**4.1 HMG Co-A reductase inhibitors**

214 Special Topics in Cardiac Surgery

patients with congenital long QT syndrome or a baseline corrected QT interval greater than 440 msec. Due to its beta-blocking properties, sotalol is contraindicated in patients intolerant of beta-blockers. Because of the aforementioned limitations of this agent, sotalol has been granted a class IIb recommendation for POAF prophylaxis behind beta-blockers according to the ACC/AHA/ESC 2006 AF Guidelines and the ACC/AHA 2004 CABG Guidelines (Fuster et al., 2006; Eagle et al., 2004). The most recent 2010 ESC guidelines have assigned a Class IIb recommendation for sotalol due to its proarrhythmic risk (ESC, 2010). However, the earlier 2006 EACTS guidelines gave sotalol a stronger grade A recommendation based upon its comparative efficacy trials versus beta-blockers (Dunning et al., 2006) similar to

Patel and Dunning evaluated seven different randomized trials comparing sotalol to conventional beta blockers (Patel et al., 2005). Out of the seven trials evaluated, five studies demonstrated a statistically significant reduction in POAF for those patients assigned to sotalol compared to conventional beta-blockade. The number of patients needed to be treated with sotalol to prevent POAF over that of conventional beta-blocker therapy was found to be 10. Conversely, because of the pro-arrythmic properties of sotalol, conventional

POAF has been associated with decreased postoperative magnesium levels (Kalman et al., 1995). In fact, plasma magnesium concentration levels less that 0.9 mmol have been found to be an independent predictor of POAF (OR 6.7) when using multivariate logistic regression models (Treggiari-Venzi et al., 2000). Multiple large, randomized, controlled trials with magnesium have failed to demonstrate superiority to usual care with no magnesium in the prevention of POAF. These trials included various delivery forms of magnesium including: IV infusion (Treggiari-Venzi et al., 2000; Serafimovski et al., 2008; Caspie et al., 1995; Bert et al., 2001; Zangrillo et al., 2005), IV infusion based on serum levels (Wilkes et al., 2002), magnesium supplementation in maintenance fluids (Colquhoun et al., 1993) and in supplementation through cardioplegia solution (Shakerinia et al., 1996). Surprising lower cumulative doses of magnesium supplementation (mean cumulative dose 8.2 g) have shown to be more effective in reducing the incidence of POAF (OR 0.36, 95% CI 0.23-0.56), compared to higher doses (mean cumulative dose 15 g) (OR 0.99, 95% CI 0.70-1.41) (Henyan et al., 2005). Results from the same meta-analysis found that preoperative administration of magnesium was more effective at decreasing the incidence of POAF (OR 0.46, 95% CI 0.31- 0.67) compared to intraoperative or postoperative administration. Results from several meta-analysis (Woodend et al., 1998; Burgess et al., 2006; Shiga et al., 2004; Miller et al., 2005; Alghamdi et al., 2005; Henyan et al., 2005; Shepard et al., 2008) have shown inconsistent efficacy with magnesium use. A few studies have demonstrated a significant benefit of magnesium when compared to usual care with absolute reductions in the incidence of POAF by 16% to 34% (Nurozler et al., 1996; Maslow et al., 2000; Kohno et al., 2005). However, at this time there is a lack of statistically significant data to support magnesium supplementation as monotherapy compared to that of beta-blocker, amiodarone, or sotalol therapy in the treatment of POAF (Bert et al., 2001; Solomon et al., 2000; Cagli et al., 2006). Only the CCS consensus statement includes magnesium as a Class IIa recommendation, however no other guidelines strongly recommend its use for the prevention POAF (Kerr & Roy, 2004). Magnesium therapy may be considered in combination with amiodarone and/or B-blocker therapy for those patients deemed at high risk or intolerant to the latter

ACC recommendations.

**3.1.4 Magnesium** 

beta-blocker therapy may be a safer option.

HMG Co-A reductase inhibitors (statins) may possess pleiotropic activity beyond lipid lowering effects and may be protective against POAF. They have been shown to reduce oxidative stress by inhibiting oxidant enzymes, up-regulate antioxidant enzymes, and enhance nitric oxide bioavailability (Paraskevas, 2008). It is also proposed that they possess direct antiarrhythmic effects mediated through cell membrane stabilization, downregulation of the renin-angiotensin-aldosterone-system (RAAS), and protection of ischemic myocardium (Howard & Barnes, 2008). They also have been shown to reduce the expression of inflammatory mediators (i.e. interleukin-6 **(**IL-6), interleukin-8 **(**IL-8), tumor necrosis factor- α (TNF-α), C-reactive protein (CRP), cyclooxygenase 2) and decrease the expression of CD11b with consequential decreased adherence to endothelial cells of vein grafts (Chello et al., 2006; Patel et al., 2007). Therefore, statins may favorably impact the acute inflammatory response and alter atrial refractoriness or sympathetic activation that could lead to POAF after cardiac surgical procedures.

Many trials have evaluated the effect of statins on the incidence of POAF in cardiac surgery patients. Prospective, randomized trials found an absolute reduction in the incidence of POAF of 14% to 22% with statins compared to placebo or usual care (Chello et al., 2006; Patti et al, 2006; Song et al., 2008; Ji et al., 2009). The largest and most robust of these three trials was the Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery study (ARMYDA-3) in which a significant reduction in POAF of 22% and a reduction in LOS of 0.6 days was observed with a statin compared to placebo (Patti et al., 2006). This study enrolled only patients who had no previous history of statin use and these patients could have less risk of pre-existing atherosclerotic disease and subsequently been at lower risk for developing POAF.

Other statin trials in CABG patients are observational, cohort studies with conflicting results of no benefit (Thielmann et al., 2007; Mithani et al., 2009) or a significant reduction in the incidence of POAF (Lertsburapa et al., 2008; Subramaniam et al., Mariscalco et al., Ozaydin et al., 2007; Miceli et al., 2009a; Kinoshita et al., 2010).

One study evaluated the combination of a statin and beta-blocker on the incidence of POAF. Monotherapy with atorvastatin or a beta-blocker reduced the risk of POAF by 61% (OR 0.39; 95% CI 0.18-0.85) and 82% (OR 0.19; 95% CI 0.08-0.44), respectively. However, the combination of atorvastatin plus a beta-blocker performed better by reducing the risk of POAF by 90% (OR 0.10; 95% CI 0.02-0.25) (Patti et al., 2006). The combination of preoperative and postoperative beta-blocker and amiodarone prophylaxis in 40% of patients may have also influenced the positive results in the statin group (Lertsburapa et al., 2008).

Strategies for the Prevention of Postoperative Atrial Fibrillation in Cardiac Surgery 217

non-familial atrial fibrillation (Tsai et al., 2004), further supporting the role RAAS plays in the development of atrial fibrillation. ACEIs and ARBs have been shown to reduce the incidence of atrial fibrillation in patients with congestive heart failure, hypertension, or post

Three potential mechanisms have been suggested to explain the antiarrhythmic benefits of ACEIs and ARBs against atrial fibrillation. It is proposed that they improve left ventricular hemodynamics, reduce atrial stretch, suppress angiotensin-induced fibrosis, and direct modulation of potassium and calcium ion channel function. These ACEI/ARB-induced changes decrease atrial vulnerability and may diminish the initiation of atrial fibrillation

Few prospective, controlled studies have been conducted to assess the efficacy of ACEIs or ARBs in reducing the incidence of POAF in cardiac surgery patients (White et al., 2007a; Ozaydin et al., 2008a). One study randomized patients to an active intervention of ACEI or combination of ACEI/ARB and then compared these two treatment groups to a historical control. Greater than 85% of patients randomized to ACEI or combination were also on betablockers preoperatively and 97% of patients in the historical control group were on betablockers (Ozaydin et al., 2008a). Despite the high percentage of preoperative beta-blocker use in the control group, the combination of an ACEI/ARB or an ACEI alone proved superior to usual care with absolute reductions in the incidence of POAF compared to controls by 23% and 21%, respectively. There was no difference in the magnitude of the reduction of the incidence of POAF using the combination of an ACEI/ARB compared to an ACEI alone. The authors also found that both the combination ACEI/ARB or ACEI alone significantly reduced the risk of POAF by 72% and 66%, respectively (RR 0.28; 95% CI 0.09- 0.83 and RR 0.34; 95% CI 0.12-0.93, respectively). The other study examined the effect of ACEI or ARBs on development of POAF from a nested cohort of patients from the AFIST II and III trials (White et al., 2007a). This study also found that preoperative use of ACEIs or ARBs were protective in reducing the risk of POAF by 29%, however the magnitude of the reduction was not statistically significant (adjusted OR 0.71; 95% CI 0.42-1.20). The clinical reduction in risk of POAF in patients on ACEIs or ARBs could have been influenced by 84% of the total population of patients receiving postoperative beta-blockade and 38% receiving amiodarone for POAF prophylaxis, therefore it remains unclear from that study the independent effect ACEIs or ARBs on POAF. Multivariate logistic regression analysis found that postoperative beta-blocker (adjusted OR 0.47, 95%CI 0.24-0.89) and prophylactic amiodarone (adjusted OR 0.32, 95%CI 0.18-0.57) were both negative predictors of POAF,

thus decreasing the risk for POAF by 53% and 68%, respectively (White et al., 2007a).

Cohort studies conducted to evaluate the risk factors associated with the development of POAF in cardiac surgery patients found that preoperative and postoperative use of ACEIs or ARBs decreased the risk of POAF by 38% (OR 0.62; 95% CI 0.48-0.79; p<0.001) and that withdrawal of ACEI or ARB increases the risk of POAF by 1.7 times (OR 1.69; 95% CI 1.38- 2.08; p<0.001) (Mathew et al., 2004) while another study in cardiac surgery patients with EF ≤ 50% confirmed this association that both ACEIs decreased the risk of POAF by 73% (OR 0.27, 95% CI 0.12-0.62, p=0.002) and ARBs by 79% (OR 0.21; 95% CI 0.07-0.62, p=0.005) (Ozaydin et al., 2010). Unfortunately, three other cohort studies did not confirm a protective effect of ACEIs or ARBs with no significant reduction in the risk of POAF compared to controls (Coleman et al., 2007; Miceli et al., 2009b; Rader et al., 2010). The largest of these cohort studies, evaluating over 10,000 patients, found that preoperative ACEI doubled the risk of death (OR 2.00, 95% CI 1.17-3.42; p= 0.013) and that preoperative ACEIs were an independent predictor of mortality (p = 0.04), postoperative renal dysfunction (p= 0.0002), use of inotropic drugs (p < 0.0001), and new onset POAF (p < 0.0001). (Miceli et al., 2009b) A

MI (Makkar et al., 2009).

(Erlich et al., 2006).

A few studies have been conducted to determine the optimal prophylactic dose of statins. Kourlioros et al found that simvastatin 40 mg and atorvastatin 40 mg had the greatest effect on POAF (Kourlioros et al., 2008). Simvastatin 20 mg and atorvastatin 20 mg maintained efficacy compared to control, but no difference was found at 10 mg or 80 mg of either drug. Lertsburapa et al analyzed patients by converting their statin dose to atorvastatin equivalents. Relative statin doses ≥40 mg of atorvastatin resulted in the greatest reduction in POAF by 55% (OR 0.45; 95% CI 0.21-0.99) (Lertsburapa et al., 2008). The 20 mg atorvastatin dose still showed a significant benefit (OR 0.6; 95% CI 0.23-0.99), while the < 20 mg dose showed no significant benefit (OR 0.75; 95% CI 0.47-1.20). Mithani et al found in their multivariate analysis that POAF was less common among patients taking higher doses of statins compared to those taking simvastatin < 20 mg/day (28% versus 34%, p=0.03). (Mithani et al., 2009) Comparing statins, only one prospective, observational study found that POAF was less frequent in patients receiving pravastatin compared to atorvastatin (9.5% versus 34.9%, p=0.0257) or no statins (9.5% versus 34.2%, p=0.0025). (Tamura et al., 2010)

A long-term study found that statins' benefit may extend beyond the immediate postoperative period and in outcomes other than POAF. Statins reduced the composite endpoint of death, MI, and unstable angina at both 60 days (OR 0.09; 95% CI 0.01-0.70, p=0.02) and one year post-CABG (OR 0.26; 95% CI 0.015-0.4, p<0.0001) (Dotani et al., 2000). Kaplan-Meier 30 day atrial fibrillation-free survival curves also indicated benefit with statins (Patti et al., 2006; Mariscalco et al., 2007; Ozaydin et al., 2007; Song et al., 2008). One meta-analysis confirmed the protective benefit of preoperative statins for POAF and early all cause mortality. This study also found a significant reduction in the risk of stroke by 26% with statins when compared to controls (OR 0.74; 95% CI 0.60-0.91) (Laikopoulos et al., 2008, Chen et al., 2010). While statins appear to reduce POAF in the short term setting in cardiac surgery patients, a recent meta-analysis found that longer term (≥ 6 months of follow-up) use of statins in cardiac patients was not associated with a significant reduction in AF (OR 0.95; 95% CI 0.88-1.03, p=0.24), however only one of the 22 studies was in CABG patients (Rahimi et al., 2011).

Statins have shown benefit in reducing the risk of POAF, LOS, mortality, and 30 day atrial fibrillation-free survival. It is less clear which statin, what dose, and for what duration will achieve the greatest benefit. While the combination of statins and standard beta-blocker therapy is safe, certain statins, such as simvastatin, should only be used in reduced doses with the combination of amiodarone due to risk of myalgias or rhabdomyolysis (FDA Alert 2008). Larger, prospective, randomized control trials are necessary to confirm that statins are effective in reducing the occurrence of POAF in addition to beta-blockers.

### **4.2 Renin-angiotensin-aldosterone-system (RAAS) modulators**

An increasing number of investigations are being conducted to evaluate the association between the RAAS, the inflammatory process, and atrial fibrillation. Interruption of the RAAS by angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers prevents the production of the regulatory hormone angiotensin II, which plays a key role in controlling blood pressure, vascular smooth muscle tone, aldosterone release, and sodium resorption from the renal tubules (Boos et al., 2006). Beyond these actions, angiotensin II has been implicated in increasing the production of pro-inflammatory cytokines (i.e. IL-6, IL-8, TNF-α), adhesion molecules, selectins, and the recruitment of neutrophils (Boos et al., 2006). Histologic evidence exists that persistent and paroxysmal atrial fibrillation leads to altered angiotensin II receptor expression (Erlich et al., 2006; Boos et al., 2006). Genetic polymorphisms in the angiotensinogen gene are also two to three times more likely to have

A few studies have been conducted to determine the optimal prophylactic dose of statins. Kourlioros et al found that simvastatin 40 mg and atorvastatin 40 mg had the greatest effect on POAF (Kourlioros et al., 2008). Simvastatin 20 mg and atorvastatin 20 mg maintained efficacy compared to control, but no difference was found at 10 mg or 80 mg of either drug. Lertsburapa et al analyzed patients by converting their statin dose to atorvastatin equivalents. Relative statin doses ≥40 mg of atorvastatin resulted in the greatest reduction in POAF by 55% (OR 0.45; 95% CI 0.21-0.99) (Lertsburapa et al., 2008). The 20 mg atorvastatin dose still showed a significant benefit (OR 0.6; 95% CI 0.23-0.99), while the < 20 mg dose showed no significant benefit (OR 0.75; 95% CI 0.47-1.20). Mithani et al found in their multivariate analysis that POAF was less common among patients taking higher doses of statins compared to those taking simvastatin < 20 mg/day (28% versus 34%, p=0.03). (Mithani et al., 2009) Comparing statins, only one prospective, observational study found that POAF was less frequent in patients receiving pravastatin compared to atorvastatin (9.5% versus 34.9%, p=0.0257) or no

A long-term study found that statins' benefit may extend beyond the immediate postoperative period and in outcomes other than POAF. Statins reduced the composite endpoint of death, MI, and unstable angina at both 60 days (OR 0.09; 95% CI 0.01-0.70, p=0.02) and one year post-CABG (OR 0.26; 95% CI 0.015-0.4, p<0.0001) (Dotani et al., 2000). Kaplan-Meier 30 day atrial fibrillation-free survival curves also indicated benefit with statins (Patti et al., 2006; Mariscalco et al., 2007; Ozaydin et al., 2007; Song et al., 2008). One meta-analysis confirmed the protective benefit of preoperative statins for POAF and early all cause mortality. This study also found a significant reduction in the risk of stroke by 26% with statins when compared to controls (OR 0.74; 95% CI 0.60-0.91) (Laikopoulos et al., 2008, Chen et al., 2010). While statins appear to reduce POAF in the short term setting in cardiac surgery patients, a recent meta-analysis found that longer term (≥ 6 months of follow-up) use of statins in cardiac patients was not associated with a significant reduction in AF (OR 0.95; 95% CI 0.88-1.03, p=0.24), however only

Statins have shown benefit in reducing the risk of POAF, LOS, mortality, and 30 day atrial fibrillation-free survival. It is less clear which statin, what dose, and for what duration will achieve the greatest benefit. While the combination of statins and standard beta-blocker therapy is safe, certain statins, such as simvastatin, should only be used in reduced doses with the combination of amiodarone due to risk of myalgias or rhabdomyolysis (FDA Alert 2008). Larger, prospective, randomized control trials are necessary to confirm that statins are

An increasing number of investigations are being conducted to evaluate the association between the RAAS, the inflammatory process, and atrial fibrillation. Interruption of the RAAS by angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers prevents the production of the regulatory hormone angiotensin II, which plays a key role in controlling blood pressure, vascular smooth muscle tone, aldosterone release, and sodium resorption from the renal tubules (Boos et al., 2006). Beyond these actions, angiotensin II has been implicated in increasing the production of pro-inflammatory cytokines (i.e. IL-6, IL-8, TNF-α), adhesion molecules, selectins, and the recruitment of neutrophils (Boos et al., 2006). Histologic evidence exists that persistent and paroxysmal atrial fibrillation leads to altered angiotensin II receptor expression (Erlich et al., 2006; Boos et al., 2006). Genetic polymorphisms in the angiotensinogen gene are also two to three times more likely to have

statins (9.5% versus 34.2%, p=0.0025). (Tamura et al., 2010)

one of the 22 studies was in CABG patients (Rahimi et al., 2011).

effective in reducing the occurrence of POAF in addition to beta-blockers.

**4.2 Renin-angiotensin-aldosterone-system (RAAS) modulators** 

non-familial atrial fibrillation (Tsai et al., 2004), further supporting the role RAAS plays in the development of atrial fibrillation. ACEIs and ARBs have been shown to reduce the incidence of atrial fibrillation in patients with congestive heart failure, hypertension, or post MI (Makkar et al., 2009).

Three potential mechanisms have been suggested to explain the antiarrhythmic benefits of ACEIs and ARBs against atrial fibrillation. It is proposed that they improve left ventricular hemodynamics, reduce atrial stretch, suppress angiotensin-induced fibrosis, and direct modulation of potassium and calcium ion channel function. These ACEI/ARB-induced changes decrease atrial vulnerability and may diminish the initiation of atrial fibrillation (Erlich et al., 2006).

Few prospective, controlled studies have been conducted to assess the efficacy of ACEIs or ARBs in reducing the incidence of POAF in cardiac surgery patients (White et al., 2007a; Ozaydin et al., 2008a). One study randomized patients to an active intervention of ACEI or combination of ACEI/ARB and then compared these two treatment groups to a historical control. Greater than 85% of patients randomized to ACEI or combination were also on betablockers preoperatively and 97% of patients in the historical control group were on betablockers (Ozaydin et al., 2008a). Despite the high percentage of preoperative beta-blocker use in the control group, the combination of an ACEI/ARB or an ACEI alone proved superior to usual care with absolute reductions in the incidence of POAF compared to controls by 23% and 21%, respectively. There was no difference in the magnitude of the reduction of the incidence of POAF using the combination of an ACEI/ARB compared to an ACEI alone. The authors also found that both the combination ACEI/ARB or ACEI alone significantly reduced the risk of POAF by 72% and 66%, respectively (RR 0.28; 95% CI 0.09- 0.83 and RR 0.34; 95% CI 0.12-0.93, respectively). The other study examined the effect of ACEI or ARBs on development of POAF from a nested cohort of patients from the AFIST II and III trials (White et al., 2007a). This study also found that preoperative use of ACEIs or ARBs were protective in reducing the risk of POAF by 29%, however the magnitude of the reduction was not statistically significant (adjusted OR 0.71; 95% CI 0.42-1.20). The clinical reduction in risk of POAF in patients on ACEIs or ARBs could have been influenced by 84% of the total population of patients receiving postoperative beta-blockade and 38% receiving amiodarone for POAF prophylaxis, therefore it remains unclear from that study the independent effect ACEIs or ARBs on POAF. Multivariate logistic regression analysis found that postoperative beta-blocker (adjusted OR 0.47, 95%CI 0.24-0.89) and prophylactic amiodarone (adjusted OR 0.32, 95%CI 0.18-0.57) were both negative predictors of POAF, thus decreasing the risk for POAF by 53% and 68%, respectively (White et al., 2007a).

Cohort studies conducted to evaluate the risk factors associated with the development of POAF in cardiac surgery patients found that preoperative and postoperative use of ACEIs or ARBs decreased the risk of POAF by 38% (OR 0.62; 95% CI 0.48-0.79; p<0.001) and that withdrawal of ACEI or ARB increases the risk of POAF by 1.7 times (OR 1.69; 95% CI 1.38- 2.08; p<0.001) (Mathew et al., 2004) while another study in cardiac surgery patients with EF ≤ 50% confirmed this association that both ACEIs decreased the risk of POAF by 73% (OR 0.27, 95% CI 0.12-0.62, p=0.002) and ARBs by 79% (OR 0.21; 95% CI 0.07-0.62, p=0.005) (Ozaydin et al., 2010). Unfortunately, three other cohort studies did not confirm a protective effect of ACEIs or ARBs with no significant reduction in the risk of POAF compared to controls (Coleman et al., 2007; Miceli et al., 2009b; Rader et al., 2010). The largest of these cohort studies, evaluating over 10,000 patients, found that preoperative ACEI doubled the risk of death (OR 2.00, 95% CI 1.17-3.42; p= 0.013) and that preoperative ACEIs were an independent predictor of mortality (p = 0.04), postoperative renal dysfunction (p= 0.0002), use of inotropic drugs (p < 0.0001), and new onset POAF (p < 0.0001). (Miceli et al., 2009b) A

Strategies for the Prevention of Postoperative Atrial Fibrillation in Cardiac Surgery 219

corticosteroids have been shown to have peak white blood cell counts were higher up to 14 days postoperatively, higher blood glucose and larger insulin requirements (Sano et al., 2006), greater risk of wound and infectious complications (Whitlock et al., 2008). Therefore it may be necessary to avoid corticosteroids in patients with uncontrolled hyperglycemia,

Corticosteroids can target the inflammatory process for the prevention of POAF in patients undergoing cardiac surgery. While some studies found a reduction in the incidence of POAF using corticosteroids as prophylaxis in cardiac surgery patients receiving standard betablocker therapy, there is no consensus on which steroid, dose, and duration has the greatest benefit. Only the 2010 European guidelines recommend corticosteroids for prophylaxis of POAF in cardiac surgery patients and include suggested dosing in dexamethasone equivalent for the prevention of POAF with a Class 2B recommendation, stating however that there is risk associated with using them (ESC, 2010). The most relevant risk in hospitalized patients after cardiac surgery includes steroid-induced hyperglycemia or leukocytosis. Corticosteroids may play a future role in targeting the inflammatory process in patients undergoing cardiothoracic surgery, however larger clinical trials are necessary to confirm if corticosteroids are effective in

The ability of omega-3 fatty acids to reduce the occurrence of POAF is thought to result from a stabilizing effect on the myocardium, anti-inflammatory properties, and possibly antioxidant activity (Kris-Etherton et al., 2002; Korantzopoulos et al., 2006). Calo et al performed a prospective, randomized, open label study in 160 patients assessing the impact of N-3 polyunsaturated fatty acids (PUFA) 2 g/day on the incidence of POAF in cardiac surgery patients (Calo et al., 2005). Approximately 60% of patients in both groups were on preoperative beta-blockers. They found a significant reduction in incidence of POAF (15.2% versus 33.3%, respectively, p=0.013) and mean LOS (7.3 + 2.1 days versus 8.2 + 2.6 days, respectively, p=0.017) in patients receiving PUFA compared to control patients. Another small prospective, randomized study found that administration of IV PUFA at 100 mg fish oil/kg/day significantly reduced the incidence of POAF compared to control (17.3% vs. 30.6%, p<0.05) however this study did not mention the percentage of patients on betablocker therapy (Heidt, et al., 2009). Similar to other new agents showing studies with conflicting results for the prevention of POAF in cardiac surgery patients, two small, prospective, randomized, double blind, placebo controlled studies found no benefit using PUFA ~ 2 g/day therapy (Heidarsdottir et al., 2010; Saravanan et al., 2010). Further studies are warranted to determine if omega-3 fatty acids are viable add-on prophylactic therapy or

The ability of ascorbic acid (vitamin C) to prevent POAF is thought to occur due its antioxidant properties and potential to attenuate inflammation and electrical remodeling (Korantzopoulos et al., 2005). Vitamin C has been studied in prospective trials for the prevention of POAF in cardiac surgery patients (Carnes et al., 2001; Eslami et al., 2007). Both studies demonstrated significant benefit using vitamin C compared to usual care with an absolute reduction in POAF between 19-22%, but no reduction in mean LOS. Both studies also had substantial rates of both pre- and postoperative beta-blocker utilization. Due to the low cost and relative safety

reducing the occurrence of POAF in addition to beta-blockers.

alternative for patients unable to take beta-blockers.

of this drug, larger placebo-controlled trials appear to be warranted.

infection, or edema.

**4.4 Omega-3 fatty acids** 

**4.5 Ascorbic acid** 

significant reduction may not have been observed in these studies as patients were propensity score matched for common predictors of atrial fibrillation. Thus groups could have been at high risk for the development of POAF (Coleman et al., 2007; Rader et al., 2010).

Further prospective, controlled trials are needed evaluate the impact of ACEIs or ARBs on the development of POAF. These studies will provide more definitive evidence concerning the effectiveness of ACEIs and ARBs in the prevention of POAF following cardiac surgical procedures. If ACIEs or ARBs are used in combination with standard therapies for the prevention of POAF, they must be used with caution or avoided in patients with renal dysfunction or electrolyte abnormalties, specifically hyperkalemia.

### **4.3 Corticosteroids**

Corticosteroids have been traditionally utilized in cardiac surgeries to reduce inflammation in an effort to achieve early extubation, enhance pulmonary function recovery, or decrease postoperative nausea and vomiting. Inflammatory biomarkers increase in patients undergoing cardiothoracic surgery and inflammation appears to play a role in the development of POAF.

Studies evaluating corticosteroids have used various types of intravenous (IV) steroids, doses, and regimens. Two studies used beta-blockers postoperatively in all of their patients found that corticosteroids were superior to placebo with absolute reductions in the incidence of POAF of 18% to 30% (Prasongsukarn et al., 2005; Halonen et al., 2007). However other trials failed to show a significant benefit (Chaney et al., 1998; Halvorsen et al., 2003) in reducing incidence of POAF compared to placebo or usual care. Halonen et al further reported that after adjusting for potential unbalanced confounders, that hydrocortisone continued to be effective in reducing the risk of POAF by 46% (HR 0.54; 95% CI 0.35-0.83) with treatment of only 5.6 patients needed to prevent one occurrence of POAF (Halonen et al., 2007). The authors further performed a meta-analysis combining results from their trial with two other similar trials for a total of 621 patients (Prasongsukarn et al., 2005; Halvorsen et al., 2003). They found that corticosteroid therapy significantly reduced the risk of POAF by 33% (OR 0.67; 95% CI 0.54-0.84) (Halonen et al., 2007). Two other metaanalyses confirmed this finding where corticosteroids significantly reduced the risk of POAF by 29% (OR 0.71; 95% CI 0.59-0.87) and 45% (OR 0.55; 95% CI 0.39-0.78) and show a significant decrease in LOS with steroids of 0.6 days and 1.6 days (Whitlock et al., 2008; Baker et al., 2007b).

At this time, specific dosing of corticosteroids that may confer optimal protection against POAF is unkown. Baker et al converted the steroid dosing to dexamethasone equivalence based on total cumulative dose and relative potencies and found that reduction in POAF appeared greatest in patients receiving intermediate doses of corticosteroids (50-120 mg dexamethasone equivalent), while lower (≤ 8 mg dexamethasone equivalent) and higher (236-2850 mg dexamethasone equivalent) dosing resulted in blunted effects (Baker et al., 2007b). The most recent meta-analysis by Ho et al converted steroid dosing to hydrocortisone equivalence and found a significant reduction of POAF in patients receiving low (< 1,000 mg hydrocortisone equivalent) and intermediate (1,000-10,000 mg hydrocortisone equivalent) doses of steroids (Ho & Tan, 2009).

While corticosteroids can attenuate biomarkers shown to regulate the inflammatory response leading to the development of POAF, they are also associated with side effects that may inhibit their widespread use. Cardiac surgery patients who have received corticosteroids have been shown to have peak white blood cell counts were higher up to 14 days postoperatively, higher blood glucose and larger insulin requirements (Sano et al., 2006), greater risk of wound and infectious complications (Whitlock et al., 2008). Therefore it may be necessary to avoid corticosteroids in patients with uncontrolled hyperglycemia, infection, or edema.

Corticosteroids can target the inflammatory process for the prevention of POAF in patients undergoing cardiac surgery. While some studies found a reduction in the incidence of POAF using corticosteroids as prophylaxis in cardiac surgery patients receiving standard betablocker therapy, there is no consensus on which steroid, dose, and duration has the greatest benefit. Only the 2010 European guidelines recommend corticosteroids for prophylaxis of POAF in cardiac surgery patients and include suggested dosing in dexamethasone equivalent for the prevention of POAF with a Class 2B recommendation, stating however that there is risk associated with using them (ESC, 2010). The most relevant risk in hospitalized patients after cardiac surgery includes steroid-induced hyperglycemia or leukocytosis. Corticosteroids may play a future role in targeting the inflammatory process in patients undergoing cardiothoracic surgery, however larger clinical trials are necessary to confirm if corticosteroids are effective in reducing the occurrence of POAF in addition to beta-blockers.

### **4.4 Omega-3 fatty acids**

218 Special Topics in Cardiac Surgery

significant reduction may not have been observed in these studies as patients were propensity score matched for common predictors of atrial fibrillation. Thus groups could have been at high risk for the development of POAF (Coleman et al., 2007; Rader et al.,

Further prospective, controlled trials are needed evaluate the impact of ACEIs or ARBs on the development of POAF. These studies will provide more definitive evidence concerning the effectiveness of ACEIs and ARBs in the prevention of POAF following cardiac surgical procedures. If ACIEs or ARBs are used in combination with standard therapies for the prevention of POAF, they must be used with caution or avoided in patients with renal

Corticosteroids have been traditionally utilized in cardiac surgeries to reduce inflammation in an effort to achieve early extubation, enhance pulmonary function recovery, or decrease postoperative nausea and vomiting. Inflammatory biomarkers increase in patients undergoing cardiothoracic surgery and inflammation appears to play a role in the

Studies evaluating corticosteroids have used various types of intravenous (IV) steroids, doses, and regimens. Two studies used beta-blockers postoperatively in all of their patients found that corticosteroids were superior to placebo with absolute reductions in the incidence of POAF of 18% to 30% (Prasongsukarn et al., 2005; Halonen et al., 2007). However other trials failed to show a significant benefit (Chaney et al., 1998; Halvorsen et al., 2003) in reducing incidence of POAF compared to placebo or usual care. Halonen et al further reported that after adjusting for potential unbalanced confounders, that hydrocortisone continued to be effective in reducing the risk of POAF by 46% (HR 0.54; 95% CI 0.35-0.83) with treatment of only 5.6 patients needed to prevent one occurrence of POAF (Halonen et al., 2007). The authors further performed a meta-analysis combining results from their trial with two other similar trials for a total of 621 patients (Prasongsukarn et al., 2005; Halvorsen et al., 2003). They found that corticosteroid therapy significantly reduced the risk of POAF by 33% (OR 0.67; 95% CI 0.54-0.84) (Halonen et al., 2007). Two other metaanalyses confirmed this finding where corticosteroids significantly reduced the risk of POAF by 29% (OR 0.71; 95% CI 0.59-0.87) and 45% (OR 0.55; 95% CI 0.39-0.78) and show a significant decrease in LOS with steroids of 0.6 days and 1.6 days (Whitlock et al., 2008;

At this time, specific dosing of corticosteroids that may confer optimal protection against POAF is unkown. Baker et al converted the steroid dosing to dexamethasone equivalence based on total cumulative dose and relative potencies and found that reduction in POAF appeared greatest in patients receiving intermediate doses of corticosteroids (50-120 mg dexamethasone equivalent), while lower (≤ 8 mg dexamethasone equivalent) and higher (236-2850 mg dexamethasone equivalent) dosing resulted in blunted effects (Baker et al., 2007b). The most recent meta-analysis by Ho et al converted steroid dosing to hydrocortisone equivalence and found a significant reduction of POAF in patients receiving low (< 1,000 mg hydrocortisone equivalent) and intermediate (1,000-10,000 mg

While corticosteroids can attenuate biomarkers shown to regulate the inflammatory response leading to the development of POAF, they are also associated with side effects that may inhibit their widespread use. Cardiac surgery patients who have received

hydrocortisone equivalent) doses of steroids (Ho & Tan, 2009).

dysfunction or electrolyte abnormalties, specifically hyperkalemia.

2010).

**4.3 Corticosteroids** 

development of POAF.

Baker et al., 2007b).

The ability of omega-3 fatty acids to reduce the occurrence of POAF is thought to result from a stabilizing effect on the myocardium, anti-inflammatory properties, and possibly antioxidant activity (Kris-Etherton et al., 2002; Korantzopoulos et al., 2006). Calo et al performed a prospective, randomized, open label study in 160 patients assessing the impact of N-3 polyunsaturated fatty acids (PUFA) 2 g/day on the incidence of POAF in cardiac surgery patients (Calo et al., 2005). Approximately 60% of patients in both groups were on preoperative beta-blockers. They found a significant reduction in incidence of POAF (15.2% versus 33.3%, respectively, p=0.013) and mean LOS (7.3 + 2.1 days versus 8.2 + 2.6 days, respectively, p=0.017) in patients receiving PUFA compared to control patients. Another small prospective, randomized study found that administration of IV PUFA at 100 mg fish oil/kg/day significantly reduced the incidence of POAF compared to control (17.3% vs. 30.6%, p<0.05) however this study did not mention the percentage of patients on betablocker therapy (Heidt, et al., 2009). Similar to other new agents showing studies with conflicting results for the prevention of POAF in cardiac surgery patients, two small, prospective, randomized, double blind, placebo controlled studies found no benefit using PUFA ~ 2 g/day therapy (Heidarsdottir et al., 2010; Saravanan et al., 2010). Further studies are warranted to determine if omega-3 fatty acids are viable add-on prophylactic therapy or alternative for patients unable to take beta-blockers.

### **4.5 Ascorbic acid**

The ability of ascorbic acid (vitamin C) to prevent POAF is thought to occur due its antioxidant properties and potential to attenuate inflammation and electrical remodeling (Korantzopoulos et al., 2005). Vitamin C has been studied in prospective trials for the prevention of POAF in cardiac surgery patients (Carnes et al., 2001; Eslami et al., 2007). Both studies demonstrated significant benefit using vitamin C compared to usual care with an absolute reduction in POAF between 19-22%, but no reduction in mean LOS. Both studies also had substantial rates of both pre- and postoperative beta-blocker utilization. Due to the low cost and relative safety of this drug, larger placebo-controlled trials appear to be warranted.

Strategies for the Prevention of Postoperative Atrial Fibrillation in Cardiac Surgery 221

it also carries a greater risk of Torsades and should be avoided in patients with prolonged QT intervals. It could be considered for add on therapy in high risk patients or in patients intolerant of beta-blockers but should first be compared to other traditional class III

Levosimendan is an intravenous calcium sensitizer agent that is used for the treatment of acute decompensated heart failure. It increases myocardial contraction without increasing myocardial oxygen consumption and produces coronary and peripheral vasodilation (Lilleberg et al., 1998). While the drug is not approved and will not be pursued for FDA approval in the US, it has been shown in one study to significantly reduce the incidence of POAF and increase stroke volume in patients with ejection fraction <30% when compared to milrinone (50% for milrinone, 5% for levosimendan started post anesthesia, and 35% for levosimendan started after cross clamp release, p<0.01) (De Hert et al., 2008). Very few patients in this study, however, were taking preoperative beta-blockers (~13-14%) and all

**5. Unestablished pharmacologic therapies for the prevention of POAF in** 

Given the availability of just a few trials with inconsistent results, propafenone is not currently recommended as first-line for POAF prophylaxis (Bradley et al., 2005; Dunning et al., 2006; Fuster et al., 2006; Eagle et al., 2004). Its use may be limited by its proarrhythmic effects in patients with structural heart disease. Current available evidence also does not support the use of procainamide for POAF prophylaxis. Although based on limited evidence, preoperative "digitalization" was historically used to prevent POAF. Currently, digoxin does not have an indication for POAF prophylaxis but can be used for rate control once atrial fibrillation occurs (Bradley et al., 2005). Only the non-dihydropyridine calcium channel blockers (non-DHP-CCB) diltiazem and verapamil, have evidence supporting their effectiveness for POAF prophylaxis from a meta-analysis evaluating twelve small studies encompassing 719 patients (Wijeysundera et al., 2003). However, two other meta-analyses found a non-significant reduction (Andrews et al., 1991) and even an increase in the risk of POAF (Woodend et al., 1998) with the CCBs. Because of this and the risk of atrioventricular block and low-output syndrome, especially in combination with beta-blockers, the guidelines recommend against routine use of CCBs for POAF prophylaxis and that the non-DHP-CCBs, diltiazem or verapamil, be reserved for rate control only once POAF has

Thiazolidinediones (TZDs) may affect POAF through pleiotropic anti-inflammatory activity against macrophage activation and pro-inflammatory cytokines (Consoli & Devangelio, 2005; Ricote et al., 1998). One study evaluated a nested cohort study of diabetic patients from the AFIST I, II, and III trials (Giri et al., 2001; White et al., 2003; White et al., 2007a) assessed whether the use of TZDs affected the incidence of POAF in diabetic patients who were also receiving beta- blockers and amiodarone (Anglade et al., 2007). In addition to substantial pre- and postoperative beta-blocker use, 43.8% of control patients and 35% of

**5.1 Propafenone, procainamide, digoxin and calcium channel blockers** 

antiarrhythmics such as amiodarone or sotalol in head to head trials.

patients received dobutamine after the release of the cross clamp.

occurred (Bradley et al., 2005; Eagle et al., 2004).

**5.2 Thiazolidinediones** 

**4.9 Levosimendan** 

**cardiac surgery** 

### **4.6 N-Acetylcysteine**

N-acetylcysteine (NAC) has been theorized to prevent POAF based on its antioxidant activity as a free radical scavenger and ability to reduce cellular damage in the atrium (Carnes et al., 2007). Two recent studies, which were randomized and placebo-controlled, found conflicting results with NAC in the prophylaxis of POAF (El-Hamamsy et al, 2007; Ozaydin et al., 2008b). The first study failed to demonstrate a significant reduction in the incidence of POAF (7% with NAC versus 12% with placebo, p=0.7). A more recent study, which included valve surgeries, did show a significant benefit with NAC compared to placebo (5% versus 21%, p=0.01). After controlling for perioperative beta-blocker use, NAC was still associated with a significant reduction in POAF (OR 0.17, 95% CI 0.04-0.69, p=0.01). Neither study found a significant reduction in LOS. Both studies reported substantial preoperative beta-blocker use while Ozaydin et al also reported substantial postoperative beta-blocker utilization. Two conflicting meta-analyses have been recently published, one that found a statistically significant reduction in POAF with NAC use (36%, 95% CI 2-58%, total n=1,338) and one larger one that did not (OR 0.67, 95% CI 0.37-1.22, p=0.19, total n=1,407) (Baker et al., 2009; Wang et al., 2011). Large, prospective, randomized clinical trials are necessary to determine if NAC is effective in reducing the occurrence of POAF in addition to beta-blockers.

### **4.7 Sodium nitroprusside**

One pilot study evaluated sodium nitroprusside as an agent for POAF prophylaxis compared to placebo (Cavolli et al., 2008). This study demonstrated a significant reduction in the incidence of POAF when compared to placebo (12% versus 36%, p=0.005) and a significant reduction in mean LOS (7.3 + 0.7 days versus 9.1 + 1.2 days, p<0.001). The authors suggest that nitric oxide (NO) function may be disrupted due to ischemiareperfusion injury and that administration of NO donors such as nSNP could recover this function. SNP may also reduce POAF by reducing left atrial stretching due to preload and afterload reduction. This study also showed a significant reduction in serum CRP levels in patients given SNP when compared to placebo (p<0.05), suggesting some possible effects on inflammation. Though not significant, more patients randomized to SNP received preoperative beta-blockers when compared to the placebo group (68% versus 58% p=0.303). Postoperative beta-blocker use was not addressed. Likewise, patients in this study had relative preserved ejection fractions (60-61%). Currently, SNP is routinely used in institutions for the management of postoperative hypertension. Patients receiving this medication may also experience an additional benefit of arrhythmia prevention.

### **4.8 Dofetilide**

Dofetilide has been compared to placebo for postoperative atrial tachycardia (POAT) prophylaxis in one study (Serafimovski et al., 2008). The investigators found that patients receiving dofetilide prophylaxis experienced a significant reduction in the incidence of POAT, including atrial fibrillation and atrial flutter, when compared to placebo (18% versus 36%, p<0.017). There was no significant decrease in mean LOS. Although the use of postoperative beta-blockers was not reported, the authors conclude that the dofetilide group experienced a significant decrease in POAT independent of concomitant beta-blocker use based on multivariate logistic regression accounting for preoperative beta-blocker use. Due to cost, stringent prescribing and monitoring guidelines, and lack of robust head to head trials, dofetilide is not currently recommended as first line POAF prophylaxis. Like sotalol, it also carries a greater risk of Torsades and should be avoided in patients with prolonged QT intervals. It could be considered for add on therapy in high risk patients or in patients intolerant of beta-blockers but should first be compared to other traditional class III antiarrhythmics such as amiodarone or sotalol in head to head trials.
