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Comparative Effectiveness of Pharmacotherapies for Prevention of Atrial Fibrillation Following Coronary Artery Bypass Surgery

      Risk of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) is high, yet the effectiveness of guideline-recommended preoperative prophylaxis in clinical practice remains uncertain. We determined the utilization and variation of preoperative AF prevention and assessed the comparative effectiveness of alternative drugs using the Society of Thoracic Surgeons multicenter Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) registry. Among 2,177 patients who underwent high-risk CABG and/or valve surgery, the mean age was 71 ± 9, 66% were men, 26% had chronic lung disease, and 21% had cerebrovascular disease. Overall use of AF prophylaxis was 84% and varied across sites (range 52% to 100%). The most common preventive agents were beta blockers (72%), followed by calcium antagonists (17%). Postoperatively, 30% (n = 646) developed AF at a median of 2 (25th to 75th percentiles: 1 to 3) days after surgery. Increasing age, height, white race, body mass index >35, New York Heart Association class IV heart failure, preoperative dialysis, and concomitant aortic valve replacement were associated with greater odds of postoperative AF (p <0.05 for all). Preoperative amiodarone use was associated with a trend to reduction of postoperative AF (26%, adjusted odds ratio 0.72 [95% confidence interval 0.51 to 1.00], p = 0.052). After adjustment, the odds of postoperative AF were not statistically different across agents. In conclusion, use of AF prophylaxis before surgery varied significantly. In this high-risk population, we were unable to demonstrate that any of the commonly used preventive agents were associated with lower rates of AF compared with alternatives or no treatment.
      Postoperative atrial fibrillation (AF) is common, affecting 25% to 40% of patients after coronary artery bypass grafting (CABG).
      • Ommen S.R.
      • Odell J.A.
      • Stanton M.S.
      Atrial arrhythmias after cardiothoracic surgery.
      • Leitch J.W.
      • Thomson D.
      • Baird D.K.
      • Harris P.J.
      The importance of age as a predictor of atrial fibrillation and flutter after coronary artery bypass grafting.
      • Creswell L.L.
      • Schuessler R.B.
      • Rosenbloom M.
      • Cox J.L.
      Hazards of postoperative atrial arrhythmias.
      Not only is this dysrhythmia highly prevalent in CABG patients, but it is also associated with considerable morbidity and mortality, including an increased risk of stroke, renal failure, and heart failure.
      • Lahtinen J.
      • Biancari F.
      • Salmela E.
      • Mosorin M.
      • Satta J.
      • Rainio P.
      • Rimpiläinen J.
      • Lepojärvi M.
      • Juvonen T.
      Postoperative atrial fibrillation is a major cause of stroke after on-pump coronary artery bypass surgery.
      • Elahi M.
      • Hadjinikolaou L.
      • Galiñanes M.
      Incidence and clinical consequences of atrial fibrillation within 1 year of first-time isolated coronary bypass surgery.
      • Villareal R.P.
      • Hariharan R.
      • Liu B.C.
      • Kar B.
      • Lee V.V.
      • Elayda M.
      • Lopez J.A.
      • Rasekh A.
      • Wilson J.M.
      • Massumi A.
      Postoperative atrial fibrillation and mortality after coronary artery bypass surgery.
      • Mathew J.P.
      • Parks R.
      • Savino J.S.
      • Friedman A.S.
      • Koch C.
      • Mangano D.T.
      • Browner W.S.
      Atrial fibrillation following coronary artery bypass graft surgery: predictors, outcomes, and resource utilization. Multi Center Study of Perioperative Ischemia Research Group.
      Postoperative AF is also costly, increasing length of stay and elevating total health care resource requirements.
      • Hravnak M.
      • Hoffman L.A.
      • Saul M.I.
      • Zullo T.G.
      • Whitman G.R.
      Resource utilization related to atrial fibrillation after coronary artery bypass grafting.
      • Auer J.
      • Weber T.
      • Berent R.
      • Ng C.K.
      • Lamm G.
      • Eber B.
      Postoperative atrial fibrillation independently predicts prolongation of hospital stay after cardiac surgery.
      Numerous trials have examined interventions for the prevention of postoperative AF; however, their applicability has been largely limited to comparison of single-treatment strategies.
      • Crystal E.
      • Garfinkle M.S.
      • Connolly S.S.
      • Ginger T.T.
      • Sleik K.
      • Yusuf S.S.
      Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery.
      Few head-to-head active comparator trials have been done, and these were often conducted in selected patient populations and/or centers. The goal of this study was to examine variation in the use of preoperative pharmacotherapy and its comparative real-world effectiveness for the prevention of postoperative AF in a large multicenter population undergoing high-risk CABG.

      Methods

      The Society of Thoracic Surgeons National Cardiac Database (STS NCD) is a nationwide quality improvement registry of cardiac surgery. The details of the STS NCD participation and data collection have been previously described.
      • Lahiri M.K.
      • Fang K.
      • Lamerato L.
      • Khan A.M.
      • Schuger C.D.
      Effect of race on the frequency of postoperative atrial fibrillation following coronary artery bypass grafting.
      The Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) is a subregistry within the STS Adult Cardiac Surgical Database that collects additional information in patients who undergo high-risk or urgent CABG with or without concomitant valvular or AF surgery. CAPS-Care was designed to study the characteristics, management, and outcomes of patients following high-risk CABG in the United States.
      • Williams J.B.
      • Hernandez A.F.
      • Li S.
      • Dokholyan R.S.
      • O'Brien S.M.
      • Smith P.K.
      • Ferguson T.B.
      • Peterson E.D.
      Postoperative inotrope and vasopressor use following CABG: outcome data from the CAPS-care study.
      Patients were eligible if they had a preoperative ejection fraction <40% or age ≥65 years, with either diabetes mellitus or an estimated glomerular filtration rate <60 ml/min per 1.73 m2.
      • Williams J.B.
      • Hernandez A.F.
      • Li S.
      • Dokholyan R.S.
      • O'Brien S.M.
      • Smith P.K.
      • Ferguson T.B.
      • Peterson E.D.
      Postoperative inotrope and vasopressor use following CABG: outcome data from the CAPS-care study.
      Patients were excluded if they were ≤18 years or if they had an emergent/salvage operation or preoperative cardiogenic shock. For the purpose of this analysis, patients in AF before surgery and those patients who underwent concomitant AF correction surgery were excluded.
      Data for the CAPS-Care study were collected from May 11, 2006, through December 31, 2006 at 48 STS NCD registry sites. A total of 2,177 patients were eligible and entered into the analysis data set. Data elements included demographics, medical history, clinical presentation, medical therapy before hospitalization and in the hospital, hospital course including procedures, in-hospital outcomes, and discharge disposition. Data elements from the patients' corresponding STS NCD files were also used in the analysis, consistent with previous CAPS-Care analyses.
      • Williams J.B.
      • Hernandez A.F.
      • Li S.
      • Dokholyan R.S.
      • O'Brien S.M.
      • Smith P.K.
      • Ferguson T.B.
      • Peterson E.D.
      Postoperative inotrope and vasopressor use following CABG: outcome data from the CAPS-care study.
      Postoperative AF was defined and recorded on the case report form as any sustained new onset AF or atrial flutter requiring an intervention that occurred during the postoperative period before discharge. Patients who were in AF at baseline were excluded. The incidence of postoperative AF was assessed as a function of preoperative drug therapy. Prespecified treatment categories included overall, beta blocker, calcium antagonist, sotalol, amiodarone, other antiarrhythmic, none. Medication dosage was not available. Prespecified operative characteristics included an urgent indication for surgery, CABG only, CABG and aortic valve replacement, CABG and mitral valve repair, CABG and mitral valve replacement, off-pump surgery, perfusion time, and cross-clamp time.
      Baseline characteristics and operative characteristics were summarized according to the occurrence of postoperative AF using medians and 25th to 75th percentile interquartile range for continuous variables and frequency and percentage for categorical variables. Preoperative AF prophylaxis was defined according to the prespecified treatment categories.
      Variation in preoperative prophylaxis was described at the site level (n = 48). To display the results graphically, use of preoperative AF prophylaxis was plotted against the number of patients at each site. We superimposed lines representing 95% binomial prediction limits, indicating the range of results that would normally occur as a result of random statistical variation for a hospital whose true frequency of using an agent was equal to the mean for the whole population.
      We explored the association between baseline clinical characteristics and postoperative AF. Logistic regression modeling was used to estimate the risk of postoperative AF as a function of baseline patient variables. Using backward selection with a significance criterion of p = 0.05, independent predictors were identified from a list of covariates including previously reported predictors of postoperative AF and potentially relevant variables (Appendix). The discrimination of the full and the reduced models were assessed by the use of Harrell's C-index.
      • Harrell Jr., F.E.
      Regression Modeling Strategies with Applications to Linear Models, Logistic Regression and Survival Analysis.
      The enhanced bootstrap was used to estimate the bias (i.e., overestimated C-index) due to model overfitting in the original sample.
      • Harrell Jr., F.E.
      Regression Modeling Strategies with Applications to Linear Models, Logistic Regression and Survival Analysis.
      Risk adjusted odds ratios (ORs) of covariates in the reduced models were then estimated. Robust sandwich variance estimates were used to obtain 95% confidence intervals (CIs) to account for statistical dependence of patients within sites.
      • Zeger S.L.
      • Liang K.Y.
      Longitudinal data analysis for discrete and continuous outcomes.
      The association between preoperative prophylaxis and postoperative AF was assessed using the unadjusted logistic model containing treatments that indicated the usage of amiodarone, sotalol, other antiarrhythmic therapy, beta blocker, or calcium antagonist therapy, and the risk-adjusted model with both treatments and a set of relevant covariates (Appendix). Unadjusted and adjusted ORs for using a specific agent versus not using that agent were reported. Combinations of agents (any antiarrhythmic + beta blocker, any antiarrhythmic + calcium antagonist) were examined in a separate adjusted model with the same covariates.

      Results

      Among 2,177 patients in the CAPS-Care registry, 30% (n = 646/2,177) had sustained AF after surgery. The median time to AF onset was 2.0 days (25th to 75th percentiles: 1.0 to 3.0). Baseline characteristics according to the occurrence of postoperative AF are shown in Table 1. Those who developed postoperative AF were older, more commonly hypertensive, and had worse renal function. There were no significant differences in the sex or body mass indices between those patients with and without postoperative AF. More patients with New York Heart Association (NYHA) class IV heart failure (vs NYHA class I to III) developed postoperative AF, although the median left ventricular ejection fraction was higher in those with postoperative AF (49% vs 43%).
      Table 1Baseline characteristics
      VariablePostoperative AFp Value
      No (n = 1,531)Yes (n = 646)
      Age (yrs)71 (65–76)74 (69–79)<0.0001
      Female517 (34%)217 (34%)0.9362
       Caucasian1,344 (88%)588 (91%)
       Black73 (5%)16 (2%)
       Hispanic34 (2%)12 (2%)
       Asian15 (1%)8 (1%)
       Native American10 (1%)1 (1%)
       Other47 (3%)20 (3%)
      Hypertension
      Hypertension was defined in the STS registry as diagnosed and treated with diet and/or exercise, systolic blood pressure >140 or >90 mm Hg diastolic on ≥2 occasions, or current treatment with an antihypertensive medication.
      1,265 (83%)556 (86%)0.0507
      Diabetes819 (53%)343 (53%)0.8648
      Hypercholesterolemia
      Hypercholesterolemia was defined in the STS registry as a clinical diagnosis with total cholesterol >200 mg/dl, LDL ≥130 mg/dl, HDL <30 mg/dl, or triglycerides >150 mg/dl.
      1,209 (79%)469 (73%)0.0025
      Current tobacco use322 (21%)78 (12%)<0.0001
      Cerebrovascular disease308 (20%)159 (25%)0.0234
      Previous stroke221 (14%)115 (18%)0.0498
      Peripheral vascular disease292 (19%)139 (22%)0.2109
      COPD (FEV1 <60%)206 (13%)78 (12%)0.3823
      Preoperative dialysis26 (2%)23 (4%)0.0079
      Demographic region0.4564
       Midwest630 (41%)254 (39%)
       Northeast163 (11%)70 (11%)
       South471 (31%)191 (30%)
       West267 (17%)131 (20%)
      Previous cardiac interventions
       Any previous cardiovascular surgery139 (9%)49 (8%)0.2571
       Previous coronary bypass109 (7%)39 (6%)0.3507
       Any previous PCI289 (19%)106 (16%)0.1527
       Previous CABG or PCI353 (23%)136 (21%)0.3061
       Previous cardiac valve surgery16 (1%)7 (1%)0.9425
      Preoperative medical therapy
       Beta blocker1,061 (69%)446 (69%)0.9041
       ACE inhibitor688 (44%)286 (44%)0.7755
       Aspirin1,123 (72%)471 (72%)0.6786
       Warfarin15 (1%)10 (2%)0.3168
       Lipid-lowering therapy (any)581 (38%)252 (39%)0.5603
       Statin562 (37%)242 (37%)0.6139
       Thienopyridine89 (6%)36 (6%)0.5978
      Preoperative clinical data
       Body mass index (kg/m2)28 (25, 32)28 (25, 32)0.5809
       Heart rate (beats/min)70 (60, 79)68 (60, 77)0.0446
       Preoperative heart rate ≥10025 (2%)15 (2%)0.3546
       Systolic blood pressure (mm Hg)130 (112–145)130 (112–145)0.7611
       Diastolic blood pressure (mm Hg)62 (56–72)60 (55–70)0.1862
       Hemoglobin (mg/dl)13 (11.6–14.2)12.7 (11.4–14.1)0.0251
       Estimated GFR (ml/min/1.73 m2)59 (49, 79)57 (45–75)<0.0001
       LVEF43 (30, 56)49 (35–60)0.0057
       Heart failure422 (28%)203 (31%)0.0712
       NYHA classification0.2137
      I167 (11%)60 (9%)
      II318 (21%)139 (22%)
      III682 (45%)270 (42%)
      IV357 (23%)174 (27%)
       Preoperative electrocardiogram0.3444
      Sinus1,397 (91%)595 (92%)
      Paced56 (4%)16 (2%)
      Other78 (5%)36 (6%)
       Preoperative CHADS2 score0.0002
      077 (5%)16 (2%)
      1322 (21%)106 (16%)
      ≥21,132 (74%)524 (81%)
      Values are presented as % or median (25th to 75th percentiles).
      ACE = angiotensin-converting enzyme; CHADS2 = congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, previous stroke/TIA/thromboembolism; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; GFR = glomerular filtration rate; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention.
      Hypertension was defined in the STS registry as diagnosed and treated with diet and/or exercise, systolic blood pressure >140 or >90 mm Hg diastolic on ≥2 occasions, or current treatment with an antihypertensive medication.
      Hypercholesterolemia was defined in the STS registry as a clinical diagnosis with total cholesterol >200 mg/dl, LDL ≥130 mg/dl, HDL <30 mg/dl, or triglycerides >150 mg/dl.
      Table 2 shows the operative data according to the occurrence of postoperative AF. Among this cohort, 1,706 patients (78.4%) underwent isolated CABG, and 1,059 patients (48.6%) urgent surgery. The incidence of postoperative AF was 27.6% in those patients who underwent isolated CABG and 41.0% in those who underwent CABG with concomitant valve surgery. Overall, 89.7% of the surgeries were performed on-pump. Patients with longer perfusion and cross-clamp times had a higher frequency of AF.
      Table 2Operative characteristics according to the occurrence of postoperative atrial fibrillation
      VariablePostoperative AFp Value
      No (n = 1,531)Yes (n = 646)
      Urgent surgery748 (49%)311 (48%)0.7503
      Procedure performed<0.0001
       Isolated CABG1,235 (81%)471 (73%)
       CABG and valve surgery214 (14%)149 (23%)
      CABG with AVR129 (8%)106 (16%)
      CABG with MV replacement33 (2%)20 (3%)
      CABG with MV repair67 (4%)42 (7%)
       CABG and other surgery82 (5%)26 (4%)
      On-pump1,371 (90%)581 (90%)0.7855
       Cardiopulmonary bypass time105 (81–136)116 (88–148)<0.0001
       Cross clamp time71 (53–99)82 (59–113)<0.0001
      Data are shown as n (%) or median (25th to 75th percentiles).
      AVR = aortic valve replacement; MV = mitral valve; All other abbreviations can be found in Table 1.
      We identified several factors that were associated with the development of postoperative AF (Table 3). Increasing age, increasing height, body mass index >35, NYHA class IV heart failure, preoperative dialysis, and concomitant aortic valve replacement were all associated with a higher frequency of postoperative AF. Alternatively, a previous diagnosis of dyslipidemia and African American race were associated with a lower frequency of postoperative AF.
      Table 3Baseline predictors of postoperative atrial fibrillation identified in multivariable analysis
      C-statistic for model is 0.65 (95% CI 0.63–0.67).
      VariablesOR95% CIp Value
      Age (increment by 10)1.741.53–1.97<0.0001
      Height in cm (increment by 10)1.171.06–1.290.0020
      Dyslipidemia0.740.60–0.920.0075
      African American0.550.31–0.970.0385
      Body mass index >351.641.24–2.180.0006
      NYHA class IV heart failure1.411.05–1.890.0205
      Preoperative dialysis2.581.40–4.760.0025
      Concomitant aortic valve replacement1.631.23–2.180.0008
      C-statistic for model is 0.65 (95% CI 0.63–0.67).
      Overall, 84% of the cohort was taking preoperative AF prophylaxis. As shown in Tables 4 and 5, beta-adrenergic blocking agents were the most commonly used medications for prophylaxis (72%). Membrane active medications were used in 19%: 11% amiodarone, 7% other antiarrhythmic therapy, and 1% sotalol. The most commonly used combinations included beta blockade with calcium antagonist (9%) and amiodarone with either beta blockade or calcium antagonist (8%; Table 4). African Americans received prophylaxis at a slightly lower rate (78% vs 84% overall). Among African Americans, 72% received beta blockers (n = 64/89). Figure 1 shows the use of preoperative AF prophylaxis at the site-level for any medication, beta blockade, sotalol, and amiodarone. There was evidence of variability across sites in the use of any prophylaxis medication, beta blocker, and amiodarone.
      Table 4Overall utilization of preoperative prophylaxis
      n = 2,177
      No therapy391 (18.0%)
      BB only1,100 (50.5%)
      CA only103 (4.7%)
      BB + CCB204 (9.4%)
      Amiodarone only45 (2.1%)
      Amiodarone + AVN blocker(s)168 (7.7%)
      Other AAD38 (1.8%)
      Other AAD + AVN blocker(s)90 (4.1%)
      Sotalol only6 (0.3%)
      Sotalol + AVN blocker(s)4 (0.9%)
      All other combinations
      These combinations included amiodarone + other AAD (n = 6), sotalol + other AAD (n = 2), amiodarone + BB + other AAD (n = 13), and amiodarone + BB + CCB + other AAD (n = 7).
      28 (1.3%)
      AAD = antiarrhythmic drug; AVN = atrioventricular node; BB = beta blocker; CCB = calcium antagonist.
      These combinations included amiodarone + other AAD (n = 6), sotalol + other AAD (n = 2), amiodarone + BB + other AAD (n = 13), and amiodarone + BB + CCB + other AAD (n = 7).
      Table 5Unadjusted and adjusted risk of atrial fibrillation by preoperative atrial fibrillation prophylaxis
      Preoperative ProphylaxisOverall Use %Adherence/Postoperative Use % (adherence/total)Frequency POAF %Risk Adjusted Analysis
      OR95% CIp Value
      Amiodarone1178 (186/239)260.720.51–1.000.052
      Sotalol0.633 (4/12)421.380.39–4.860.612
      Other AAD744 (68/156)280.890.60–1.320.574
      BB7270 (1,105/1,568)301.060.85–1.330.608
      CCB1730 (113/372)331.100.86–1.420.447
      Any AAD
      Any AAD included amiodarone, sotalol, or other antiarrhythmic. These combinations were examined in a separate adjusted model with the same covariates.
       + BB
      1261 (161/264)250.720.52–1.030.0673
      Any AAD
      Any AAD included amiodarone, sotalol, or other antiarrhythmic. These combinations were examined in a separate adjusted model with the same covariates.
       + CCB
      331 (20/65)291.040.57–1.890.8964
      AAD = antiarrhythmic drug; BB = beta blocker; CCB = calcium antagonist; POAF = postoperative AF.
      Any AAD included amiodarone, sotalol, or other antiarrhythmic. These combinations were examined in a separate adjusted model with the same covariates.
      Figure thumbnail gr1
      Figure 1Variation in hospital use of preoperative AF prophylaxis. The four panels show (A) overall prophylaxis; (B) beta-blocker; (C) sotalol; and (D) amiodarone use. Preoperative AF prophylaxis utilization was plotted against the number of patients at each of the 48 sites with 95% binomial prediction limits. The overall use rate for each agent across sites is also shown.
      Following adjustment for clinical covariates, the use of amiodarone was associated with a nonsignificant trend toward decreased postoperative AF: 30% overall versus 26% with amiodarone (adjusted OR 0.75 [95% CI 0.51 to 1.00], p = 0.052). The use of sotalol, other antiarrhythmic therapy, beta blocker, and calcium antagonist therapy were not associated with decreased odds of postoperative AF (Table 5). Combination therapy with any antiarrhythmic and beta-blocker therapy was associated with a nonsignificant trend in reduced postoperative AF (OR 0.72 [95% CI 0.52 to 1.03], p = 0.0673), and any antiarrhythmic in combination with calcium antagonist therapy was not. As shown in Table 5, continued use of these agents postoperatively was varied. Adherence was highest with amiodarone (78%) and lowest with calcium antagonists (30%).
      We conducted a sensitivity analysis restricted to those patients without concomitant surgery (isolated CABG only, n = 1,706). As shown in Supplementary Table 1 (Appendix), patients with isolated CABG who developed postoperative AF were older, had worse renal function, and higher preoperative CHADS2 (congestive heart failure; hypertension; age ≥75 years; diabetes mellitus; previous stroke, TIA, thromboembolism) scores. When we examined the use of specific pharmacologic therapies, these data were similar to the overall cohort (Supplementary Table 2). Finally, when we examined the unadjusted and adjusted risk of postoperative AF according to specific prophylactic agents, the results in the isolated CABG group were also similar to the overall cohort (Supplementary Table 3).

      Discussion

      In this multicenter U.S. registry, we found that AF remains a frequent complication of high-risk CABG, occurring in 3 of every 10 patients. Despite guideline recommendations, the use of preoperative prophylaxis is variable, inconsistent, and subject to high rates of discontinuation. We were unable to demonstrate that any of the commonly used AF prophylaxis agents were associated with lower rates of postoperative AF compared with alternatives or no treatment.
      The incidence of postoperative AF has remained relatively constant over the past 15 years, despite advances in surgical technique, medical therapy, and improvements in postoperative survival.
      • Mathew J.P.
      • Parks R.
      • Savino J.S.
      • Friedman A.S.
      • Koch C.
      • Mangano D.T.
      • Browner W.S.
      Atrial fibrillation following coronary artery bypass graft surgery: predictors, outcomes, and resource utilization. Multi Center Study of Perioperative Ischemia Research Group.
      • Mathew J.P.
      • Fontes M.L.
      • Tudor I.C.
      • Ramsay J.
      • Duke P.
      • Mazer C.D.
      • Barash P.G.
      • Hsu P.H.
      • Mangano D.T.
      • Investigators of the Ischemia Research and Education Foundation
      • Multicenter Study of Perioperative Ischemia Research Group
      A multicenter risk index for atrial fibrillation after cardiac surgery.
      • Zaman A.G.
      • Archbold R.A.
      • Helft G.
      • Paul E.A.
      • Curzen N.P.
      • Mills P.G.
      Atrial fibrillation after coronary artery bypass surgery: a model for preoperative risk stratification.
      In our cohort, several well-known risk factors, including age, body mass index >35, end stage renal disease, class IV heart failure, and concomitant aortic valve replacement were associated with an increased odds of postoperative AF.
      • Mathew J.P.
      • Fontes M.L.
      • Tudor I.C.
      • Ramsay J.
      • Duke P.
      • Mazer C.D.
      • Barash P.G.
      • Hsu P.H.
      • Mangano D.T.
      • Investigators of the Ischemia Research and Education Foundation
      • Multicenter Study of Perioperative Ischemia Research Group
      A multicenter risk index for atrial fibrillation after cardiac surgery.
      • Auer J.
      • Lamm G.
      • Weber T.
      • Berent R.
      • Ng C.K.
      • Porodko M.
      • Eber B.
      Renal function is associated with risk of atrial fibrillation after cardiac surgery.
      • Gami A.S.
      • Hodge D.O.
      • Herges R.M.
      • Olson E.J.
      • Nykodym J.
      • Kara T.
      • Somers V.K.
      Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation.
      Additionally, as noted in the Atherosclerosis Risk in Communities Study, increasing height was also associated with a higher risk of postoperative AF.
      • Chamberlain A.M.
      • Agarwal S.K.
      • Folsom A.R.
      • Soliman E.Z.
      • Chambless L.E.
      • Crow R.
      • Ambrose M.
      • Alonso A.
      A clinical risk score for atrial fibrillation in a biracial prospective cohort (from the Atherosclerosis Risk in Communities [ARIC] study).
      Height has been shown to correlate with absolute left atrial size, which is a known predictor of AF.
      • Pritchett A.M.
      • Jacobsen S.J.
      • Mahoney D.W.
      • Rodeheffer R.J.
      • Bailey K.R.
      • Redfield M.M.
      Left atrial volume as an index of left atrial size: a population-based study.
      Consistent with previous observations, African Americans also appear to have a significantly lower risk of postoperative AF, even after accounting for co-morbidity and other potential confounders.
      • Lahiri M.K.
      • Fang K.
      • Lamerato L.
      • Khan A.M.
      • Schuger C.D.
      Effect of race on the frequency of postoperative atrial fibrillation following coronary artery bypass grafting.
      Professional society guidelines recommend beta-adrenergic blocking agents as first-line prophylaxis for the prevention of postoperative AF in patients undergoing cardiac surgery.
      • Fuster V.
      • Rydén L.E.
      • Cannom D.S.
      • Crijns H.J.
      • Curtis A.B.
      • Ellenbogen K.A.
      • Halperin J.L.
      • Le Heuzey J.Y.
      • Kay G.N.
      • Lowe J.E.
      • Olsson S.B.
      • Prystowsky E.N.
      • Tamargo J.L.
      • Wann S.
      • Smith Jr., S.C.
      • Jacobs A.K.
      • Adams C.D.
      • Anderson J.L.
      • Antman E.M.
      • Hunt S.A.
      • Nishimura R.
      • Ornato J.P.
      • Page R.L.
      • Riegel B.
      • Priori S.G.
      • Blanc J.J.
      • Budaj A.
      • Camm A.J.
      • Dean V.
      • Deckers J.W.
      • Despres C.
      • Dickstein K.
      • Lekakis J.
      • McGregor K.
      • Metra M.
      • Morais J.
      • Osterspey A.
      • Zamorano J.L.
      ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation).
      • Dunning J.
      • Treasure T.
      • Versteegh M.
      • Nashef S.A.
      Guidelines on the prevention and management of de novo atrial fibrillation after cardiac and thoracic surgery.
      Despite this recommendation, only 71% of this cohort received a beta blocker before surgery. Among those who received beta-adrenergic blocking agents, 3 of 10 patients discontinued them in the postoperative period. Although beta-adrenergic blocker use in this registry was higher than some previous estimates, it remains short of optimal guideline adherence, particularly given that all the patients in this cohort had coronary artery disease.
      • Mathew J.P.
      • Fontes M.L.
      • Tudor I.C.
      • Ramsay J.
      • Duke P.
      • Mazer C.D.
      • Barash P.G.
      • Hsu P.H.
      • Mangano D.T.
      • Investigators of the Ischemia Research and Education Foundation
      • Multicenter Study of Perioperative Ischemia Research Group
      A multicenter risk index for atrial fibrillation after cardiac surgery.
      • Price J.
      • Tee R.
      • Lam B.K.
      • Hendry P.
      • Green M.S.
      • Rubens F.D.
      Current use of prophylactic strategies for postoperative atrial fibrillation: a survey of Canadian cardiac surgeons.
      In a recent clinical trial, prophylaxis with a 48-hour infusion of metoprolol was associated with a postoperative AF incidence of 24%, compared with an incidence of 29% in patients treated with beta-adrenergic blockers in CAPS-Care. Meta-analyses of beta-blocker prophylaxis clinical trials have estimated a 64% reduction in the odds of AF following surgery.
      • Burgess D.C.
      • Kilborn M.J.
      • Keech A.C.
      Interventions for prevention of post-operative atrial fibrillation and its complications after cardiac surgery: a meta-analysis.
      The data from this registry fail to identify a significant reduction in postoperative AF. This may reflect differences in the patient populations and co-morbidities in trials versus clinical practice. Alternatively, withdrawal of beta-blocker therapy may have limited the effectiveness of beta blockade.
      • Mathew J.P.
      • Fontes M.L.
      • Tudor I.C.
      • Ramsay J.
      • Duke P.
      • Mazer C.D.
      • Barash P.G.
      • Hsu P.H.
      • Mangano D.T.
      • Investigators of the Ischemia Research and Education Foundation
      • Multicenter Study of Perioperative Ischemia Research Group
      A multicenter risk index for atrial fibrillation after cardiac surgery.
      These data raise the hypothesis of whether continued high rates of postoperative AF are due to limited effectiveness of prophylaxis versus inconsistent application of treatment regiments. Future work should help identify strategies to improve adherence and continuation of therapy and clarify which beta-adrenergic blockers are the most effective.
      • Merritt J.C.
      • Niebauer M.
      • Tarakji K.
      • Hammer D.
      • Mills R.M.
      Comparison of effectiveness of carvedilol versus metoprolol or atenolol for atrial fibrillation appearing after coronary artery bypass grafting or cardiac valve operation.
      Following adjustment, amiodarone was associated with a trend toward a 25% reduction in the odds of postoperative AF. Given that amiodarone is often used in patients with more co-morbidities and higher surgical risk, this risk reduction in postoperative AF is notable. Nevertheless, amiodarone is associated with several well-known adverse events, including bradyarrhythmia, acute lung injury, and infusion-related hypotension.
      • Goldschlager N.
      • Epstein A.E.
      • Naccarelli G.
      • Olshansky B.
      • Singh B.
      Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology.
      Acute lung injury, although rare, is more likely to occur under high oxygen tensions common in ventilated patients after cardiac surgery.
      • Ashrafian H.
      • Davey P.
      Is amiodarone an underrecognized cause of acute respiratory failure in the ICU?.
      • Saussine M.
      • Colson P.
      • Alauzen M.
      • Mary H.
      Postoperative acute respiratory distress syndrome. A complication of amiodarone associated with 100 percent oxygen ventilation.
      One in 5 patients discontinued amiodarone in CAPS-Care. Taken together, the aggregate data on preoperative prophylaxis highlights the need for more safe, effective, and better tolerated agents.
      Unless preoperative prophylaxis is associated with significant risk reductions in clinical practice, clinicians are not likely to view the risk-to-benefit ratio favorably. Although several options are available for preoperative prophylaxis, none are strikingly effective or free of adverse events. The variability across sites in the utilization of any prophylaxis medication, beta-blocker, and amiodarone likely reflects the variety of opinions on prophylaxis in the community. The use of “other” antiarrhythmics in 7% of the cohort also highlights the variation in prescribing patterns. Although multiple trials have focused on comparisons between placebo or single agents, these studies are limited by their inclusion of select patients. Additionally, placebo-controlled studies or single-comparison trials fail to inform the main decision confronting clinicians before surgery: how to select from multiple agents. Future trials could improve the evidence base, and subsequent utilization, by comparing overall treatment strategies, including cardioversion, drug therapy, and anticoagulation for stroke prevention.
      • Wyse D.G.
      • Waldo A.L.
      • DiMarco J.P.
      • Domanski M.J.
      • Rosenberg Y.
      • Schron E.B.
      • Kellen J.C.
      • Greene H.L.
      • Mickel M.C.
      • Dalquist J.E.
      • Corley S.D.
      • Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      This study has several limitations. First, as with any observational study, comparison of treatment groups is challenging because of patient selection and accompanying bias. Our analysis focused on high-risk patients and therefore, these findings may not be representative of lower-risk populations. Second, we did not have a detailed history of previous AF other than the rhythm status at enrollment. Third, because the case report form captured the use of preoperative AF medications in a uniform data field, we did not have information regarding the duration of prophylaxis nor the exact reasons for prescription. For example, some beta-blocker use may have been predominantly for angina relief and treatment of heart failure. Notwithstanding, our ability to include all prophylactic medications (regardless of intended etiology) allows us to analyze their overall use in clinical practice, rather than in the confines of carefully controlled clinical trials. Finally, although our sample size included >2,000 patients, the use of some agents was limited (e.g., <1% sotalol use); therefore, our ability to detect differential outcomes may have been hindered by inadequate power.

      Acknowledgment

      We thank Erin LoFrese for her editorial and graphics assistance. Ms. LoFrese did not receive compensation for her assistance apart from her employment at the institution where the study was conducted. We dedicate this manuscript to the memory of our good friend and colleague, Winslow Klaskala, PhD.

      Disclosures

      Dr. Piccini receives grants for clinical research from Johnson & Johnson and provides consulting to Forest Laboratories, Janssen Pharmaceuticals, Medtronic, and Spectranetics. Dr. Hernandez receives research support from Johnson & Johnson and honoraria from AstraZeneca and Medtronic. An itemized list of disclosures for Drs. Piccini, Hernandez, and Peterson can be found at: https://dcri.org/about-us/conflict-of-interest. Dr. Peterson reports research support from Eli Lilly & Company and Janssen Pharmaceuticals, Inc. Drs. Mills and Klaskala report being full-time employees for Janssen Research & Development, LLC. Drs. Zhao, Steinberg, He, Mathew, Fullerton, and Hegland have no disclosures to report.

      Supplementary Data

      References

        • Ommen S.R.
        • Odell J.A.
        • Stanton M.S.
        Atrial arrhythmias after cardiothoracic surgery.
        N Engl J Med. 1997; 336: 1429-1434
        • Leitch J.W.
        • Thomson D.
        • Baird D.K.
        • Harris P.J.
        The importance of age as a predictor of atrial fibrillation and flutter after coronary artery bypass grafting.
        J Thorac Cardiovasc Surg. 1990; 100: 338-342
        • Creswell L.L.
        • Schuessler R.B.
        • Rosenbloom M.
        • Cox J.L.
        Hazards of postoperative atrial arrhythmias.
        Ann Thorac Surg. 1993; 56: 539-549
        • Lahtinen J.
        • Biancari F.
        • Salmela E.
        • Mosorin M.
        • Satta J.
        • Rainio P.
        • Rimpiläinen J.
        • Lepojärvi M.
        • Juvonen T.
        Postoperative atrial fibrillation is a major cause of stroke after on-pump coronary artery bypass surgery.
        Ann Thorac Surg. 2004; 77: 1241-1244
        • Elahi M.
        • Hadjinikolaou L.
        • Galiñanes M.
        Incidence and clinical consequences of atrial fibrillation within 1 year of first-time isolated coronary bypass surgery.
        Circulation. 2003; 108: II207-II212
        • Villareal R.P.
        • Hariharan R.
        • Liu B.C.
        • Kar B.
        • Lee V.V.
        • Elayda M.
        • Lopez J.A.
        • Rasekh A.
        • Wilson J.M.
        • Massumi A.
        Postoperative atrial fibrillation and mortality after coronary artery bypass surgery.
        J Am Coll Cardiol. 2004; 43: 742-748
        • Mathew J.P.
        • Parks R.
        • Savino J.S.
        • Friedman A.S.
        • Koch C.
        • Mangano D.T.
        • Browner W.S.
        Atrial fibrillation following coronary artery bypass graft surgery: predictors, outcomes, and resource utilization. Multi Center Study of Perioperative Ischemia Research Group.
        JAMA. 1996; 276: 300-306
        • Hravnak M.
        • Hoffman L.A.
        • Saul M.I.
        • Zullo T.G.
        • Whitman G.R.
        Resource utilization related to atrial fibrillation after coronary artery bypass grafting.
        Am J Crit Care. 2002; 11: 228-238
        • Auer J.
        • Weber T.
        • Berent R.
        • Ng C.K.
        • Lamm G.
        • Eber B.
        Postoperative atrial fibrillation independently predicts prolongation of hospital stay after cardiac surgery.
        J Cardiovasc Surg (Torino). 2005; 46: 583-588
        • Crystal E.
        • Garfinkle M.S.
        • Connolly S.S.
        • Ginger T.T.
        • Sleik K.
        • Yusuf S.S.
        Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery.
        Cochrane Database Syst Rev. 2004; : CD003611
        • Lahiri M.K.
        • Fang K.
        • Lamerato L.
        • Khan A.M.
        • Schuger C.D.
        Effect of race on the frequency of postoperative atrial fibrillation following coronary artery bypass grafting.
        Am J Cardiol. 2011; 107: 383-386
        • Williams J.B.
        • Hernandez A.F.
        • Li S.
        • Dokholyan R.S.
        • O'Brien S.M.
        • Smith P.K.
        • Ferguson T.B.
        • Peterson E.D.
        Postoperative inotrope and vasopressor use following CABG: outcome data from the CAPS-care study.
        J Card Surg. 2011; 26: 572-578
        • Harrell Jr., F.E.
        Regression Modeling Strategies with Applications to Linear Models, Logistic Regression and Survival Analysis.
        Springer-Verlag, New York2001
        • Zeger S.L.
        • Liang K.Y.
        Longitudinal data analysis for discrete and continuous outcomes.
        Biometrics. 1986; 42: 121-130
        • Mathew J.P.
        • Fontes M.L.
        • Tudor I.C.
        • Ramsay J.
        • Duke P.
        • Mazer C.D.
        • Barash P.G.
        • Hsu P.H.
        • Mangano D.T.
        • Investigators of the Ischemia Research and Education Foundation
        • Multicenter Study of Perioperative Ischemia Research Group
        A multicenter risk index for atrial fibrillation after cardiac surgery.
        JAMA. 2004; 291: 1720-1729
        • Zaman A.G.
        • Archbold R.A.
        • Helft G.
        • Paul E.A.
        • Curzen N.P.
        • Mills P.G.
        Atrial fibrillation after coronary artery bypass surgery: a model for preoperative risk stratification.
        Circulation. 2000; 101: 1403-1408
        • Auer J.
        • Lamm G.
        • Weber T.
        • Berent R.
        • Ng C.K.
        • Porodko M.
        • Eber B.
        Renal function is associated with risk of atrial fibrillation after cardiac surgery.
        Can J Cardiol. 2007; 23: 859-863
        • Gami A.S.
        • Hodge D.O.
        • Herges R.M.
        • Olson E.J.
        • Nykodym J.
        • Kara T.
        • Somers V.K.
        Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation.
        J Am Coll Cardiol. 2007; 49: 565-571
        • Chamberlain A.M.
        • Agarwal S.K.
        • Folsom A.R.
        • Soliman E.Z.
        • Chambless L.E.
        • Crow R.
        • Ambrose M.
        • Alonso A.
        A clinical risk score for atrial fibrillation in a biracial prospective cohort (from the Atherosclerosis Risk in Communities [ARIC] study).
        Am J Cardiol. 2011; 107: 85-91
        • Pritchett A.M.
        • Jacobsen S.J.
        • Mahoney D.W.
        • Rodeheffer R.J.
        • Bailey K.R.
        • Redfield M.M.
        Left atrial volume as an index of left atrial size: a population-based study.
        J Am Coll Cardiol. 2003; 41: 1036-1043
        • Fuster V.
        • Rydén L.E.
        • Cannom D.S.
        • Crijns H.J.
        • Curtis A.B.
        • Ellenbogen K.A.
        • Halperin J.L.
        • Le Heuzey J.Y.
        • Kay G.N.
        • Lowe J.E.
        • Olsson S.B.
        • Prystowsky E.N.
        • Tamargo J.L.
        • Wann S.
        • Smith Jr., S.C.
        • Jacobs A.K.
        • Adams C.D.
        • Anderson J.L.
        • Antman E.M.
        • Hunt S.A.
        • Nishimura R.
        • Ornato J.P.
        • Page R.L.
        • Riegel B.
        • Priori S.G.
        • Blanc J.J.
        • Budaj A.
        • Camm A.J.
        • Dean V.
        • Deckers J.W.
        • Despres C.
        • Dickstein K.
        • Lekakis J.
        • McGregor K.
        • Metra M.
        • Morais J.
        • Osterspey A.
        • Zamorano J.L.
        ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation).
        J Am Coll Cardiol. 2006; 48: 854-906
        • Dunning J.
        • Treasure T.
        • Versteegh M.
        • Nashef S.A.
        Guidelines on the prevention and management of de novo atrial fibrillation after cardiac and thoracic surgery.
        Eur J Cardiothorac Surg. 2006; 30: 852-872
        • Price J.
        • Tee R.
        • Lam B.K.
        • Hendry P.
        • Green M.S.
        • Rubens F.D.
        Current use of prophylactic strategies for postoperative atrial fibrillation: a survey of Canadian cardiac surgeons.
        Ann Thorac Surg. 2009; 88: 106-110
        • Burgess D.C.
        • Kilborn M.J.
        • Keech A.C.
        Interventions for prevention of post-operative atrial fibrillation and its complications after cardiac surgery: a meta-analysis.
        Eur Heart J. 2006; 27: 2846-2857
        • Merritt J.C.
        • Niebauer M.
        • Tarakji K.
        • Hammer D.
        • Mills R.M.
        Comparison of effectiveness of carvedilol versus metoprolol or atenolol for atrial fibrillation appearing after coronary artery bypass grafting or cardiac valve operation.
        Am J Cardiol. 2003; 92: 735-736
        • Goldschlager N.
        • Epstein A.E.
        • Naccarelli G.
        • Olshansky B.
        • Singh B.
        Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology.
        Arch Intern Med. 2000; 160: 1741-1748
        • Ashrafian H.
        • Davey P.
        Is amiodarone an underrecognized cause of acute respiratory failure in the ICU?.
        Chest. 2001; 120: 275-282
        • Saussine M.
        • Colson P.
        • Alauzen M.
        • Mary H.
        Postoperative acute respiratory distress syndrome. A complication of amiodarone associated with 100 percent oxygen ventilation.
        Chest. 1992; 102: 980-981
        • Wyse D.G.
        • Waldo A.L.
        • DiMarco J.P.
        • Domanski M.J.
        • Rosenberg Y.
        • Schron E.B.
        • Kellen J.C.
        • Greene H.L.
        • Mickel M.C.
        • Dalquist J.E.
        • Corley S.D.
        • Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators
        A comparison of rate control and rhythm control in patients with atrial fibrillation.
        N Engl J Med. 2002; 347: 1825-1833