Rhythm versus Rate Control Trials in Atrial Fibrillation

The recent completion of five trials comparing the strategy of rhythm control versus the strategy of rate control in the management of recurrent atrial fibrillation has advanced considerably our understanding of the treatment of this common clinical problem. The background to this research question is outlined, followed by an overview of the five trials and their results. Data on important clinical events from four of the trials are pooled and presented. The aggregate results of the trials do not demonstrate any clear advantage of the rhythm control approach. The findings elevate rate control to the position of an acceptable primary therapy in the types of patients studied and underline the concept that the primary goal of antiarrhythmic therapy for atrial fibrillation at this time is control of symptoms. Under these circumstances, a "safety first" approach is prudent and monitoring for adverse drug effects is mandatory. The results underscore the importance of continuous anticoagulation in patients with stroke risk factors. Finally, the results from these trials help to set the agenda for future research on rhythm management in atrial fibrillation. (J Cardiovasc Electrophysiol, Vol. 14, pp. S35-S39, September 2003, Suppl.)     

Implication from Randomized Trials of Rate and Rhythm Controls on Management of Patients with Persistent Atrial Fibrillation

Recently, several randomized trials were published on the issue of rate or rhythm control for patients with atrial fibrillation (AF). Patients were typically minor symptomatic, relatively old, with age above 70, presenting with a recurrence of AF and suffering from only mild to moderate underlying heart disease. The main outcome of these trials is that rate control is not inferior to rhythm control for the management of patients with AF concerning morbidity and mortality. Also patients' quality of life did not differ significantly in follow‐up in these trials. However, rhythm control is not redundant in the treatment of AF. Focus is now on subgroups of patients who could still have benefit being in sinus rhythm. For severely symptomatic patients, patients presenting with the first episode of AF and probably those with severe congestive heart failure, to restore and maintain sinus rhythm should still be the goal. With the failure of antiarrhythmic therapy, nonpharmacological approaches such as pulmonary vein isolation can be performed. Another finding of the randomized trials is that being in sinus rhythm does not prevent from the occurrence of thromboembolic complications. This means that for patients with AF, with risk factors for thromboembolic events, adequate anticoagulant therapy is indicated irrespective of the current heart rhythm. As with antiarrhythmic therapy, the search for new and safer anticoagulant therapy is underway. This review will focus on the key aspects we have learned from the randomized trials on rate and rhythm controls for patients with AF.     

Trials of Pacing to Control Ventricular Rate During Atrial Fibrillation

Pharmacologic therapy to achieve rate control in patients with atrial fibrillation is often difficult and inadequate. For this reason, ventricular pacing strategies have been developed as an alternative to drug therapy to alleviate symptoms due to rapid and irregular ventricular rates. Ventricular pacing in combination with AV junctional ablation provides palliative improvement in a wide range of clinical outcomes. Because of the irreversible complete AV block associated with this procedure, strategies to control the ventricular response to atrial fibrillation by ventricular pacing alone have been investigated. These strategies are primarily directed at regularizing the ventricular response by pacing at or near the mean intrinsically conducted ventricular rate. These specialized ventricular pacing algorithms provide striking ventricular regularity at rest but may be less effective during activity. No study has yet demonstrated clinically significant improvements in clinical outcomes with these algorithms. The clinical benefits of rate regularization alone without the strict rate control provided by AV junctional ablation are likely to be very limited. Other device based approaches to control ventricular rate in atrial fibrillation include transvenous vagal stimulation. This strategy is in early stages of development but may be promising.     

Assessment of Rhythm and Rate Control in Patients with Atrial Fibrillation

A recent series of randomized prospective clinical trials that compared rate control with rhythm control in patients with atrial fibrillation (AF) found no significant difference in primary outcome between the two strategies. However, these trials lacked clear criteria for defining "successful" rate or rhythm control. Various measures have been used to gauge the success of antiarrhythmic drug therapy, including time to first recurrence of AF, any AF recurrence, AF burden, and a reduction in symptoms. Determining the success of antiarrhythmic therapy can be relatively straightforward by using how patients feel during therapy as a key endpoint. Most patients are satisfied with a major reduction in symptomatic AF episodes and can live comfortably with occasional episodes of AF. For those who are bothered by even infrequent, brief AF episodes, a treatment regimen that eliminates nearly all AF recurrences is required, although often hard to achieve. Catheter ablation may be necessary to achieve a successful outcome in these patients. Suppression of AF in a patient at high risk of stroke does not, however, remove the need for concomitant warfarin therapy. The endpoints of ventricular rate control are not clear, and the recently published rhythm versus rate control trials lacked standard criteria for judging acceptable rate control. One relatively simple method is to try and achieve a 24-hour heart rate that mimics expected normal sinus rhythm. It is important to achieve good rate control to minimize symptoms and the risk of tachycardia-mediated cardiomyopathy.     

Confounding Factors in Rate Versus Rhythm Control Trials in Patients with Atrial Fibrillation: Lessons from the Strategies of Treatment of Atrial Fibrillation (STAF) Pilot Study

Background: The Strategies of Treatment of Atrial Fibrillation (STAF) multicenter pilot trial was one of five completed clinical studies to compare two treatment strategies in patients with atrial fibrillation: the strategy of rhythm control (restoration and maintenance of sinus rhythm) and the strategy of rate control (pharmacologic or invasive rate control and anticoagulation). Methods: In STAF 200 patients (100 per group) with persistent atrial fibrillation were randomized to rhythm or rate control. The combined primary endpoint was a combination of death, cardiopulmonary resuscitation, cerebrovascular event, and systemic embolism. Results: After 19.6 ± 8.9 (0–36) months there was no difference in the primary endpoint between rhythm control (9/100; 5.54%/year) and rate control (10/100; 6.09%/year; p = 0.99). The percentage of patients in sinus rhythm in the rhythm control group after up to four cardioversions during the follow-up period was 23% at 36 months compared to 0% in the rate control group. Eighteen primary endpoints occurred in atrial fibrillation, only 1 occurred in sinus rhythm (p = 0.049). Conclusions: The STAF pilot trial did not show any differences between the two treatment strategies in common with other trials of rhythm versus rate control. These data suggest that there is no benefit in attempting rhythm control in this group of patients with a high risk of arrhythmia recurrence. It remains unclear whether the results in the group of rhythm control would have been better if sinus rhythm had been maintained in a higher proportion of patients since all but one endpoint occurred during atrial fibrillation.Atrial fibrillation; Electric Countershock; Anti-Arrhythmia Agents; Clinical trial, randomized clinical trial     

Atrial Fibrillation and Flutter: Maintaining Stability of Sinus Rhythm Versus Ventricular Rate Control

Atrial Fibrillation and Flutter. Two major treatment strategies have emerged for managing atrial fibrillation: maintaining sinus rhythm by chronic administration of suppressive antiarrhythmic agents versus controlling the ventricular rate and chronic anticoagulation. Potential benefits of maintenance of sinus rhythm include improvement of the hemodynamic profile of the patient, a decreased risk of cerebrovascular accidents, reduced symptoms, and, if atrial fibrillation is successfully suppressed, possible elimination of the need for chronic anticoagulation. When selecting long-term antiarrhythmic drug therapy for suppression of atrial fibrillation, it should he recalled that at least 50% of patients have a recurrence of the arrhythmia within the first year and the majority of other patients have a recurrence within the next 3 to 5 years. In addition, the risk of proarrhythmia and sudden cardiac death must be considered: this has stimulated interest in nonpharmacologic approaches to maintaining sinus rhythm. Large multicenter randomized trials are now under way to compare the benefits and risks of maintaining sinus rhythm versus controlling the ventricular rate and chronically anti-coagulating patients in atrial fibrillation. Important endpoints of these trials include mortality, functional capacity, and quality of life.     

Some Recent Randomized Clinical Trials in the Management of Atrial Fibrillation

It is not possible to review all the recent randomized clinical trials in management of atrial fibrillation. The author has chosen to select a few that illustrate key points. Immediate or early recurrence of atrial fibrillation after electrical cardioversion is an important part of inefficacy of drug therapy and more insight into the mechanisms of this phenomenon is needed. Two recent trials in which verapamil, a calcium channel blocker, and irbesartan, an angiotensin receptor blocking agent, added to a standard antiarrhythmic attenuated early recurrences of atrial fibrillation are of particular interest.Trials of drugs and pacing for maintenance of sinus rhythm continue to demonstrate only modest efficacy. Amiodarone, the most effective agent, is not markedly better and there are concerns about its adverse effect profile during long-term use. Other nonpharmacologic therapies have not yet been, but will need to be, evaluated in properly designed randomized clinical trials with clinically important end-points.The absence of a simple, highly effective treatment for the maintenance of sinus rhythm with few adverse effects has been part of the foundation for recent trials comparing the rate control strategy to the rhythm control strategy, particularly in the elderly patient. Six such trials have been completed and one is in progress. The data from these trials is quite consistent for the elderly patient with stroke risk factors and predominantly persistent atrial fibrillation: (1) any advantage for the rhythm control strategy remains unproven; (2) the rate control strategy has some clear advantages and should be considered more often as a primary approach in such patients; and (3) anticoagulation should not be discontinued in such high risk patients, even when it is felt that sinus rhythm has been maintained. Anticoagulation is under-utilized in this setting and alternatives to warfarin are badly needed. Trials in progress may be helpful in this regard.Finally, primary prevention of atrial fibrillation needs more attention. Recent randomized trials with trandolapril after myocardial infarction and physiologic pacing have given some insight into how this might be accomplished.     

国产美托洛尔静脉制剂控制阵发性心房颤动时快速心室反应的疗效评价

目的：研究国产美托洛尔静脉制剂用于控制阵发性心房颤动时快速心室率的效果。方法：３３例阵发性心房颤动患者分别接受了静脉美托洛尔（美托洛尔组，１６例）和毛花甙Ｃ（毛花甙Ｃ组，１７例）治疗。结果：１６例接受静脉美托洛尔５ｍｇ治疗的患者用药３０分钟后心室率从１２８±２１次／分降至９０±１８次／分（Ｐ＜０００１）；接受静脉毛花甙Ｃ０．４ｍｇ至０．６ｍｇ治疗者用药３０分钟后的心室率从１３４±１７次／分降至１０８±１７次／分（Ｐ＜００１）；用药３０分钟后美托洛尔组心率明显慢于毛花甙Ｃ组（Ｐ＜００１），而与毛花甙Ｃ组６小时后的心室率相当（８４±１８次／分，Ｐ＞００５）。两组患者用药前后的血压无明显变化。所有患者都没有因为药物副作用而终止试验。结论：国产美托洛尔静脉制剂能迅速有效和安全地控制阵发性心房颤动时快速心室反应     

Rate Versus Rhythm Control in Heart Failure Patients with Post-Operative Atrial Fibrillation After Cardiac Surgery

BackgroundWhether rhythm control for post-operative atrial fibrillation after cardiac surgery (POAF) is superior to rate control in patients with heart failure or systolic dysfunction (HF) is not known.MethodsWe performed a post-hoc analysis of a trial by the Cardiothoracic Surgical Trials Network, which randomized patients with POAF after cardiac surgery to rate control or rhythm control with amiodarone/cardioversion. We assessed subgroups of trial participants defined by heart failure/cardiomyopathy history or left ventricular ejection fraction (LVEF) < 50%. We conducted a stratified analysis in patients with and without HF to explore outcomes of rhythm versus rate control strategy.ResultsOf 523 subjects with POAF after cardiac surgery, 131 (25%) had HF. 49% of HF patients were randomized to rhythm control. In HF patients, rhythm control was associated with less atrial fibrillation within the first 7 days. There were no differences in rhythm at 30- and 60-day follow-up. In the HF group, there were significantly more subjects with AF < 48 hours in the rhythm control group compared to rate control group- 68.8% compared to 46.3%, P=0.009. By comparison, in the non-HF stratum, 54.4% of the rate control group had AF < 48 hours compared to 63.5% of the rhythm control group (P=0.067).), though there was no significant interaction of heart failure with cardiac rhythm at 7 days (Pinteraction 0.16).ConclusionRhythm control for HF patients with POAF after cardiac surgery increases early restoration of sinus rhythm. Rate and rhythm control are both reasonable for HF patients with AF after cardiac surgery     

Trials of New Antiarrhythmic Drugs for Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation

Despite the recent results of the AFFIRM trail showing that either strategy of rate control or rhythm control is acceptable, there is general agreement that therapy must be individualized. Antiarrhythmic drugs while being effective in maintaining sinus rhythm are not without side effects. Thus, there continues to be a search for safer and better tolerated agents.Azimilide is a novel class 3 agent that blocks both components of the delayed rectifier current, while dofetilide blocks only the slow component. Dronedarone is somewhat similar to aminodarone, but perhaps with the side effects. Tedisamil is a complex class 3 agent, blocking multiple channels. Piboserod is a selective 5-HT receptor antagonist that is being investigated in clinical trials.     

The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT)

OBJECTIVES: The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial was a multicenter trial of atrioventricular junction ablation and pacing (AVJAP) compared with pharmacologic ventricular rate control (medication [MED]) in patients with mild to moderately symptomatic permanent atrial fibrillation (AF). BACKGROUND: There have been very few prospective randomized trials, undertaken in highly symptomatic patients, comparing AVJAP with pharmacologic methods of ventricular rate control for patients with permanent AF. METHODS: There were 99 patients (70 men, mean age 68 +/- 8.6 years) at five centers. Forty-nine patients were randomized to AVJAP while 50 patients were randomized to pharmacologic control. The primary end point was cardiac function measured by echocardiography and exercise tolerance. The secondary end points were ventricular rate control, evaluated by 24-h ambulatory electrocardiographic monitoring, and quality of life. Data were collected at randomization and then at one month, six months, and 12 months post-randomization. RESULTS: At 12 months follow-up there was no significant difference in left ventricular ejection fraction (AVJAP: 54 +/- 17%; MED: 61 +/- 13% [p = ns]) or exercise duration on treadmill testing (AVJAP: 4.1 +/- 2 min; MED: 4.6 +/- 2 min [p = ns]); however, the peak ventricular rate was lower in the AVJAP group during exercise (112 +/- 17 beats/min vs. 153 +/- 36 beats/min, p < 0.05) and activities of daily life (117 +/- 16 beats/min vs. 152 +/- 37 beats/min, p < 0.05). The CAST quality-of-life questionnaire revealed that patients in the AVJAP group had fewer symptoms at six months (p = 0.003) and at 12 months (p = 0.004). The observed relative risk reduction in symptoms at 12 months was 18%. Global subjective semiquantitative measurement of quality of life using the "ladder of life" revealed that the AVJAP group reported a 6% better quality of life at six months (p = 0.011). CONCLUSIONS: In this trial, AVJAP for patients with mild to moderately symptomatic permanent AF did not worsen cardiac function during long-term follow-up, and quality of life was improved.