Dofetilide

While there is a deficiency in the number of randomized control studies dealing with the pharmacologic control of the ventricular response to atrial fibrillation (AF) or atrial flutter (AFL) after cardiac surgery, evidence-based recommendations are presented from those studies that are available. Because of the hyperadrenergic state after surgery, beta-blockers are recommended as the first line of therapy for patients with AF or AFL who do not require urgent cardioversion. Calcium channel blockers are recommended as second-line therapeutic agents. Digoxin has little efficacy because of the heightened adrenergic tone that is present postoperatively. Agents that are proarrhythmic, such as dofetilide, or agents that are contraindicated in patients with coronary artery disease, such as flecainide and propafenone, are not recommended.

Key words: atrial fibrillation; atrial flutter; cardiopulmonary bypass; coronary artery bypass graft; rapid ventricular response

Abbreviations: AF = atrial fibrillation; AFL = atrial flutter; CABG = coronary artery bypass grafting; RCT = randomized controlled trial; VR = ventricular rate

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Despite efforts to identify patients who are at increased risk for experiencing atrial fibrillation (AF) and atrial flutter (AFL) following cardiac surgery, these arrhythmias remain the most common arrhythmia complications of coronary artery bypass grafting (CABG) and valvular surgical procedures with cardiopulmonary bypass. (1) AF and AFL occur in 11 to 40% of patients after CABG, (2) and in up to 60% of patients after valvular surgery. (3)

Postoperative AF and AFL are associated with increased risk for stroke, other morbidity, and mortality following cardiac surgery. (4) In addition, AF and AFL are associated with increased ICU and hospital lengths of stay, and additional costs. (1) While some episodes of AF and AFL are self-limited, others require aggressive management to control the ventricular rate or to restore and maintain sinus rhythm.

The purpose of this systematic review is to synthesize the evidence on the efficacy and safety of agents used to control the ventricular response to AF and AFL following cardiac surgery. The evidence-grading methodology has been used extensively in guideline development. (5) After abstract review, nine studies were eligible for inclusion in this review of pharmacologic ventricular rate control. (6-14)

Beta-blockers and calcium channel blockers are generally accepted as the mainstay of therapy for ventricular rate control. The following are summaries of the articles included in the review with their associated evidence grades, grouped by drug class.

SUMMARIES OF EVIDENCE REVIEW

Class II Drugs (Beta-Blockers)

One randomized controlled trial (RCT) compared the efficacy of esmolol to that of diltiazem in the management of patients with postoperative AF and AFL following CABG and or valve surgery. (6) Esmolol was as efficacious as diltiazem for ventricular rate control at 24 h in patients who did not convert to sinus rhythm. This trial had important limitations including small size (30 patients), differences in ancillary medications between groups, and other key factors. One patient in each group had the drug discontinued due to hypotension. We concluded that [beta]-blockade may be as efficacious as diltiazem in controlling the ventricular rate in postoperative AF and AFL based on weak evidence.

Class IV Drugs (Calcium Channel Blockers)

Diltiazem: Two trials assessed the efficacy of diltiazem for the control of the ventricular rate in patients experiencing AF and AFL following cardiac surgery. Mooss et al (6) reported that diltiazem was as efficacious as esmolol for ventricular rate control. Tisdale et al (7) showed that the ventricular rate was significantly slower at 2 h in patients treated with diltiazem compared to those treated with digoxin, but was no different at 24 h. The mean ([+ or -] SD) time to rate control was shorter with diltiazem (10 [+ or -] 20 min) than with digoxin (352 -+ 312 min; p < 0.001). The number of withdrawals due to adverse effects was slightly greater with diltiazem than with digoxin, but the difference was not statistically significant. We concluded that diltiazem may be efficacious for controlling the ventricular response in patients with postoperative AF and AFL, but that the evidence to support this recommendation is weak.

Verapamil: Three randomized, crossover trials assessed the efficacy of verapamil compared to placebo for controlling the ventricular response in patients with postoperative AF and AFL. (8-10) The total number of patients in the three trials was only 62, and the trials had other limitations with an average overall quality score of only 57%. All three trials showed a decrease in heart rate in the verapamil-treated patients, but did not clearly report whether the decrease was statistically significant. No significant side effects were reported. We conclude that verapamil may be efficacious for controlling the ventricular response in patients with postoperative AF and AFL, but the evidence is weak.

Class IC Drugs

Propofenone: Two trials (11,12) assessed the efficacy of propafenone for heart rate control. One study (11) used a crossover design, included only 14 patients, and had other serious study limitations. Propafenone was reported to be significantly better than placebo in the control of the ventricular rate in patients with postoperative AF and AFL. (1) No patient had the drug discontinued due to adverse effects. The other study (12) was an RCT with 84 patients that compared propafenone and amiodarone. The drugs were reported to be equally efficacious in controlling the ventricular rate in patients with postoperative AF and AFL. Side effects were more common with the use of propafenone, but the difference was not statistically significant. Six patients in each group had the drug discontinued for bradyarrhythmia, and at least some of the patients required temporary epicardial pacing. We concluded that propafenone might be efficacious for controlling the ventricular response in patients with postoperative AF and AFL, with a potential for bradycardia, but the evidence is weak. It must also be recognized that class IC drugs are contraindicated in patients with coronary artery disease.

Class III Drugs

Amiodarone: Two RCTs assessed the efficacy of amiodarone in ventricular rate control compared to propafenone (12) or digoxin. (13) In the latter study, amiodarone was as emeacious as digoxin in heart rate control with a nonsignificant trend toward better rate control than with digoxin at 24 h. No patient experienced an adverse drug reaction. The study had moderate limitations including small study size (30 patients) and an overall quality score of 53%. We concluded that amiodarone might be efficacious in controlling the ventricular response in patients with postoperative AF and AFL, with a potential moderate risk of excessive bradycardia, but the evidence is weak.

Dofetilide: One well-done RCT (14) reported that dofetilide was not significantly better than placebo in controlling the ventricular rate of patients with postoperative AF or AFL. This trial assessed two dosing regimens of dofetilide (4 and 8 mcg/kg). An important limitation of this trial was the short follow-up time of 3 h after arrhythmia onset. Four patients in the high-dose dofetilide group had short episodes of ventricular tachycardia. We concluded that dofetilide was not efficacious for controlling the ventricular response in patients with postoperative AF and AFL, and that it potentially had significant risks, but the evidence is based on only one study.

Digoxin

Two RCTs (7,13) (discussed above) assessed the efficacy of digoxin. Tisdale et al (7) reported that digoxin was as efficacious as diltiazem in slowing the ventricular response in patients with AF at 24 h, with the use of diltiazem resulting in more rapid rate control. Cochrane et al (13) showed there was no difference between the use of amiodarone and digoxin for heart rate control. We concluded that digoxin may not be more efficacious than diltiazem or amiodarone in controlling the ventricular response in patients with postoperative AF, but the evidence is weak.

Table 1 summarizes the results of the various studies for pharmacologic rate control in patients with AF or AFL following cardiac surgery. Table 2 summarizes the evidence grade, net benefit, and overall strength of the recommendations for pharmacologic heart rate control for postoperative AF/ AFL.

DISCUSSION

Although spontaneous conversion is common, (13,15-17) pharmacologic management of the ventricular rate in postoperative AF and AFL patients with a rapid ventricular response continues to be an important problem following cardiac surgery. However, since atrial arrhythmias are usually self-limited, the relative risks and benefits of therapy must be carefully considered. Little guidance based on scientific evidence exists regarding the best pharmacologic agents with which to achieve ventricular rate control. On the basis of this data review, we are unable to state definitively the relative efficacy of the agents because of the inability to ensure comparable study groups, comparable outcome measures, and monitoring methods. However, this data synthesis in combination with studies in the non-cardiac surgery literature (18,19) forms a body of evidence for the optimal management of heart rate control with beta-blockers and calcium channel blockers as the mainstays of therapy. Furthermore, since beta-blockers are indicated for other reasons in patients with coronary artery disease, (20,21) they remain an excellent choice for management. Although many guidelines do not recommend the use of beta-blockers in patients with low ejection fractions, these agents have a clear use and provide a benefit in survival and quality of life in nonsurgical patients with heart failure. (22,23) Finally, many patients with coronary artery disease receive beta-blockers preoperatively, and their withdrawal increases the risk of postoperative AF and AFL, thereby giving another compelling reason for their use. (24) If providing therapy with calcium channel blockers, diltiazem should be considered as the agent of choice as it has been shown to have a more hemodynamically stable profile. (25)

It should be noted that although there is a long tradition of using digoxin postoperatively for treating AF and AFL, the lack of effect of digoxin on adrenergic tone makes it a less than ideal agent. Furthermore, studies (26,27) have shown that it not only does not convert AF and AFL, but also it may increase the incidence of AF and AFL and may prolong any episodes that occur.

Limitations

There are suggestions in the literatures (8,10,11,14,19) that the use of many ventricular rate-controlling agents is better than placebo, at least in the early course of AF or AFL. However, these studies are marked by significant limitations. Very few RCTs are available, and, in particular, few placebo-controlled trials exist. Additionally, none of the rate control agents received a grade of evidence better than low quality. These issues limit our ability to make firm recommendations based on RCT data.

Another serious limitation is the heterogeneity of the methods and outcome measures used. Many of the trials failed to define the ancillary medications that were administered to subjects, and some trials allowed the concomitant use of multiple rate-controlling agents (eg, beta-blockers and digoxin). Last, the generalizability of the results is limited because many of the studies excluded patients who make up a large and growing portion of the population of patients with postoperative arrhythmias such as those with congestive heart failure, decreased left ventricular function, and conduction abnormalities.

SUMMARY OF RECOMMENDATIONS

The pharmacologic management of the ventricular rate in postoperative AF or AFL patients with a rapid ventricular response is a problem that must frequently be addressed after cardiac surgery. A summary of the evidence grade, net benefit, and overall strength of the recommendations for pharmacologic agents is presented in Table 2. The pharmacologic management of ventricular rate must be considered in the total context of the management of postoperative AF and AFL.

1. In patients with postoperative AF and AFL who do not need urgent cardioversion and have no contraindication to anticoagulation therapy, therapy with beta-blockers is recommended as the first-line pharmacologic choice for ventricular rate control. (28-30) This recommendation is based on a limited amount of evidence, but the recommendation is made in consideration of the hyperadrenergic state that typically exists after surgery, and the effect of beta-blockers on adrenergic tone (strength of recommendation, B; evidence grade, low quality; net benefit, intermediate).

2. For patients with postoperative AF and AFL, we recommend the calcium channel blockers diltiazem and verapamil as second-line choices for ventricular rate control (strength of recommendation, B; evidence grade, low quality; net benefit, intermediate).

3. In the setting of postoperative AF or AFL, we do not consider amiodarone to be a first-line or first-alternative choice for ventricular rate control. While amiodarone may be used as an alternative to beta-blockers or calcium channel blockers, limited evidence suggests that excessive bradycardia or respiratory dysfunctional may be side effects in some patients (strength of recommendation, I; evidence grade, low; net benefit, small/weak).

4. In the setting of postoperative AF or AFL, digoxin is not considered to be a first-line or first-alternative choice for ventricular rate control. Although digoxin is widely used to treat postoperative AF and AFL, it has no effect on adrenergic tone and therefore may not be as efficacious for rate control in patients with AF or AFL. Limited evidence indicates that digoxin may not be more effective than diltiazem or amiodarone in controlling ventricular rate in patients with postoperative AF (strength of recommendation, I; evidence grade, low; net benefit, none).

5. For the control of ventricular rate in patients with postoperative AF or AFL, we recommend against the use of any drugs that may be, or have been shown to be, proarrhythmic. While propafenone may be efficacious in controlling ventricular rate in patients with postoperative AF or AFL, it has a potential to cause bradycardia and should not be given to patients with coronary artery disease. (32) Dofetilide is not considered to be efficacious and may be proarrhythmic (strength of recommendation, D; evidence grade, low quality; net benefit, negative).

REFERENCES

(1) Aranki SF, Shaw DP, Adams DH, et al. Predictors of atrial fibrillation after coronary artery surgery: current trends and impact on hospital resources. Circulation 1996; 94:390-397

(2) Ommen SR, Odell JA, Stanton MS. Atrial arrhythmias after cardiothoracic surgery. N Engl J Med 1997; 336:1429-1434

(3) Creswell LL, Schuessler RB, Rosenbloom M, et al. Hazards of postoperative atrial arrhythmia. Ann Thorac Surg 1993; 56:539-549

(4) Hogue CW, Hyder ML. Atrial fibrillation after cardiac operation: risks, mechanisms, and treatment. Ann Thorac Surg 2000; 69:300-306

(5) Garbutt JC, West SL, Carey TS, et al. Pharmacological treatment of alcohol dependence: a review of the evidence. JAMA 1999; 281:1318-1325

(6) Mooss AN, Wurdeman RL, Mohiuddin SM, et al. Esmolol versus diltiazem in the treatment of postoperative atrial fibrillation/atrial flutter after open heart surgery. Am Heart J 2000; 140:176 180

(7) Tisdale JE, Padhi ID, Goldberg AD, et al. A randomized, double-blind comparison of intravenous diltiazem and digoxin for atrial fibrillation after coronary artery bypass surgery. Am Heart J 1998; 135:739-747

(8) Gray RJ, Conklin CM, Sethna DH, et al. Role of intravenous verapamil in supraventricular tachyarrhythmias after open-heart surgery. Am Heart J 1982; 104:799-802

(9) Hwang MH, Danoviz J, Pacold I, et al. Double-blind crossover randomized trial of intravenously administered verapamil: its use for atrial fibrillation and flutter following open heart surgery. Arch Intern Med 1984; 144:491-494

(10) Plumb VJ, Karp RB, Kouchoukos NT, et al. Verapamil therapy of atrial fibrillation and atrial flutter following cardiac operation. J Thorac Cardiovasc Surg 1982; 83:590-596

(11) Connolly SJ, Mulji AS, Hoffert DL, et al. Randomized placebo-controlled trial of propafenone for treatment of atrial tachyarrhythmias after cardiac surgery. J Am Coll Cardiol 1987; 10:1145-1148

(12) Di Biasi P, Serofani R, Paje A, et al. Intravenous amiodarone versus propafenone for atrial fibrillation and flutter after cardiac operation. Eur J Cardiothorac Surg 1995; 9:587-591

(13) Cochrane AD, Siddins M, Rosenfeldt FL, et al. A comparison of amiodarone and digoxin for treatment of supraventricular arrhythmias after cardiac surgery. Eur J Cardiothorac Surg 1994; 8:194-198

(14) Frost L, Mortensen PE, Tingleff J, et al. Efficacy and safety of dofetilide, a new class III antiarrhythmic agent, in acute termination of atrial fibrillation or flutter after coronary artery bypass surgery: Dofetilide Post-CABG Study Group. Int J Cardiol 1997; 58:135-140

(15) Campbell TJ, Morgan JJ. Treatment of atrial arrhythmias after cardiac surgery with intravenous disopyramide. Aust N Z J Med 1980; 10:644-649

(16) Gavaghan TP, Feneley MP, Campbell TJ, et al. Atrial tachyarrhythmias after cardiac surgery: results of disopyramide therapy. Aust N Z J Med 1985; 15:27-32

(17) Vanderlugt JT, Mattioni T, Denker S, et al. Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery. Circulation 1999; 100:369-375

(18) Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC 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 and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation). Circulation 2001; 104: 2118-2150

(19) Segal JB, McNamara RL, Miller MR, et al. The evidence regarding the drugs used for ventricular rate control. J Faro Pract 2000; 49:47-59

(20) Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 2002; 39:542-553

(21) Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic Stable Angina. Circulation 1999; 99:2829-2848

(22) Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure); developed in collaboration with the International Society for Heart and Lung Transplantation--endorsed by the Heart Failure Society of America. 2001; 104:2996-3007

(23) Heart Failure Society of America. HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction: pharmacological approaches. J Card Fail 1999; 5:357-382

(24) All IM, Sanalla AA, Clark V. Beta-blocker effects on postoperative atrial fibrillation. Eur J Cardiothorac Surg 1997; 11:1154-1157

(25) Heywood JT. Calcium channel blockers for heart rate control on atrial fibrillation complicated by congestive heart failure. Can J Cardiol 1995; 11:823-826

(26) Falk RH, Knowlton AA, Bernard SA, et al. Digoxin for converting recent onset atrial fibrillation to sinus rhythm: a randomized, double-blinded trial. Ann Intern Med 1987; 106:503-506

(27) Falk RH. Proarrhythmia in patients treated for atrial fibrillation or flutter. Ann Intern Med 1992; 117:141-150

(28) Andrews TC, Reimold SC, Berlin JA, et al. Prevention of supraventricular arrhythmias after coronary artery bypass surgery: a recta-analysis of randomized control trials. Circulation 1991; 84:III236-II244

(29) Balser J, Martinez EA, Winter BD, et al. Beta-adrenergic blockade accelerates conversion of postoperative supraventricular tachyarrhythmias. Anesthesiology 1998; 89:1052-1059

(30) Maisel WH, Raven JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001; 135:1061-1073

(31) Ashrafian H, Davey P. Is amiodarone an underrecoguized cause of acute respiratory failure in he ICU? Chest 2001; 120:275-282

(32) Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrences of atrial fibrillation: Canadian trial of atrial fibrillation. N Engl J Med 2000; 342:913-921

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

Correspondence to: Elizabeth A. Martinez, MD, The Johns Hopkins, Hospital, 600 N Wolfe St, Meyer 296, Baltimore, MD 21287-7294; e-mail: emartine@jhmi.edu

* From the Departments of Anesthesia (Dr. Martinez) and Medicine (Dr. Bass), The Johns Hopkins University School of Medicine, Baltimore, MD; and the Department of Medicine (Dr. Epstein), Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL.

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