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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 3  |  Page : 116-121

Benefits of preoperative use of statins in minimizing the incidence of postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting surgery for unstable angina


1 Department of Anaesthesia and Surgical Intensive Care, Alexandria University Hospitals, Alexandria, Egypt
2 Department of Cardiology, Alexandria University Hospitals, Alexandria, Egypt
3 Department of Anaesthesia and Surgical Intensive Care, Damanhur Teaching Hospital, Damanhur, Egypt

Date of Submission09-Nov-2015
Date of Acceptance24-May-2016
Date of Web Publication4-Nov-2016

Correspondence Address:
Mohamed S Elhadidy
Department of Anesthesia, Alexandria University Hospital, Alexandria, 21648
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2356-9115.193410

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  Abstract 

Background
Several drug therapies and perioperative techniques have been proposed to prevent episodes of atrial fibrillation (AF) after cardiac surgery. Preoperative preparation and evaluation by the anesthesiologist in conjugation with the cardiologist and the surgeon is a new important role. These conjugations augment preoperative treatment and reduce much of the perioperative morbidity and mortality.
Aim
The aim of this work was to assess preoperative use of two regimens of statins in minimizing the incidence of postoperative AF in patients undergoing coronary artery bypass grafting operation.
Patients and methods
Written informed consent was obtained from all patients before the operation as regards their acceptance to be subjected to the procedure after a full explanation of its benefits and potential risks. Diagnosis of unstable angina was confirmed and patients were randomly allocated into three equal groups using the closed envelop method, according to the statin management protocol. Group I (n=15) (the control group) included patients who did not receive any statins before the operation. Group II included (n=15) patients who received atorvastatin 80 mg orally once daily starting 7 days before operation (including the morning of the operation). Group III (n=15) included patients who received atorvastatin 80 mg orally once on the day before the operation and in the morning of the day of the surgery. On the first postoperative day, all patients received atorvastatin 40 mg orally once daily and continued for 30 days postoperatively. Incidence of postoperative in-hospital AF was assessed. AF is defined as episodes of AF that lasted more than or equal to 5 min that was registered by the monitoring system and/or on a rhythm strip or 12-lead ECG and the incidence of episodes that required intervention for angina or hemodynamic compromise.
Results
There was no significant difference between the three groups as regards the incidence, onset, and duration of in-hospital AF (P>0.05). There were no reported cases of AF after discharge from the hospital until day 30 postoperatively (12-lead ECG was performed during every outpatient visit and on day 30 postoperatively). Moreover, there was a significantly decreased incidence of AF on increasing the duration of preoperative statin use (studied using the Mann–Whitney test).
Conclusion
The incidence of postoperative AF reduced in patients who received atorvastatin 80 mg for 7 days before operation. However, two doses of atorvastatin 80 mg before operation failed to reduce the incidence of postoperative AF.

Keywords: atrial fibrillation, coronary artery bypass grafting surgery, statins


How to cite this article:
Afifi MK, Omar SY, Sobhy MA, Elhadidy MS, El-Taweel TM. Benefits of preoperative use of statins in minimizing the incidence of postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting surgery for unstable angina. Res Opin Anesth Intensive Care 2016;3:116-21

How to cite this URL:
Afifi MK, Omar SY, Sobhy MA, Elhadidy MS, El-Taweel TM. Benefits of preoperative use of statins in minimizing the incidence of postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting surgery for unstable angina. Res Opin Anesth Intensive Care [serial online] 2016 [cited 2020 Jun 4];3:116-21. Available from: http://www.roaic.eg.net/text.asp?2016/3/3/116/193410


  Introduction Top


Open heart surgery became a standard practice throughout the world and indeed it saved the lives of millions of people [1].

Preoperative preparation and evaluation by the anesthesiologist in conjugation with the cardiologist and the surgeon is a new important role. These conjugations augment preoperative treatment and reduce much of the perioperative morbidity and mortality. In recent years, there has been an increased emphasis on the role of anesthesiologists as perioperative physicians. By virtue of training and experience, anesthesiologists are perioperative physicians; the scope of their practice includes preoperative evaluation and preparation, intraoperative anesthetic and medical management, and acute postoperative care [2].

Despite advances in cardiopulmonary bypass (CPB) technology and myocardial protection during surgery, the mortality and morbidity of patients undergoing coronary artery bypass grafting (CABG) is still high, especially in patients with unstable angina. Much of the increased perioperative morbidity and mortality is due to arrhythmia, myocardial infarction (MI), and renal insufficiency [2].

Atrial fibrillation (AF), which is frequent after cardiac surgery may lead to prolonged ventilatory and inotropic support, significant morbidity, and increased length of hospital stay and costs. Several drug therapies and perioperative techniques have been proposed to prevent episodes of AF after cardiac surgery, but its incidence remains high, occurring in 10–65% of patients [3].

The causes and pathogenesis of this complication are multifactorial and are related to technical intraoperative factors and to a multitude of clinical factors. Recently, inflammatory mechanisms have also been discovered to be involved [3].

Significant cholesterol reductions may be produced by the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, commonly named statins. It is implicit that the beneficial effect of statins on coronary events is related to their hypocholesterolemic properties. However, the immediate product of 3-hydroxy-3-methylglutaryl-CoA reductase, mevalonic acid, is not only the substrate for cholesterol synthesis but also the precursor of isoprenoids and other metabolites involved in different cellular pathways of atherogenesis and thrombosis [4].

Statins stabilize and reduce inflammatory cells located in the fibrous cap, as well as the lipid core of the atheromatous plaque, and reduce the possibility of plaque rupture. Fatal postoperative MIs are secondary to plaque rupture and oxygen demand/supply mismatch [5].

In this study, atorvastatin was chosen because it differs from other statins in its potency, which lies in its ability to inhibit the activation of nuclear factor-κ β-signaling in human monocytes. Atorvastatin also reduces the procoagulant activity of monocytes in whole human blood, supporting the hypothesis that some statin medications inhibit the inflammatory response more than others [6].


  Patients and methods Top


A prospective randomized controlled study was carried on 45 adult patients with unstable angina undergoing elective CABG surgery at the Alexandria Main University Hospital.

Approval of the ethical committee was obtained before conduction of the study. Written informed consent was obtained from all patients before the operation as regards their acceptance to be subjected to the procedure after a full explanation of its benefits and potential risks.

Patients were randomly allocated into three equal groups using the closed envelop method, according to the statin management protocol. Group I (n=15) (the control group) included patients who did not receive any statins before the operation. Group II (n=15) included patients who received atorvastatin 80 mg orally once daily starting 7 days before operation (including the morning of the operation). Group III (n=15) included patients who received atorvastatin 80 mg orally once on the day before the operation and in the morning of the day of the surgery.

On the first postoperative day, all patients received atorvastatin 40 mg orally once daily and were continued on it for 30 days postoperatively. All patients were interviewed by the anesthesiologist for a detailed history and physical examination. The following routine investigations were carried out: complete blood count; bleeding and clotting times; prothrombin time and partial thromboplastin time; urea and creatinine levels; serum Na+ and K+ levels; aspartate aminotransferase and alanine aminotransferase levels; serum albumin and total protein; fasting blood sugar; serum cholesterol and lipid profile; urine analysis; plain chest radiograph; ECG; transthoracic echocardiography; and cardiac catheterization.

All patients were monitored using standard monitors (five-lead ECG, pulse oximetry, end-tidal cabnogram, noninvasive arterial blood pressure, and nasopharyngeal temperature) and specialized monitors (invasive arterial blood pressure and central venous pressure). Serial arterial blood sampling was carried out for determination of blood pH, arterial partial pressure of oxygen (mmHg), arterial partial pressure of carbon dioxide (mmHg), serum bicarbonate (meq/dl), hematocrit, serum sodium, and potassium concentrations (meq/dl). Urine output was assessed through a foley catheter.

Anesthesia was induced using intravenous fentanyl 5–10 µg/kg followed by intravenous propofol at a dose of 1 mg/kg (guided by hemodynamics) and rocuronium at a dose of 0.6–0.9 mg/kg. Anesthesia was maintained with 50% oxygen and isoflurane 1–1.5 minimum alveolar concentration. Fentanyl and rocuronium were given according to patient’s needs.

All operations were performed by experienced cardiac surgeons using standard techniques. During CPB, hematocrit was maintained between 20 and 25%, and pump flows were kept between 2.0 and 2.5 l/min m−2 to maintain mean arterial pressure between 50 and 70 mmHg. All patients were cooled to moderate hypothermia (mean 32°C), and cardioplegic arrest was achieved with cold blood cardioplegia (4°C) infused into the ascending aorta. No patient received retrograde cardioplegia. Heparin was given at a dose of 300 IU/kg to obtain an activated clotting time more than 400 s, on completion of anastomoses. Heparin effects were reversed with intravenous protamine sulfate (1 mg/300 IU of heparin) to achieve an activated clotting time similar to preoperative values. All anastomoses were sutured by hand.

After separation of CPB and according to hemodynamics, inotropes and/or vasoactive drugs (vasoconstrictor or vasodilator) were added accordingly.

During the postoperative care, all patients were transferred to the ICU, intubated, and were on mechanical ventilation. The standard and special monitoring previously mentioned was carried out continuously during the ICU stay. Fluid intake and output, including drainage tubes, were monitored hourly and when needed. All patients remained in the ICU until weaning from mechanical ventilation and successful extubation. From the ICU, patients were transferred to a monitored unit, where three-lead monitoring was performed continuously for at least 6 days after the operation; in addition, patients were subjected to a 12-lead ECG daily (and when indicated) until hospital discharge.

Those patients who developed AF during their stay in the ICU or after discharge were managed in the ICU under close monitoring. All patients who developed AF were treated with intravenous amiodarone (bolus 5 mg/kg followed by infusion 15 mg/kg/24 h). Patients were discharged from the ICU after regaining sinus rhythm and were discharged with instructions to undergo oral amiodarone therapy for at least 30 days. Patients were scheduled for weekly visits in the outpatient clinic for the first month, where 12-lead ECG was performed.

ECG strip was obtained preoperatively, after immediate postoperative admission to the ICU, daily from day 1 until day 7 postoperatively, on day 30 postoperatively (in the outpatient clinic), and when indicated for all patients. Incidence of postoperative in-hospital AF was defined as episodes of AF that lasted more than 5 min that was registered by the monitoring system and/or on a rhythm strip or 12-lead ECG.

Statistical analysis

Data were fed to the computer using IBM SPSS software package (Chicago, Tribune, USA), version 20.0.

Qualitative data were described using number and percent. Comparison between different groups as regards categorical variables was tested using the χ2-test. When more than 20% of the cells had expected count less than 5, correction for χ2 was conducted using Fisher’s exact test or Monte Carlo correction.

The distributions of quantitative variables were tested for normality using the Shapiro–Wilk test and the D’Agstino test. Moreover, histogram and QQ plot were used for vision test. If they revealed normal data distribution, parametric tests were applied. If the data were abnormally distributed, nonparametric tests were used.

Quantitative data were described using mean and SD for normally distributed data, whereas abnormally distributed data were expressed using median, minimum, and maximum.

For normally distributed data, comparison between two independent populations was made using the independent t-test, whereas more than two populations were analyzed using F-test (analysis of variance) and post-hoc test (lysergic acid diethylamide); the paired t-test was also used to analyze two paired data, comparison between different periods using analysis of variance with repeated measures, and post-hoc test was assessed using Bonferroni adjusted.

For abnormally distributed data, the Mann–Whitney test (for data distribution that was significantly deviated from normal) was used to analyze two independent populations. If more than two populations were analyzed, the Kruskal–Wallis test was used. To compare the different periods the Friedman test and the Wilcoxon signed-rank test were used. Correlations between two quantitative variables were assessed using Spearman coefficient.

Univariate and multivariate logistic regression were assessed.

Significance test results are quoted as two-tailed probabilities. Significance of the obtained results was judged at the 5% level.


  Results Top


In this study, there was no significant difference as regards age, sex, incidence of hypertension, and diabetes mellitus. There was no significant difference as regards intraoperative variables such as anesthetic technique, duration of cross clamping, duration of CPB, and number of coronary artery grafts.

The incidence of postoperative in-hospital AF was 40, 6.6, and 13.3% in group I, II, and III, respectively.

The mean onset of in-hospital AF was 25.0±15.38, 72, and 24 h postoperatively in patients of group I, II, and III, respectively.

The mean duration of in-hospital AF was 14.67±8.55, 12, and 15.0±12.73 h in patients of group I, II, and III, respectively.

Statistically, there was no significant difference between the three groups as regards the incidence, onset, and duration of in-hospital AF (P>0.05) [Figure 1] and [Figure 2].
Figure 1: Incidence of postoperative inpatient atrial fibrillation in the three studied groups. AF, atrial fibrillation.

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Figure 2: Mean duration of postoperative in-hospital atrial fibrillation in the three studied groups. AF, atrial fibrillation.

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There were no reported cases of AF after discharge from the hospital until day 30 postoperatively (12-lead ECG was performed during every outpatient visit and on day 30 postoperatively).

The relation between the incidence of in-hospital AF and the preoperative atorvastatin use in the entire studied population (n=45) was significantly decreased on increasing the duration of preoperative statin use (studied using the Mann–Whitney test). The incidence of AF in the entire study population (n=45 patients) was 13.3, 4.4, and 2.2% in patients of group I (statin 0), group III (statin 1), and group II (statin 2), respectively [Figure 3].
Figure 3: Incidence of postoperative in-hospital atrial fibrillation in relation to preoperative atorvastatin use in all studied patients (n=45). AF, atrial fibrillation.

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  Discussion Top


Statins are being used in a number of clinical situations where inflammation may affect the improvement in the outcome of patients undergoing CABG. Systemic inflammatory response occurs frequently after coronary artery bypass surgery, and it is strongly correlated with the risk for postoperative morbidity and mortality.

Several factors may contribute to the development of AF after cardiac surgery through alterations in atrial refractoriness and/or local re-entry: operative trauma, rise in atrial pressure due to postoperative ventricular stunning, increase in atrial electrical susceptibility from rapid return of temperature after cardioplegic arrest, atrial distension by fluid overload, chemical stimulation during infusion of inotropic drugs, reflex sympathetic activation, and pericardial or respiratory complications [7].

This study is one of the few prospective studies to assess the effect of high dose of atorvastatin on the incidence of postoperative AF. The percent of patients who had postoperative AF (n=9) in the population studied (n=45) was 20%.

Atorvastatin 80 mg for 7 days before surgery (group II) reduced the incidence of postoperative AF by ∼6 times less than that in the control group (group I).

Atorvastatin 80 mg for two consecutive doses before surgery (group III) reduced the incidence of postoperative AF by ∼3 times less than that in the control group (group I). The percent was 4.4% in group III and 13.4% in group I. However, the difference in the incidence of AF between the three groups did not reach statistical significance.

It has been suggested that statins may have a protective role against AF in postoperative patients through a statin-induced autonomous nervous system modulation against the enhanced postoperative sympathetic activity [8], which increases the susceptibility to AF [9]. This could represent an alternative antiarrhythmic mechanism of statins against AF in such patients.

Clinical studies have also explored the possible role of inflammatory mechanisms in the pathogenesis of AF after cardiac surgery [10][13]. Other data from clinical trials showed that cytokine release, leukocyte–endothelial adhesion, and levels of circulating adhesion molecules after cardiac surgery with CPB are attenuated in patients receiving statins [14],[15].

Patti and colleagues (ARMYDA 3) in a prospective randomized controlled study showed a significant reduction in the incidence of post-CABG surgery in-hospital AF in patients (n=101) who received preoperative 40 mg atorvastatin for 7 days versus placebo (n=99). They also related the incidence of AF to the rise in CRP (inflammatory marker). Thus, it is in agreement with our study. They suggested that higher inflammatory status is an important factor in the development of postoperative AF [16].

Meta-analysis of 30 000 patients undergoing cardiac surgery by Liakopoulos et al. [17] showed a significant reduction in the incidence of postoperative new-onset AF in patients who received preoperative statins.

Elahi et al. found in their review that the inflammatory factors and oxidative stress (reperfusion injury) play a major role in the pathogenesis of postcardiac surgery AF. They also concluded that preoperative uses of statin reduce the incidence of postcardiac surgery AF through its anti-inflammatory and antioxidant effects [18].

Kourliouros and colleagues showed in their cohort study a significant dose-dependent reduction in the incidence of AF in 623 patients (who received preoperative statin at different doses) undergoing CABG and/or aortic valve replacement. They found a significant reduction in the incidence of AF in the statin group versus the non-atorvastatin group. Moreover, this reduction was more significant in patients who received atorvastatin 40 mg than those of received 20 mg. However, there was no significant reduction in patients who received atorvastatin 10 mg [19].

Kourliouros and colleagues in a prospective randomized study, showed a nonsignificant reduction in the incidence of postoperative in-hospital AF in patients (n=104) who underwent CABG and valvular surgeries. Patients were receiving a regular dose of statin and were randomized to receive atorvastatin 80 mg or atorvastatin 10 mg for 7 days before surgery in a single-blind manner [20]. In contrast to our study, they found no difference between high and low doses of atorvastatin. This contrast could be explained by the higher incidence of β-blocker usage in their low-dose group, higher incidence of previous MI in their high-dose group, and valvular surgeries that may be associated with a higher incidence of AF.

Miceli et al. [21] showed in a retrospective study conducted on patients (n=8946) who received statins before isolated CABG surgery versus the control group that the incidence of new-onset post-CABG AF was significantly higher in the statin group than in the control group. There were no data in this study about the dose, the type, or the duration of statins given to these patients. Moreover, there was lack of information on perioperative β-blocker use, unreported or undiagnosed episodes of postoperative AF, chronic inflammatory disease, or postoperative variables such as volume overload or electrolyte imbalance (e.g. hypokalemia).


  Conclusion Top


The current study showed that the incidence of postoperative AF is reduced in patients who received atorvastatin 80 mg for 7 days before operation. However, atorvastatin 80 mg for two doses before operation failed to reduce the incidence of postoperative AF.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Pillarisetti J, Patel A, Bommana S, Guda R, Falbe J, Zorn GT et al. Atrial fibrillation following open heart surgery: long-term incidence and prognosis. J Interv Card Electrophysiol 2014;39:69–75.  Back to cited text no. 1
    
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[PUBMED]  Medknow Journal  
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Gaudino M, Andreotti F, Zamparelli R, Di Castelnuovo A, Nasso G, Burzotta F et al. The −174 G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication?. Circulation 2003;108:195–199.  Back to cited text no. 13
    
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