Predictors, prevention, and long-term prognosis of atrial fibrillation after coronary artery bypass graft operations

J

THoRAc CARDIOVASC SURG

1987;94:331-5

Predictors, prevention, and long-term prognosis of atrial fibrillation after coronary artery bypass graft operations Multiple trials have suggested the use of digoxin, digoxin and propranolol, or timolol to prevent atrial fibrillation after coronary artery bypass grafting. No trial has evaluated the efficacy of digoxin verus propranolol. Furthermore, the predictors of postoperative atrial fibrillation and the long-term consequence of atrial fibrillation that reverts to sinus rhythm have not been established. One hundred fifty patients were randomized to receive no drug, propranolol (20 mg every 6 hours), or digoxin (0.5 mg followed by 0.25 mg daily). Twenty-seven patients were excluded from data analysis. In the remaining 123 patients, no preoperative parameter (age, sex, diabetes, hypertension, smoking, electrocardiographic p wavemorphology, or preoperative digoxin or propranolol therapy), intraoperative parameter (bypass time, aortic cross-clamp time, or number of vessels bypassed), or postoperative parameter (peak creatinine kinase, congestive heart failure, or pericarditis) by univariate or multivariate analysis predicted patients at risk for atrial' fibrillation. Sustained atrial fibrillation developed in 37.5% of control and 32.6% of digoxin-treated patients. Only 16.2 % of propranolol-treated patients had sustained atrial fibrillation (p < 0.03). There were no in-hospital complications in those patients with atrial fibrillation. After 26 ± 7 months follow-up, those patients with postoperative atrial fibrillation had no increased incidence of angina, cerebral vascular accident, myocardial infarction, or sudden death. Therefore, in this select population, propranolol prophylaxis is effective but discretionary.

David A. Rubin, M.D., FAe.C., Karen E. Nieminski, R.N., e.C.R.N., George E. Reed, M.D., FAe.C., and Michael V. Herman, M.D.,

r.x.c.c,

Atrial fibrillation is a frequent problem after coronary artery bypass graft operations. Multiple series have addressed the question of antiarrhythmic drug prophylaxis.':" Some recommend digoxin,':" some proprano101,4-7 others a combination of digoxin and proprano101,9,10 and still others advocate timolol." The more recent series favor beta blocker prophylaxis. However, no study has compared the efficacy and toxicity of propranolol to that of digoxin. Furthermore, no study has attempted to define adequately a patient population From the Divisionof Cardiology and Cardiothoracic Surgery, Departments of Medicine and Surgery, New York Medical College, Westchester County Medical Center, Valhalla, N. Y. Supported by a grant from the Dr. I Fund Foundation, New York, N. Y. Received for publication Aug. 18, 1986, Accepted for publication Oct. 6, 1986. Address for reprints: David A. Rubin, M.D., Division of Cardiology, Westchester County Medical Center, Valhalla, N. Y. 10595.

Valhalla. N. Y

at high risk for postoperative atrial fibrillation who would most benefit from prophylaxis. Last, no study has addressed the question of early or late morbidity and mortality in patients who have atrial fibrillation after coronary artery bypass grafting. It is not at all clear that prophylaxis is required. To attempt answers to these questions, we prospectively studied digoxin and propranolol prophylaxis after coronary artery bypass graft operations. Methods We prospectively randomized by lot 150 consecutive patients into three groups before coronary artery bypass graft operations. Group 1 received no drug. Group 2 received intravenous digoxin 0.5 mg on postoperative day 1, followed by 0.25 mg daily by mouth. Group 3 received propranolol 20 mg every 6 hours beginning on postoperative day 1. Drugs were continued for approximately 6 weeks. Exclusion criteria included prior history of atrial fibrillation, lung disease with bronchospasm,

331

The Journal of Thoracic and Cardiovascular Surgery

3 3 2 Rubin et al.

Table I. Comparison of patients with postoperative atrial fibrillation (AF) and normal sinus rhythm (NSR) * AF No. of patients Age (yr) Patients who smoked Patients with diabetes Patients with hypertension Patients receiving preop. propranolol Patients receiving preop. digoxin Pump time (min) Cross-clamp time (min) Vessels bypassed Peak creatinine kinase (U) Patients with pericarditis'[

36 58.8 ± 7 22 3 13 20

NSR 87 54.4 ± 8 56 II 46 66

2

4

114 ± 36 60 ± 26 4± I 667 ± 309 12

128 ± 39 69 ± 27 4±1 712 ± 421 49

"There were no significant differences between the two groups of patients. tDefined as presence of pericardial friction rub heard of two observers on two separate occasions.

brittle diabetes, previous severe bradycardia, highdegree atrioventricular block or known sensitivity to digoxin or propranolol, and ejection fraction less than 0.50. Patients with an ejection fraction less than 0.50 were excluded because the safety of early postoperative propranolol in patients with depressed myocardial function was not established at the time of this study. Patients with wall motion abnormalities were included if the overall ejection fraction was more than 0.50. Patients who had an intraoperative myocardial infarction or cerebral vascular accident, who died intraoperatively, or who developed a problem necessitating discontinuation of the drug were also excluded from analysis. Twenty-seven patients were excluded: two patients, perioperative death; two patients, myocardial infarction; two patients, cerebral vascular accident; two patients, postoperative contraindications to propranolol (bronchospasm, hypotension); and 19 patients, protocol deviations. The remaining 123 patients form the basis of this report. All patients underwent at least 96 hours of continuous electrocardiographic monitoring in the intensive care unit (bedside monitors and central nursing station monitors) plus 24 hour ambulatory monitoring (two-channel recorder, Del Mar Avionics, Irvine, Calif.). on postoperative day 3 and before discharge (day 12 to 14). Patients were seen daily and all rhythm strips and 24 hour recordings were reviewed. Sustained atrial fibrillation was defined as an episode lasting more than 30 seconds. This definition was chosen because all episodes in this series lasting longer than 30 seconds persisted until pharmacologic intervention. No episode

Table II. Comparison of control, propranolol, and digoxin groups

I No. of patients Age (yr) Patients who smoked Patients with diabetes Patients with hypertension Patients receiving preop. propranolol Patients receiving preop. digoxin Pump time (min) Cross-clamp time (min) Vessels bypassed Peak creatinine kinase (U) Pericarditis

Digoxin

I Propranolol

46 37 55.7 ± 7.4 55.0 ± 8.6 31 20 8 0 23 14 29 28

o

3

3

125 ± 42 126 ± 33 116 ± 42 69 ± 22 70 ± 31 61 ± 27 4 ± 1.5 4 ± I 4 ± 1.6 694 ± 454 653 ± 315 736 ± 433 24 14 23

lasting longer than 30 seconds terminated spontaneously. All 123 patients and their physicians participated in long-term follow-up. Contact was made by telephone. Patients and their physicians were asked a standardized series of questions regarding cerebral vascular accidents, recurrence of arrhythmia, angina, and related problems. Standard statistical techniques were used to analyze data. Incidence of phenomenon was analyzed by chi square or Student's t test. Multivariate analysis was performed. All subjects gave informed consent before entering the study. This protocol was approved by the Institutional Review Board of Westchester County Medical Center and New York Medical College. Results Incidence of atrial fibrillation. The overall incidence of atrial fibrillation was 29% (36 of 123 patients). Table I outlines the characteristics of those patients with and without atrial fibrillation. There is no single group of preoperative, intraoperative, or postoperative characteristics which identifies a patient population at higher risk for the development of atrial fibrillation. Drug efficacy. Sustained atrial fibrillation developed in 37.5% (15/40) of control patients and 32.6% (15/46) of patients receiving digoxin (p = NS*). Atrial fibrillation developed in only 16.2% (6/37) of patients receiving propranolol (p < 0.03). Table II outlines the characteristics of each group and shows that the groups are comparable for all analyzed characteristics. Atrial fibrillation occurred most commonly on the third postopera*NS

= No

significant difference.

Volume 94 Number 3 September 1987

tive day. All patients in the digoxin group received a minimum of 1 mg of digoxin before atrial fibrillation developed. Atrial fibrillation occurring in those patients receiving digoxin or propranolol was not slower or shorter in duration. Morbidity and mortality. Table III demonstrates that there was no higher incidence of cardiovascular morbidity or mortality in those patients with sustained atrial fibrillation after 26 ± 7 months' follow-up. There was one late death in the atrial fibrillation group and one in the sinus rhythm group. Both deaths were due to myocardial infarction. There was no in-hospital morbidity associated with atrial fibrillation. All patients required only pharmacologic measures for conversion to sinus rhythm. No patient required direct-current cardioversion. Table IV outlines the medications used for conversion to sinus rhythm. Digoxin was the most popular single drug for conversion. Drugs were chosen by the patient's private physician and were not administered in a controlled fashion. Therefore, no conclusion can be drawn regarding the relative efficacy of the different medications.

Discussion Our study demonstrates that, in patients with normal left ventricular function, (1) no preoperative, intraoperative, or postoperative characteristic(s) predict patients who have increased risk for postoperative atrial fibrillation, (2) propranolol but not digoxin reduces the incidence of atrial fibrillation, and (3) patients who have atrial fibrillation have slightly longer hospitalizations but have no increased early or late morbidity and mortality. The reported incidence of atrial arrhythmias after coronary artery bypass grafting depends upon the length and type of monitoring as well as the definition of arrhythmia. Tyras and colleagues,' using intensive care unit monitoring and citing only sustained atrial fibrillation, atrial flutter, or "paroxysmal atrial tachycardia," found an incidence of only 11.4%. White and associates," using continuous 24 hour electrocardiographic monitoring and allowing nonsustained supraventricular tachycardia, found an incidence of 100%. Those studies examining only sustained supraventricular arrhythmia report an incidence ranging from 11.4%3 to 40%.7 We found an incidence of 29%, confirming previous studies. Risk factor analysis is limited in prior studies. Only four of eleven series concerning postoperative atrial fibrillation report an analysis. In a study of 128 patients, Mills and co-workers? examined six preoperative and intraoperative variables (diabetes, smoking, hyperten-

Atrial fibrillation after coronary bypass 3 3 3

Table

m. Morbidity and mortality

No. of patients Hospital stay (days) Patients with angina Patients with syncope Patients with eVA No. of deaths

AF

NSR

p Value

36 14.4 ± 6 3 2

87 12.4 ± 4 14 4

p < 0.02 NS NS

0 1

0

1

NS NS

Legend: AF, Atrial fibrillation. NSR. Normal sinus rhythm. CV A. Cerebral vascular accident.

sion, prior myocardial infarction, family history of coronary artery disease, and aortic cross-clamp times). They found that atrial fibrillation was more common in older patients, diabetic patients, and patients with longer cross-clamp times. Multivariate analysis was not performed. Roffman's and Fieldman's study'? of 225 patients examined six variables (sex, age, aortic crossclamp time, number of bypass grafts, prior myocardial infarction, and mean preoperative propranolol dose). They concurred that age and longer aortic cross-clamp time were risk factors. They did not examine diabetes, smoking, or other preoperative risk factors. Furthermore, the fact that this study was not prospectively randomized sheds some doubt upon its validity. Silverman, Wright, and Levitsky," on the other hand, in a study of 100 patients, examined five preoperative characteristics (age, hypertension, prior myocardial infarction, extent of coronary artery disease, and preoperative propranolol dosage) and found no characteristic predictive of postoperative atrial fibrillation. They did not examine diabetes or intraoperative risk factors and did not perform a multivariate analysis. In an early study (1975), Johnson and associates! evaluated sex, age, coronary risk factors, extent of coronary disease, and postoperative potassium levels and hypoxia. In their series of 120 patients, none of these risk factors was predictive. Because of newer operative techniques, this study could be invalid and, again, no multivariate analysis was performed. We performed an extensive analysis of 14 preoperative, intraoperative, and postoperative risk factors. No single risk factor or group of risk factors, including the previously suggested age, diabetes, extent of coronary artery disease, or aortic cross-clamp time, defines a group of patients at increased risk for postoperative atrial fibrillation. Therefore, there is no defined subset of patients with a high incidence of atrial fibrillation who would particularly benefit from prophylaxis. Early series recommended the use of digoxin. Johnson and colleagues' demonstrated a reduction of 21.5% in

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3 3 4 Rubin et al.

Table IV. Acute therapy for atrial fibrillation Digoxin Digoxin + verapamil Digoxin + quinidine Digoxin + procainamide Propranolol Propranolol + quinidine

Cantral patients

Digoxin patients

9

4

7* 4* 1* 2*

0 0

0

I I

Propranolol patients

Total patients

2

18 5

0

1* 1*

I

I I

3

7 2 1

'These patients received intravenous digoxin in addition to their maintenance drug therapy.

the incidence of postoperative atrial fibrillation by prophylactic digoxin. Csicsko, Schatzlein, and King' also recommended digoxin, but their study was not prospectively randomized. Tyras and co-workers,' however, found a higher incidence of supraventricular arrhythmias in those patients receiving digoxin (27.8% versus 11.4%). Our prospective randomized study shows that digoxin has little or no effect upon postoperative atrial fibrillation. We cannot exclude the possibility that a small beneficial effect of digoxin was overlooked because of the small sample size. Prior studies report conflicting data regarding the efficacy of beta blocker prophylaxis. Williams and associates" found a significant reduction in postoperative atrial fibrillation. This study was randomized, but control patients received a variety of other antiarrhythmic drugs (including digoxin and quinidine) which could invalidate the conclusions. Both Stephenson,' Silverrnan," and their associates reported a significant reduction in postoperative atrial fibrillation in those patients who received propranolol. To confound the issue, Mohr, Smolinsky, and Goor? found a significant decrease in the incidence of atrial fibrillation in only those patients who received preoperative propranolol. White and colleagues" found no reduction in the incidence of atrial fibrillation in patients receiving timolol, although the incidence of other supraventricular arrhythmias was reduced. Matangi and co-workers" recently reported a reduction in the frequency of supraventricular arrhythmias from 23% to 9.8% by very low-dose propranolol therapy (5 mg every 6 hours). This study only randomized patients receiving preoperative propranolol and therefore the conclusions are limited to this select group. In our controlled, prospectively randomized series of all patients with preserved left ventricular function, postoperative propranolol significantly reduced the incidence of postoperative atrial fibrillation. Although prior studies demonstrated the efficacy of digoxin and propranolol over no drug therapy? and the

efficacy of propranolol and digoxin over propranolol alone,' no study compared the relative efficacy of digoxin and propranolol. In our direct comparison, propranolol is effective and digoxin is not. Digoxin is therefore not recommended for arrhythmia prophylaxis. All studies (including our study) exclude patients at high risk for propranolol therapy. Therefore, the incidence of complications in this select group of patients is low, ranging from 0%6 to 10%.7 In our series, 5% of patients could not receive postoperative propranolol. Although propranolol is effective and safe, it may not be necessary. No previous study has examined morbidity and mortality in patients with postoperative atrial fibrillation. Except for a slightly prolonged hospitalization, there is no in-hospital morbidity or mortality as a result of atrial fibrillation. Furthermore, the long-term prognosis of patients with postoperative atrial fibrillation is no different from that of patients who remain in normal sinus rhythm. Perioperative atrial fibrillation is a benign epiphenomenon with no short-term or long-term consequences. Prophylaxis is therefore discretionary. Limitations of this study. There are two major limitations to this study: 1. A higher dose of digoxin might be' effective. The dosage used, however, is an accepted standard dosage and no patient receiving digoxin had atrial fibrillation before receiving an adequate dose. 2. This series addresses only patients with preserved left ventricular function. The morbidity, mortality, and drug therapy may be markedly different in patients with depressed left ventricular function. The results of this study should not be extrapolated to patients with depressed left ventricular function. REFERENCES I. Johnson LW, Dickson A, Fryehan CT, et al: Prophylactic digitalization for coronary artery bypass graft surgery. Circulation 1976;53:819-22. 2. Csicsko JF, Schatzlein MH, King RD. Immediate post-

Volume 94 Number 3 September 1987

operative digitalization in the prophylaxis of supraventricular arrhythmias following coronary artery bypass graft surgery. J THORAC CARDIOVASC SURG 1981;81:419-22. 3. Tyras DH, Stothert JC, Kaiser GC, et al. Supraventricular tachyarrhythmias after myocardial revascularization: a randomized trial of prophylactic digitalization. J THORAC CARDIOVASC SURG 1979;79:310-4. 4. Williams JB, Stephenson LW, Halford FO, Langer T, Dunkam WB, Josephson ME. Arrhythmia prophylaxis using propranolol after coronary artery surgery. Ann Thorac Surg 1982;34:435-8. 5. Stephenson LW, MacVaugh H, Tomasello DN, Josephson ME. Propranolol for prevention of postoperative cardiac arrhythmias: a randomized study. Ann Thorac Surg 1980;29:113-6. 6. Silverman NA, Wright R, Levitsky S. Efficacy of lowdose propranolol in preventing postoperative supraventricular tachyarrhythmias. Ann Surg 1982;196:194-7. 7. Mohr R, Smolinsky A, Goor D. Prevention of supraventricular tachyarrhythmia with low dose propranolol after coronary bypass. J THORAC CARDJOVASC SURG 1981 ;81:840-5.

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8. Parker FB, Greiner-Hayes C, Bove EL, Marvastti MA, Johnson LW, Eich RH. Supraventricular arrhythmias following coronary artery bypass. J THORAC CARDIOVASC SURG 1983;86:594-600. 9. Mills SA, Poole GU, Breyer RH, et al. Digoxin and propranolol in the prophylaxis of dysrhythmias after coronary artery bypass grafting. Circulation 1983;68(Pt 2):11222-5. 10. Roffman JA, Fieldman A. Digoxin and propranolol in the prophylaxis of supraventricular tachydysrhythmias after coronary artery bypass graft surgery. Ann Thorac Surg 1981;31:496-501. 11. White HD, Antman EM, Glynn MA, et al. Efficacy and safety of timolol for prevention of supraventricular tachyarrhythmias after coronary artery bypass graft surgery. Circulation 1984;70:479-84. 12. Matangi MF, Neutze JM, Graham KJ, Hill DG, Kerr AB, Barratt-Boyes BG. Arrhythmia prophylaxis after aorta-coronary bypass. J THORAC CARDIOVASC SURG 1985;89:439-43.