)

Discontinued intervention (n = 0)

Allocated to saline plus amiodarone(n = 33)

Received allocated saline plus amiodarone (n = 33)

Analysed (n = 33)

Excluded from analysis (n = 0)

Analysis

Follow-Up

Randomized (n = 62)

Enrollment

Allocated to NAC plus amiodarone (n = 29)

Received allocated NAC plus

amiodarone (n = 29)

Allocation

Fig. 1. Flow diagram of the patients.

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cardiac surgeons do not prefer their patients to undergo EC. Therefore,pharmacological SR restoration is a viable treatment method. Currentlyrecommend agents for SR restoration have significant side effects andthey are relatively ineffective [1,3,4,20]. Therefore, new agents arerequired.

Patients with AF have increased oxidative stress and inflamma-tion [5–9,21,22]. Anti-oxidant vitamin C attenuated inflammation and

reduced AF incidences [10–12] and conflicting results have beenobtainedwith the administration of anti-oxidantNAC on the preventionof POAF [13–16]. However, to the best of our knowledge, no previousstudy evaluated its efficacy on the restoration of SR. Therefore, the useNAC for conversion of POAF to SR is a novel idea. The present studyshowed that oxidative stress index may block and NAC may facilitateconversion of POAF into SR.

N-acetyl cysteine has anti-inflammatory and anti-oxidant effects[23,24]. It may increase Ito density and may block atrial electricalremodeling [25].

We commenced the study agents as soon as we detected an AFepisode lasting N5 min and we did not wait to observe if spontaneous

Table 1Preoperative and postoperative characteristics, procedural profile and markers ofoxidative status and inflammation.

Characteristics Amiodarone + NAC(n=29)

Amiodarone + saline(n=33)

p

Age (years) 66±10 68±8 0.55Male gender 26 (78.8) 18 (62.1) 0.17Heart failure 3 (10.3) 4 (12.1) 1Stable angina pectoris 13 (44.8) 14 (42.4) 1Unstable angina pectoris/myocardial infarction

16 (55.2) 19 (57.6)

Body mass index (kg/m2) 25 (18–40) 27 (18–44) 0.95#Ejection fraction (%) 45 (25–65) 50 (30–65) 0.09#Left atrial diameter (mm) 43 (34–54) 43 (32–50) 0.34#Preoperative medicationsACEI and/or ARB 11 (37.9) 12 (36.4) 1Spironolactone 5 (17.2) 6 (18.2) 1Statin 6 (20.7) 11 (33.3) 0.39Beta-blocker 29 (100) 33 (100) 1

Procedure performed 1CABG 26 (89.7) 30 (90.3)CABG+valve surgery 3 (10.3) 3 (9.1)

Beating heart surgery (%) 11 (37.9) 12 (36.4) 1Cross-clamp duration (min) 59±21 69±23 0.18By-pass duration (min) 110±44 128±40 0.11Postoperative medicationsACEI and/or ARB 2 (7.1) 4 (12.9) 0.67Spironolactone 2 (6.9) 2 (6.1) 1Statin 3 (10.7) 8 (24.2) 0.19Beta blockers 27 (100) 27 (87.1) 0.12

Preoperative TAC(mmol Trolox equivalent/L)

1.62±0.58 1.44±0.42 0.18

Preoperative TOS(mmol H2O2 equiv./L)

23.05±7.09 22.26±6.4 0.66

Preoperative oxidative stressindex

16.18±7.55 16.65±6.46 0.80

Preoperative WBC (/mm3) 8270±2190 7900±1880 0.49

Data presented as mean±SD, number (%) of patients or median (minimum–maximum).Abbreviations: NAC, N-acetyl cysteine; ACEI, angiotensin converting enzyme inhibitor;ARB, angiotensin receptor blocker; CABG, coronary artery by-pass graft; TAC, totalantioxidant capacity; TOS, total oxidative stress; H2O2, hydrogen peroxide; WBC, whiteblood count. #Mann–Whitney U test.

Fig. 2. Probability of conversion of postoperative atrial fibrillation into sinus rhythm.

Table 2Follow-up findings.

Characteristics Amiodarone+NAC(n=29)

Amiodarone+saline(n=33)

p

Conversion into SR 26 (89.7) 19 (57.6) 0.02Time to conversion intoSR (h)

3 (0.3–26) 3 (0.3–26) 20 (8–36) b0.0001

Need for EC 0 8 (24.2) 0.005Cumulative incidence ofconversion into SRincluding successful EC

26 (89.7) 22 (66.7) 0.03

Required energy forelectrical cardioversion(Joule)

– 360 (200–360)

Liver enzyme elevationof 3× ULN

4 (13.8) 4 (12.1) 1

Data presented as mean±SD or number (%) of patients. Abbreviations: NAC, n-acetylcysteine; SR, sinus rhythm; EC, electrical cardioversion; ULN, upper limit of normal.

Table 3Comparison of patients with and without conversion into sinus rhythm.

Characteristics No conversion intosinus rhythm(n=17)

Conversion intosinus rhythm(n=45)

p

Randomization group, n (%)Amiodarone plus saline 14 (82.4) 19 (42.2) 0.009Amiodarone plus NAC 3 (17.6) 26 (57.8)

Preoperative TAC(mmol Trolox equivalent/L)

1.32±0.30 1.60±0.55 0.055

Preoperative TOS(mmol H2O2 equiv./L)

26 (14.5–29) 21 (5–38) 0.06 #

Preoperative oxidative stress index 19.91±5.20 15.08±7.08 0.02Preoperative WBC (/mm3) 7829±2000 8173±2047 0.56Stable angina pectoris, n (%) 5 (29.4) 22 (48.9) 0.25Unstable angina pectoris/MI, n (%) 12 (70.6) 23 (51.1)Heart failure, n (%) 2 (11.8) 5 (11.1) 1Preoperative treatment, n (%)Spironolactone 3 (17.6) 8 (17.8) 1Statin 3 (17.6) 18 (25.4) 0.35ACEI/ARB 5 (29.4) 18 (40) 0.56Beta-blockers 17 (100) 45 (100) 1

Postoperative treatment, n (%)Spironolactone 2 (13.3) 2 (4.5) 0.24Statin 3 (20) 8 (18.2) 1ACEI/ARB 2 (11.8) 4 (9.1) 0.62Beta-blockers 12 (85.7) 42 (95.5) 0.24

Operation performed, n (%)CABG only 14 (82.4) 42 (93.3) 0.3CABG+valve surgery 3 (17.6) 3 (6.7)

Beating heart surgery, n (%) 5 (29.4) 18 (40) 0.56Age (years) 71 (60–84) 68 (42–83) 0.02 #Male gender, n (%) 11 (67.4) 33 (73.3) 0.54Body mass index (k/m2) 25.7 (22–33) 25.5 (18–44) 0.89 #Ejection fraction (%) 49.7±11.9 44.9±11.5 0.15Left atrial diameter (mm) 43.1±3.2 42.6±4.2 0.66Cross-clamp duration (min.) 70.9±26 61.7±21.0 0.23By-pass duration (min.) 131±38 115±43 0.18

Data presented as mean (SD), number (%) of patients or median (minimum–maximum).Abbreviations: As in Table 2. # Mann–Whitney U test.

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conversion occurs. Although it was a pilot study, population size wassmall. Therefore, larger studies are required.

When added to amiodarone, NAC may be an effective agent forconversion of POAF into SR.

The authors would like to thank Daiichi-Sankyo Co. for the provisionof kits for TAC and TOS.

References

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0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.http://dx.doi.org/10.1016/j.ijcard.2012.09.031

Table 4Predictors of conversion into sinus rhythm.

Predictor Odds ratio Confidence Interval p

Univariate predictorsPreoperative oxidative stress index 0.9 0.82–0.99 0.023Age of the patients 0.9 0.84–0.98 0.018NAC vs. saline 6.39 1.6–25.39 0.008

Multivariate predictorsPreoperative oxidative stress index 0.88 0.78–0.99 0.03Age of the patients 0.9 0.83–0.99 0.04NAC vs. saline 8.66 1.65–45.29 0.01

Abbreviations: NAC, n-acetyl cysteine.

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