New Insights Into the Pharmacologic Management of Atrial Fibrillation
New Insights Into the Pharmacologic Management of Atrial Fibrillation
Atrial fibrillation (AF) may be the most common cardiac arrhythmia requiring pharmacologic management for symptom control. One option for AF management is rate control with drugs such as beta-blockers, calcium channel blockers, or digoxin, or a combination thereof. Another strategy is to use antiarrhythmic drugs to try to maintain sinus rhythm in conjunction with rate-controlling agents to prevent rapid rates during AF. Still, after a number of years, the debate continues as to whether one strategy is preferable to the other with regard to outcome.
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial directly tested the 2 strategies -- rhythm vs rate control -- in patients with paroxysmal or persistent AF who also had at least 1 risk factor for stroke, which justified anticoagulant treatment. . As announced at the American College of Cardiology meeting in March, neither strategy was found to be superior with respect to the primary outcome, total mortality. There was also no difference between the 2 strategies with regard to the secondary composite end point of total mortality, disabling stroke or anoxic encephalopathy, major bleeding, or cardiac arrest. However, it was noted that patients in the rhythm control arm required hospitalization during follow-up significantly more often than patients in the rate control arm. In addition, after an adjustment for variables such as age and ejection fraction in a multivariate Cox model, rate control had a significantly lower risk of death than rhythm control. Such findings indicate that there appears to be no advantage to the use of antiarrhythmic drugs for the maintenance of sinus rhythm in AF patients.
At the just-completed Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology in San Diego, new information from substudies of the AFFIRM trial as well as from other clinical trials was presented that addresses other management issues relevant to patients with AF.
In a substudy of the AFFIRM Trial, the First Antiarrhythmic Drug Substudy, patients were randomized to amiodarone, sotalol, or a class I antiarrhythmic drug as the first antiarrhythmic drug. The primary end point of the study was a composite end point of survival at 1 year in sinus rhythm, with no cardioversion, while still taking the assigned antiarrhythmic drug. The most successful drug for maintenance of sinus rhythm was amiodarone; 62% of patients treated with this drug met the primary end point. With sotalol, 39% of patients were successfully treated at 1 year, while only 23% of patients taking class I agents met the primary end point. Despite the differences in primary outcome, approximately 80% of patients in each of the treatment groups were in sinus rhythm at 1 year. However, this outcome was achieved using 2 or more antiarrhythmic drugs in many of the patients initially assigned to sotalol or a class I drug.
It is prudent to remember that, although amiodarone was shown to be the most effective drug for control of AF, it has the potential for serious side effects in the long term. Despite this caution, as compared to other antiarrhythmic drug treatment, amiodarone is a good choice for antiarrhythmic drug treatment to maintain sinus rhythm in patients with serious structural heart disease because it is less likely to cause serious cardiac toxicity, including torsade de pointes. A reasonable approach to rhythm control in patients without serious structural heart disease is to attempt to treat patients with less toxic antiarrhythmic drugs as first-line agents, and only to move on to amiodarone if the first or second antiarrhythmic drug chosen is ineffective.
Another substudy of the AFFIRM Trial, the Functional Status and Quality of Life Substudy evaluated a subset of 716 patients from AFFIRM. The substudy found that patients in the AFFIRM trial had a lower quality of life (QOL) compared with a general population of a similar age. Improvement over time was noted with regard to QOL, mental summary, and symptom frequency and severity. However, there was no difference in QOL outcomes in the rhythm control vs the rate control arms of the trial. Thus, in patients similar to those enrolled in AFFIRM, choice of a rhythm control strategy to improve QOL is not warranted.
As noted, the main finding of AFFIRM was that clinical outcome was the same regardless of whether a rate control or a rhythm control strategy was selected as the initial therapy. This finding was confirmed by the preliminary results of a Canadian study that examined nearly 500 patients with AF hospitalized in Nova Scotia during the period from 1997-1999. . The study compared patients treated with antiarrhythmic drugs at the discretion of the treating physician to those patients taking rate control agents alone. The only significant differences between the 2 groups were that the patients treated with antiarrhythmic drugs were more likely to have a history of AF and less likely to have congestive heart failure. In 17 +/- 7 months of follow-up, the group treated with antiarrhythmic drugs was more likely to be readmitted to the hospital, but the difference was explained entirely by the fact that this group had a higher prevalence of prior AF. The study found that treatment with antiarrhythmic drugs does not reduce hospital readmission rates in patients with a history of AF, a finding that confirms the results of the larger multicenter AFFIRM Trial.
In other clinical studies, strategies for safe and effective cardioversion of AF were investigated. For instance, one study examined the effectiveness of type 1C antiarrhythmic drugs flecainide and propafenone on an intermittent use for chemical cardioversion of AF. The use of either drug at a single dose is a known strategy for chemical cardioversion. For propafenone, 600 mg is given orally as a single dose, and for flecainide, 300 mg is given orally. In the present study, the long-term safety, efficacy, and number of recurrent episodes of AF and need for hospitalization were studied in 83 patients with sporadic AF. None of the patients had evidence of structural heart disease or conduction abnormalities on a 12-lead electrocardiogram, and all were under the age of 75 years. The first administration of either propafenone or flecainide was done under observation, with documentation of termination of AF. Patients also took either metoprolol or diltiazem if they had rapid rates while in AF. Subsequently, patients took their medication at home. Over the course of the 2-year minimum follow-up, a median of 3 episodes of AF recurred, and a total of 298 episodes of AF were analyzed. At follow-up, only 25 episodes (8%) of AF were not terminated by the given antiarrhythmic drug, and only 1 patient reported symptoms of dizziness with termination of the arrhythmia. While the median number of hospitalizations for all patients prior to entering the study was 2, only 6 patients (7%) were hospitalized over a mean follow-up period of 31 +/- 8 months. The regimen had to be changed for 9 patients to daily antiarrhythmic drug administration (11%). The study found that this strategy yields a marked reduction in hospitalizations and demonstrates the safety of this approach. It should be noted, however, that both flecainide and propafenone are contraindicated in patients with structural heart disease, given the well-known adverse impact of type 1C antiarrhythmic drugs on survival in patients after myocardial infarction.
One option for chemical cardioversion of AF in a monitored setting has been ibutilide. One of the well-known problems with this drug's use is the potential development of torsade de pointes following administration. Magnesium sulfate has been used for a number of years for the acute treatment of torsade de pointes. In a clinical study reported at NASPE, magnesium sulfate was given prophylactically to patients in AF prior to the administration of ibutilide, under the hypothesis that such a strategy could reduce the incidence of torsade de pointes. Ninety-five patients were studied, in whom structural heart disease was present in 55%, with a mean ejection fraction of 45% +/- 10%. Importantly, the patients in the study were already taking antiarrhythmic drugs, with amiodarone in 40 patients, sotalol in 20, and flecainide or propafenone in the remainder. Baseline QTc was < 450 ms in all patients, and serum potassium level was normal. Intravenous magnesium was given as a 2-g bolus over 1 minute, 5 minutes before ibutilide was administered. Ibutilide was then given as a 1-g bolus over 10 minutes, followed by another 1 g in 5 minutes if the atrial arrhythmia persisted. Conversion to sinus rhythm occurred in 60% of patients with ibutilide, with 90% converting to sinus rhythm either chemically or electrically. There were no episodes of torsade de pointes in the entire patient cohort. Thus, it appears that prophylactic administration of magnesium prior to giving ibutilide may help to reduce the incidence of torsade de pointes.
Preliminary results of a clinical trial studying a new antiarrhythmic drug, dronedarone, were released. Dronedarone is a benzofuran derivative, structurally related to amiodarone. It has an electrophysiologic profile similar to that of amiodarone, but its lack of iodine and its different pharmacokinetic profile make it a promising alternative to amiodarone. In a dose-ranging study of 199 patients, 400 mg of dronedarone given twice daily led to a significant increase in time to first recurrence of AF (60 days for the dronedarone group vs 5 days for the placebo group [P = .001]). There was no proarrhythmia and the drug was well tolerated. Further investigations of this promising drug are warranted.
Population-based studies of patients with AF have shown that patients treated with angiotensin-converting enzyme (ACE) inhibitors have a reduced risk of AF. To test the risk of recurrence in patients with a known history of the arrhythmia, 154 patients with persistent AF were divided into 2 groups, one treated with amiodarone alone and the other with amiodarone plus irbesartan, an angiotensin II receptor antagonist. After cardioversion, patients were followed to first recurrence of AF. After a median follow-up time of 163 days, the group treated with irbesartan had a lower incidence of recurrent AF, 80% vs 56%, P = .007. The mechanism of the effect is not known, but the results suggest that an ACE inhibitor may be a useful adjunct to the management of AF, particularly when hypertension is coexistent.
The implications from recent clinical trials are that the use of antiarrhythmic drugs for the treatment of AF solely for any theoretical benefits on QOL, survival, prevention of stroke, or reduction in hospital admission rates is not warranted. Thus, for patients with infrequent or short-lived episodes of AF, particularly when they are only minimally symptomatic, a strategy of rate control only, along with anticoagulation in appropriately selected patients, is a simple and useful approach. This strategy has been found to be at least as advantageous as the use of antiarrhythmic drugs. However, when patients' symptoms warrant additional treatment, new data on methods for chemical or electrical cardioversion of AF allow us to restore sinus rhythm safely in the majority of patients.
References
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial directly tested the 2 strategies -- rhythm vs rate control -- in patients with paroxysmal or persistent AF who also had at least 1 risk factor for stroke, which justified anticoagulant treatment. . As announced at the American College of Cardiology meeting in March, neither strategy was found to be superior with respect to the primary outcome, total mortality. There was also no difference between the 2 strategies with regard to the secondary composite end point of total mortality, disabling stroke or anoxic encephalopathy, major bleeding, or cardiac arrest. However, it was noted that patients in the rhythm control arm required hospitalization during follow-up significantly more often than patients in the rate control arm. In addition, after an adjustment for variables such as age and ejection fraction in a multivariate Cox model, rate control had a significantly lower risk of death than rhythm control. Such findings indicate that there appears to be no advantage to the use of antiarrhythmic drugs for the maintenance of sinus rhythm in AF patients.
At the just-completed Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology in San Diego, new information from substudies of the AFFIRM trial as well as from other clinical trials was presented that addresses other management issues relevant to patients with AF.
In a substudy of the AFFIRM Trial, the First Antiarrhythmic Drug Substudy, patients were randomized to amiodarone, sotalol, or a class I antiarrhythmic drug as the first antiarrhythmic drug. The primary end point of the study was a composite end point of survival at 1 year in sinus rhythm, with no cardioversion, while still taking the assigned antiarrhythmic drug. The most successful drug for maintenance of sinus rhythm was amiodarone; 62% of patients treated with this drug met the primary end point. With sotalol, 39% of patients were successfully treated at 1 year, while only 23% of patients taking class I agents met the primary end point. Despite the differences in primary outcome, approximately 80% of patients in each of the treatment groups were in sinus rhythm at 1 year. However, this outcome was achieved using 2 or more antiarrhythmic drugs in many of the patients initially assigned to sotalol or a class I drug.
It is prudent to remember that, although amiodarone was shown to be the most effective drug for control of AF, it has the potential for serious side effects in the long term. Despite this caution, as compared to other antiarrhythmic drug treatment, amiodarone is a good choice for antiarrhythmic drug treatment to maintain sinus rhythm in patients with serious structural heart disease because it is less likely to cause serious cardiac toxicity, including torsade de pointes. A reasonable approach to rhythm control in patients without serious structural heart disease is to attempt to treat patients with less toxic antiarrhythmic drugs as first-line agents, and only to move on to amiodarone if the first or second antiarrhythmic drug chosen is ineffective.
Another substudy of the AFFIRM Trial, the Functional Status and Quality of Life Substudy evaluated a subset of 716 patients from AFFIRM. The substudy found that patients in the AFFIRM trial had a lower quality of life (QOL) compared with a general population of a similar age. Improvement over time was noted with regard to QOL, mental summary, and symptom frequency and severity. However, there was no difference in QOL outcomes in the rhythm control vs the rate control arms of the trial. Thus, in patients similar to those enrolled in AFFIRM, choice of a rhythm control strategy to improve QOL is not warranted.
As noted, the main finding of AFFIRM was that clinical outcome was the same regardless of whether a rate control or a rhythm control strategy was selected as the initial therapy. This finding was confirmed by the preliminary results of a Canadian study that examined nearly 500 patients with AF hospitalized in Nova Scotia during the period from 1997-1999. . The study compared patients treated with antiarrhythmic drugs at the discretion of the treating physician to those patients taking rate control agents alone. The only significant differences between the 2 groups were that the patients treated with antiarrhythmic drugs were more likely to have a history of AF and less likely to have congestive heart failure. In 17 +/- 7 months of follow-up, the group treated with antiarrhythmic drugs was more likely to be readmitted to the hospital, but the difference was explained entirely by the fact that this group had a higher prevalence of prior AF. The study found that treatment with antiarrhythmic drugs does not reduce hospital readmission rates in patients with a history of AF, a finding that confirms the results of the larger multicenter AFFIRM Trial.
In other clinical studies, strategies for safe and effective cardioversion of AF were investigated. For instance, one study examined the effectiveness of type 1C antiarrhythmic drugs flecainide and propafenone on an intermittent use for chemical cardioversion of AF. The use of either drug at a single dose is a known strategy for chemical cardioversion. For propafenone, 600 mg is given orally as a single dose, and for flecainide, 300 mg is given orally. In the present study, the long-term safety, efficacy, and number of recurrent episodes of AF and need for hospitalization were studied in 83 patients with sporadic AF. None of the patients had evidence of structural heart disease or conduction abnormalities on a 12-lead electrocardiogram, and all were under the age of 75 years. The first administration of either propafenone or flecainide was done under observation, with documentation of termination of AF. Patients also took either metoprolol or diltiazem if they had rapid rates while in AF. Subsequently, patients took their medication at home. Over the course of the 2-year minimum follow-up, a median of 3 episodes of AF recurred, and a total of 298 episodes of AF were analyzed. At follow-up, only 25 episodes (8%) of AF were not terminated by the given antiarrhythmic drug, and only 1 patient reported symptoms of dizziness with termination of the arrhythmia. While the median number of hospitalizations for all patients prior to entering the study was 2, only 6 patients (7%) were hospitalized over a mean follow-up period of 31 +/- 8 months. The regimen had to be changed for 9 patients to daily antiarrhythmic drug administration (11%). The study found that this strategy yields a marked reduction in hospitalizations and demonstrates the safety of this approach. It should be noted, however, that both flecainide and propafenone are contraindicated in patients with structural heart disease, given the well-known adverse impact of type 1C antiarrhythmic drugs on survival in patients after myocardial infarction.
One option for chemical cardioversion of AF in a monitored setting has been ibutilide. One of the well-known problems with this drug's use is the potential development of torsade de pointes following administration. Magnesium sulfate has been used for a number of years for the acute treatment of torsade de pointes. In a clinical study reported at NASPE, magnesium sulfate was given prophylactically to patients in AF prior to the administration of ibutilide, under the hypothesis that such a strategy could reduce the incidence of torsade de pointes. Ninety-five patients were studied, in whom structural heart disease was present in 55%, with a mean ejection fraction of 45% +/- 10%. Importantly, the patients in the study were already taking antiarrhythmic drugs, with amiodarone in 40 patients, sotalol in 20, and flecainide or propafenone in the remainder. Baseline QTc was < 450 ms in all patients, and serum potassium level was normal. Intravenous magnesium was given as a 2-g bolus over 1 minute, 5 minutes before ibutilide was administered. Ibutilide was then given as a 1-g bolus over 10 minutes, followed by another 1 g in 5 minutes if the atrial arrhythmia persisted. Conversion to sinus rhythm occurred in 60% of patients with ibutilide, with 90% converting to sinus rhythm either chemically or electrically. There were no episodes of torsade de pointes in the entire patient cohort. Thus, it appears that prophylactic administration of magnesium prior to giving ibutilide may help to reduce the incidence of torsade de pointes.
Preliminary results of a clinical trial studying a new antiarrhythmic drug, dronedarone, were released. Dronedarone is a benzofuran derivative, structurally related to amiodarone. It has an electrophysiologic profile similar to that of amiodarone, but its lack of iodine and its different pharmacokinetic profile make it a promising alternative to amiodarone. In a dose-ranging study of 199 patients, 400 mg of dronedarone given twice daily led to a significant increase in time to first recurrence of AF (60 days for the dronedarone group vs 5 days for the placebo group [P = .001]). There was no proarrhythmia and the drug was well tolerated. Further investigations of this promising drug are warranted.
Population-based studies of patients with AF have shown that patients treated with angiotensin-converting enzyme (ACE) inhibitors have a reduced risk of AF. To test the risk of recurrence in patients with a known history of the arrhythmia, 154 patients with persistent AF were divided into 2 groups, one treated with amiodarone alone and the other with amiodarone plus irbesartan, an angiotensin II receptor antagonist. After cardioversion, patients were followed to first recurrence of AF. After a median follow-up time of 163 days, the group treated with irbesartan had a lower incidence of recurrent AF, 80% vs 56%, P = .007. The mechanism of the effect is not known, but the results suggest that an ACE inhibitor may be a useful adjunct to the management of AF, particularly when hypertension is coexistent.
The implications from recent clinical trials are that the use of antiarrhythmic drugs for the treatment of AF solely for any theoretical benefits on QOL, survival, prevention of stroke, or reduction in hospital admission rates is not warranted. Thus, for patients with infrequent or short-lived episodes of AF, particularly when they are only minimally symptomatic, a strategy of rate control only, along with anticoagulation in appropriately selected patients, is a simple and useful approach. This strategy has been found to be at least as advantageous as the use of antiarrhythmic drugs. However, when patients' symptoms warrant additional treatment, new data on methods for chemical or electrical cardioversion of AF allow us to restore sinus rhythm safely in the majority of patients.
References
Wyse DG, AFFIRM Investigators. Survival in patients presenting with atrial fibrillation: the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. Program and abstracts of the American College of Cardiology 51st Annual Meeting; March 17-20, 2002; Atlanta, Georgia. Abstract 405-1.
Basta M, Gardner MJ, Anderson DR, Cox JL. Readmissions of patients hospitalized with atrial fibrillation: antiarrhythmia agents versus rate limiting drug therapy. Program and abstracts of the North American Society of Pacing and Electrophysiology 23rd Annual Scientific Sessions; May 8-11, 2002; San Diego, California. Abstract 101743.
Natale A, Marrouche N, Martin DO, et al. Outpatient intermittent administration of IC antiarrhythmic drugs for sporadic atrial fibrillation: long-term safety and efficacy. Program and abstracts of the North American Society of Pacing and Electrophysiology 23rd Annual Scientific Sessions; May 8-11, 2002; San Diego, California. Abstract 101502.
Marrouche NF, Tamassoni G, Saliba W, Schweikert R, Bash D, Natale A. Intravenous magnesium sulfate prevents ibutilide associated development of torsade de pointes in patients undergoing cardioversion of atrial arrhythmias. Program and abstracts of the North American Society of Pacing and Electrophysiology 23rd Annual Scientific Sessions; May 8-11, 2002; San Diego, California. Abstract 101221.
Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of recurrent atrial fibrillation after cardioversion: results from a randomized, placebo-controlled, double-blind multicenter study. Program and abstracts of the North American Society of Pacing and Electrophysiology 23rd Annual Scientific Sessions; May 8-11, 2002; San Diego, California. Abstract 102401.
Madrid A, Rebollo JMG, Bueno M, et al. A prospective and randomized study of irbesartan in patients with persistent atrial fibrillation. Program and abstracts of the North American Society of Pacing and Electrophysiology 23rd Annual Scientific Sessions; May 8-11, 2002; San Diego, California. Abstract 100521.
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